Alisa G. Woods, PhD

Dr John Bradford of Ottawa, Canada, had a long, successful career as a forensic psychiatrist, spanning several decades. Bradford’s extensive experience with brutal people, such as sexual sadists and killers, led him to believe that he was resilient to trauma. The years of work, however, may have taken their toll. After watching highly disturbing video evidence of 2 women being assaulted as part of a high-profile case, Bradford began drinking excessively, and 

 Despite 2 years of initial denial, he ultimately sought treatment for PTSD and admirably now speaks out about his experience. Although he still practices, Bradford avoids cases that involve graphic videos. His example illustrates that even seasoned professionals may fall prey to PTSD, and the toughest psychiatrists are not immune.

, Professor of Clinical Psychiatry in the Department of Psychiatry & Behavioral Sciences at SUNY Downstate Medical Center in Brooklyn, New York, spoke at the American Psychiatric Association (APA) meeting in Toronto, Canada, in May 2015. His presentation “PTSD in Psychiatrists: A Hidden Epidemic” underscored the under-recognition of this prevalent condition in those who treat mental health conditions and discussed methods for increased recognition of PTSD as well as its treatment.

[[{"type":"media","view_mode":"media_crop","fid":"28795","attributes":{"alt":"","class":"media-image media-image-right","height":"156","id":"media_crop_4141830503460","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"4793","media_crop_rotate":"0","media_crop_scale_h":"0","media_crop_scale_w":"0","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","style":"float: right;","title":" ","typeof":"foaf:Image","width":"169"}}]]Ironically, mental health care providers may readily encourage their patients to confront psychiatric issues, but they are not always as willing to identify and address these problems in themselves, despite the frequent occurrence of PTSD in physicians. The lifetime prevalence of PTSD is between 8% and 9% in the general population, but is higher in physicians. For example, PTSD rates in physicians exposed to war range between 11% and 18% and are about 12% in those who practice 

 It makes sense that the prevalence of PTSD would be high in psychiatrists as well, owing not only to frequent traumatic encounters with those who have serious psychiatric conditions, but also to the vicarious transfer of their patients’ experiences.

PTSD can strike at any professional stage, from the experienced psychiatrist such as Dr John Bradford, to physicians in training. In his talk at the APA meeting, Myers presented data from several studies that focused on medical students and PTSD. The hazing and overworking of medical students is a tradition that continues, possibly with the notion that extremely difficult conditions will prepare students for a doctor’s life. The practice may however come with a cost. According to 

, 73% of medical students reported witnessing or experiencing mistreatment.

 In another study, 13% of 212 residents met the diagnostic criteria for PTSD based on a standard questionnaire; women were more often affected (20%) than men (9%). Lack of social support increased the risk of PTSD.

Myers cautioned that residents may experience PTSD because they are not psychologically prepared for the traumatic events they might witness.

 He discussed several clinical situations that could be disturbing to physicians in training, including observing severe injuries, treating battered infants, seeing amputations, or observing death in a young, healthy-seeming individual. Even being put-down and humiliated by a senior physician might trigger PTSD, something for traditionalists who think students need “toughening up” to consider.

According to Myers, circumstances that may precipitate PTSD include not only medical training but also traumatic events that took place before medical school. For example, immigrants who left war-torn countries or physicians who are specifically training to deal with traumatic situations may be vulnerable; military psychiatrists also may be particularly susceptible.

Adding to the list of those at risk provided by Myers, Dr Arthur Lazarus has identified several 

• Physicians practicing in remote areas with limited medical services

• Physicians involved in malpractice litigation

• “Second victims,” physicians who are exposed to trauma via their patients

Certainly psychiatrists would fall under the last category and may be members of the other categories as well. Understanding who is at risk can help predict and assess symptoms of PTSD in susceptible individuals.

Identification is of course the first step; however, treatment is crucial for improvement in the lives of the individual psychiatrists, as well as for those they affect professionally and personally. But if PTSD in psychiatrists is so deeply buried because of denial and a lack of social acceptance, what can be done about this problem?

Myers suggests several tactics. First, the culture of medicine needs to change. Physicians in training can be better prepared for possibly upsetting situations through debriefing, normalizing, and learning to accept the events. New institutional attitudes are needed, specifically encouraging physicians with PTSD symptoms to come forward and seek help early. The stigma and belief system that views physicians as being bulletproof to PTSD needs to change. Finally, coworkers should realize that some physicians will live chronically with residual symptoms. Again, acceptance is a key to improving the situation.

For the psychiatrist treating a colleague with possible PTSD, Myers recommends getting buy-in as a first start: for example, “see whether your patient is in agreement” when suggesting possible PTSD, and ask how the symptoms are affecting that person’s ability to work. Reassurance that treatment is effective can be helpful, as well as noting that help through therapy or medication will positively affect the psychiatrist’s professional and personal life.

But what if you are the psychiatrist or mental health care 

? Myers believes that the signs can be there, but as psychiatrists “there can be a certain amount of denial at first. We practice differently: we don’t listen as carefully; we shut the person down and reach for the prescription pad.” To these individuals, he evokes the adage “physician, heal thyself.” He suggests that psychiatrists should seek assistance and advice from a colleague and should not feel that they must abandon the profession. Treatment can actually maintain their ability to be effective psychiatrists.

Recognition naturally needs to be followed by treatment, including a complete assessment of PTSD symptoms as well as of comorbid symptoms. PTSD treatment may include medication, individual cognitive-behavioral therapy, and group therapy as needed. However, care does not stop at the individual with PTSD symptoms, since treatment of the family and marital therapy can also help. Balint groups-the presentation of clinical cases among physicians-help prepare people working together to deal with PTSD in psychiatrists specifically. Myers encourages the psychiatrist to “be an advocate and change maker.”

Indeed, for PTSD in psychiatrists and other mental health care providers to finally be addressed, a major shift in medical culture and thinking is needed. Psychiatrists will hopefully learn to recognize signs of PTSD in their colleagues and also in themselves. The condition exists in psychiatrists and may even be common, and it needs to be treated.

 Cobb C. “Tough forensic guy” John Bradford opens up about his PTSD. Ottawa Citizen. November 2013. 

http://www.ottawacitizen.com/health/Tough+forensic+John+Bradford+opens+about+PTSD/ 9152171/story.html

 Wilberforce N, Wilberforce K, Aubrey-Bassler FK. Post-traumatic stress disorder in physicians from an underserviced area. 

 Heru A, Gagne G, Strong D. Medical student mistreatment results in symptoms of posttraumatic stress. 

 Klamen DL, Grossman LS, Kopacz D. Posttraumatic stress disorder symptoms in resident physicians related to their internship. 

 Myers MF. The support and welfare of the student. In: Gask L, Coskun B, Baron D, eds. 

 Lazarus A. Traumatized by practice: PTSD in physicians. 

Articles

For PTSD in psychiatrists and other mental health care providers to be addressed, a major shift in medical culture and thinking is needed. 

When the Psychiatrist Has PTSD

[[{"type":"media","view_mode":"media_crop","fid":"40389","attributes":{"alt":"Â© KUCO/shutterstock.com, Tai Chi, depression","class":"media-image media-image-right","id":"media_crop_6921050655268","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"4132","media_crop_rotate":"0","media_crop_scale_h":"151","media_crop_scale_w":"150","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","style":"float: right;","title":"Â© KUCO/shutterstock.com","typeof":"foaf:Image"}}]]“Mind-body medicine” is frequently used to describe the balancing effects between mind and body of nonpharmacological behavioral interventions applied to stress-related psychiatric disorders-including MDD. Recent studies find powerful biological changes associated with mind-body interventions comparable to those associated with conventional antidepressants or psychotherapies.

, of the UCLA Semel Institute for Neuroscience and Human Behavior is interested in the neurobiological mechanisms of mindful exercise, such as Tai Chi and yoga. She discussed her work at the recent 

 symposium “Anti-inflammatory and Antidepressant Effects in Older Adults With Chronic Stress and Mood Disorders.” Lavretsky studies the effects of various interventions on depression or stress in older adults. She is a certified yoga instructor who uses the technique for clinical treatment of depression or caregiver stress. She is particularly interested in complementary and integrative treatments that use the power of a patient’s mind and intention to get well, includ- ing resilience-building interventions (eg, well-being therapy, learned optimism training, yoga and 

Tai Chi Chih refers to a set of 20 movements, learned over 8 weeks, that are a form of “mindful exercise.” The beneficial effects of Tai Chi Chih include lowering blood pressure and weight. “Chi” refers to the intrinsic universal energy present in all individuals. Tai Chi Chih is derived from Tai Chi Chuan, a Chinese martial art used both for exercise and for health benefits.

Tai Chi Chih is an intervention that Lavretsky has studied in several different trials. In one investigation, she and her colleagues 

Tai Chi Chih to augment the antidepressant escitalopram in 112 individuals with major depression, aged 60 or older.

 Following 6 weeks of treatment with 10 mg of escitalopram, 73 partial responders were randomized to an additional 10 weeks of either Tai Chi Chih or health education, both for 2 hours per week. Lavretsky and her team performed evaluations for depression, anxiety, resilience, health-related quality of life, cognition, and inflammation at the start of the study and 16 weeks later.

Participants in the Tai Chi Chih group were more likely to have reductions in depression symptoms and to experience depression remission. They also had greater improvement of physical functioning, and they performed better on cognitive tests. Moreover, those in the Tai Chi Chih group had greater declines in levels of C-reactive protein (CRP) than those in the control group. The study showed both behavioral and biological benefits of augmenting an antidepressant with Tai Chi Chih.

According to Lavretsky, the downside of Tai Chi is that because it is a physical exercise, it is “not easy for everybody.” However, for those patients who are willing to put in the time and effort, it seems to be a beneficial add-on to depression treatment.

focused on the effects of yogic meditation when performed by the caregivers of those with dementia.

 Caregiving for a person with a chronic illness, and in particular dementia, often results in excessive stress and potentially, depression. Thirty-nine caregivers with mild symptoms of depression participated in the study. The study subjects, with an average age of 60, were divided into 2 groups: one group practiced a form of meditation known as Kirtan Kriya, the other group listened to relaxing music-for 12 minutes a day for 8 weeks. The researchers measured depressive symptoms as well as mental and cognitive function at the beginning and end of the study.

The group that practiced meditation had significantly lower levels of depressive symptoms and greater improvement in mental health and cognitive functioning than the group that listened to relaxing music.

What was particularly interesting was that the meditation group showed 43% improvement in telomerase activity versus only 3.7% improvement in the group that listened to relaxing music. This is particularly tantalizing information for those interested in successful aging and life prolongation-suggesting that a lifestyle intervention can change telomere length and perhaps reduce the impact of stress on biological aging. In her 2015 APA presentation, Lavretsky noted that these are “very promising results for future studies of medita-tion versus drugs versus behavioral interventions.”

, of the UCLA Cousins Center for Psychoneuroimmunology spoke at the 

 symposium “Sleep Disturbance and Inflammation Reciprocally Contribute to Depression: Implications for the Treatment and Prevention of Depression in Older Adults.” He discussed his research on sleep, depression, and inflammation. Through his work, Irwin has found that “sleep disturbance is an early prodromal symptom of depression.” Sleep problems are associated with inflammatory responses in depression, including higher CRP levels and high levels of the cytokine interleukin-6. In fact, according to Irwin, sleep disturbances drive inflammation in depression. In addition, Irwin noted that “sleep disturbance is a robust predictor of depression recurrence.”

Like Lavretsky, Irwin is also interested in the possible benefits of Tai Chi. Along with Lavretsky and other researchers, Irwin

that compared cognitive- behavioral therapy (CBT) with Tai Chi for insomnia and inflammation in the elderly. In this study, he included a control group that attended an educational sleep seminar. A total of 123 adults, aged 55 to 85, participated; 112 completed the initial trial (4 months) and 108 completed the follow-up to the study (16 months).

Of all the interventions, CBT was the most effective for insomnia and for improving sleep quality, fatigue, and depressive symptoms. Participants who received CBT had lower levels of CRP at the 16-month follow-up. Tai Chi was more effective than the sleep seminar for improving sleep quality, fatigue, and depressive symptoms, but not insomnia. CBT was best for depressive symptoms and sleep problems, although Tai Chi was more effective than the sleep seminar. The effect of CBT on reducing CRP levels again shows that a behavioral intervention can have potent positive effects on biology.

What is perhaps most interesting about this research is its application to current ideas about depression and its link to inflammation across the life span, especially in aging adults. As Irwin noted in his presentation, the research provides evidence for the idea that “targeting with a behavioral treatment can reduce inflammation” possibly providing a biological explanation for the effects of interventions such as Tai Chi and meditation on alleviating symptoms of depression.

 Lavretsky H, Alstein LL, Olmstead RE, et al. Complementary use of tai chi chih augments escitalopram treatment of geriatric depression: a randomized controlled trial. 

 Lavretsky H, Epel ES, Siddarth P, et al. A pilot study of yogic meditation for family dementia caregivers with depressive symptoms: effects on mental health, cognition, and telomerase activity. 

 Irwin MR, Olmstead R, Carrillo C, et al. Cognitive behavioral therapy vs Tai Chi for late life insomnia and inflammatory risk: a randomized controlled comparative efficacy trial. 

Recent studies find powerful biological changes associated with mind-body interventions comparable to those associated with conventional antidepressants or psychotherapies.

Tai Chi Is a Biological Treatment for Depression

[[{"type":"media","view_mode":"media_crop","fid":"39889","attributes":{"alt":"diabetes in  bipolar disorder (EdlerVonRabenstein/shutterstock.com)","class":"media-image media-image-right","id":"media_crop_7443218913661","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"4023","media_crop_rotate":"0","media_crop_scale_h":"180","media_crop_scale_w":"148","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","style":"float: right;","title":" EdlerVonRabenstein/shutterstock.com","typeof":"foaf:Image"}}]]Many psychiatrists know that neuroimaging studies do not provide consistent data about brain changes in persons with bipolar disorder. Tomas Hajek, MD, PhD, of Dalhousie University in Halifax, Nova Scotia, believes that this might in part be explained by the existence of comorbid conditions. As he described in his recent talk (Insulin Resistance or Type 2 Diabetes Mellitus: Risk Factors for Brain Alterations in Bipolar Disorders) at APA 2015, comorbidities are “more of a rule than an exception” in bipolar disorder-and diabetes in particular is important to consider.

In fact, persons with bipolar disorder have up to a 3-fold elevated risk for type 2 diabetes mellitus, and 53% of bipolar patients have pre- diabetes or diabetes. It comes as no surprise then, that cardiovascular disease is the leading cause of death in persons with bipolar disorder.

Those with bipolar disorder and diabetes do not respond as well to bipolar treatment, and their illness tends to be more severe. To make matters even worse, diabetes is also harder to control in these patients than it is in persons without bipolar disorder. Because of the high prevalence of diabetes in patients with bipolar disorder and the difficulties in treatment associated with the two disorders in tandem, screening for glucose abnormalities in those who have bipolar disorder is particularly important.

Although often not a focus of treatment, cognitive problems are common in patients with bipolar disorder, and this can be further exacerbated by the coexistence of diabetes. This connection makes sense, noted Hajek, since glucose is the principal source of brain energy, and insulin can act as a brain growth factor.

Hajek wanted to further understand whether diabetes is a risk factor for brain changes in patients who have bipolar disorder. He and his colleagues used MRI to measure prefrontal cortex N-acetylaspartate, which is the second most concentrated molecule in the brain after glutamate and is primarily found in neurons.

 The investigators also measured total creatine, a metabolite that indicates energy expenditure. Included in this study were 19 patients with prediabetes (insulin resistance and glucose intolerance) comorbid with bipolar disorder, 14 patients with bipolar disorder and type 2 diabetes mellitus, 15 patients without diabetes but with bipolar disorder, and 11 controls with neither diabetes nor bipolar disorder.

Amounts of the two markers were lowest in the patients with diabetes and bipolar disorder, followed by those with prediabetes and bipolar disorder. The changes could indicate poor prefrontal functioning and psychosocial problems as well as impaired brain energy expenditure in persons with bipolar disorder comorbid with diabetes or prediabetes.

 measured hippocampal and cortical volumes in the same subjects, again using neuroimaging. Those with bipolar disorder and either diabetes or prediabetes had significantly smaller hippocampal volumes than did controls and those with bipolar disorder only. The researchers found similar atrophy in the cerebral cortex and the insula. The researchers concluded that “abnormal glucose metabolism may accelerate the age-related decline in hippocampal volumes in BD.”

Based on the findings, hippocampal atrophy “may contribute to the neuroprogressive nature of bipolar disorder,” particularly in those also affected by diabetes.

The researchers considered that because persons with diabetes might have a higher incidence of stroke, this could possibly explain the atrophy they observed. They excluded those patients who might have strokes by identifying white matter hyperintensities, but this did not change the effect of diabetes or prediabetes on brain atrophy. Because second-generation antipsychotics are well known to exacerbate metabolic problems, they also excluded patients who took these medications, and they did a separate analysis excluding those who took lithium. There was no difference in the atrophy they observed when the possible effects of these medications were taken into account. Thus, it appeared that the effect was truly due to the presence of diabetes or prediabetes.

Hajek has received a Brain and Behavior Research Foundation (NARSAD) grant to study these effects further and, in particular, to examine whether food impulsivity contributes to type 2 diabetes mellitus in patients with bipolar disorder. His research underscores the importance of screening for diabetes in patients with bipolar disorder, and for the need to control not only the symptoms of bipolar disorder, but to screen for and control this common comorbidity as well.

This article was originally posted on May 21, 2015 and has since been updated.

Calkin CV, Gardner DM, Ransom T, Alda M. The relationship between bipolar disorder and type 2 diabetes. More than just co-morbid disorders. 

http://www.researchgate.net/publication/225057390_The_relationship_between_bipolar_disorder_and_type_2_diabetes_More_than_just_co-morbid_disorders

Hajek T, Calkin C, Blagdon R, et al. Type 2 diabetes mellitus: a potentially modifiable risk factor for neurochemical brain changes in bipolar disorders. 

http://www.ncbi.nlm.nih.gov/pubmed/24331546.

 Hajek T, Calkin C, Blagdon R, et al. Insulin resistance, diabetes mellitus, and brain structure in bipolar disorders. 

http://www.ncbi.nlm.nih.gov/pubmed/25074491.

Abnormal glucose metabolism may accelerate the age-related decline in hippocampal volumes in BD, according to one new study. 

Diabetes in Bipolar Disorder Takes Its Toll 

Physicians recognize many features of schizophrenia, including positive and negative symptoms, social/occupational effects, cognitive problems, comorbid substance abuse disorders, and mood changes. However, one neglected area is the common symptom of a poor self-other boundary-in fact, this has also been neglected as a criterion for DSM, despite the fact that it is a common symptom of schizophrenia and that there is a vast literature on the topic.

In his talk, “Beyond Dopamine: the Evolving Therapeutics of Schizophrenia,” at APA 2015, Henry A. Nasrallah, MD, Chair of the Department of Neurology and Psychiatry at the St Louis University School of Medicine, noted that 95% of patients with a first episode of psychosis have had contact with the health care system before the first psychotic episode. This makes recognition of prodromal symptoms and risk factors especially important.

[[{"type":"media","view_mode":"media_crop","fid":"38663","attributes":{"alt":"dopamine, Â© Christopher Meade/shutterstock.com","class":"media-image media-image-right","id":"media_crop_612741986218","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"3867","media_crop_rotate":"0","media_crop_scale_h":"178","media_crop_scale_w":"150","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","style":"float: right;","title":"Â© Christopher Meade/shutterstock.com","typeof":"foaf:Image"}}]]Schizophrenia needs to be recognized, according to Nasrallah, as a disorder with a neurodevelopmental basis that is characterized by progressive brain atrophy. With increased psychotic episodes, the ventricular system of persons with schizophrenia enlarges. “Why can’t we do something?” asked Nasrallah.

 “The parietal lobe, temporal lobe, and prefrontal cortex take a huge loss,” said Nasrallah. There is also a loss of dendritic spines,

“But we focus on dopamine,” Nasrallah noted, despite the evidence for neurodegeneration in schizophrenia.

In addition to the loss of global gray matter and dendritic spines, Nasrallah stated that glial cells die in schizophrenia-perhaps accounting for gray matter deficits rather than neuronal loss. “When the glial cells die during a psychotic episode, the neurons become helpless,” observed Nasrallah. Effects on glia in schizophrenia remains a topic of much research, although controversy about the exact nature of glial effects might remain.

To add further insult to injury, trophic factors-from which neu-rons derive their support and ability to differentiate, grow axons, and survive-are also affected, such as brain-derived neurotrophic factor.

Researchers have conducted numerous studies of neurogenesis and antipsychotics, finding that atypical antipsychotics increase neurogenesis, but that haloperidol may be neurotoxic.

 In addition, atypical antipsychotics appear to boost levels of neurotrophins in the brains of persons with schizophrenia.

Given this evidence for numerous other processes, can the neurochemical model of schizophrenia go beyond dopamine? Nasrallah questioned the focus on that sole neuro-transmitter system, asking “why aren’t we using GABA agonists in conjunction with the dopamine antagonists?” He also mentioned that the antihypertensive agent nitroprusside could be effective for treating schizophrenia.9 Oxytocin might also hold potential.

Nasrallah believes that therapeutic approaches should concentrate on the neurodevelopmental dimension of schizophrenia. Prevention might also help, for example, protect pregnant women from the risk factors associated with increased schizophrenia risk-such as maternal infections, toxoplasmosis, and gestational diabetes-and ensuring safe deliveries.

In addition, Nasrallah suggested that it might be possible to prevent neurodegeneration and minimize the risk of psychosis through the early use of long-acting atypical antipsychotics. In general, he advocated the urgent need for “therapeutic approaches and strategies that go beyond what we are doing now.”

This article was originally posted on May 22, 2015 and has since been updated.

 Pauly K, Kircher T, Weber J, et al. Self-concept, emotion and memory performance in schizophrenia. 

 Thompson PM, Vidal C, Giedd JN, et al. Mapping adolescent brain change reveals dynamic wave of accelerated gray matter loss in very early-onset schizophrenia. 

 Konopaske GT, Lange N, Coyle JT, Benes FM. Prefrontal cortical dendritic spine pathology in schizophrenia and bipolar disorder. 

 Schnieder TP, Dwork AJ. Searching for neuropathology: gliosis in schizophrenia. 

 Buckley PF, Pillai A, Howell KR. Brain-derived neurotrophic factor: findings in schizophrenia. 

 Benninghooff J, Grunze H, Schindler C, et al. Ziprasidone-not haloperidol-induces more de-novo neurogenesis of adult neural stem cells derived from murine hippocampus. 

 Martins MR, Petronilho FC, Gomes KM, et al. Antipsychotic-induced oxidative stress in rat brain. 

 Rizos E, Papathanasiou MA, Michalopoulou PG, et al. A longitudinal study of alterations of hippocampal volumes and serum BDNF levels in association to atypical antipsychotics in a sample of first-episode patients with schizophrenia. 

 Hallak JE, Maia-de-Oliveira JP, Abrao J, et al. Rapid improvement of acute schizophrenia symptoms after intravenous sodium nitroprusside: a randomized, double-blind, placebo-controlled trial. 

Physicians recognize many features of schizophrenia, but one neglected area is the common symptom of a poor self-other boundary-in fact, this has also been neglected as a criterion for the DSM.

Schizophrenia: It’s Not Just About Dopamine

Many individuals live with pain, either chronic or acute. An estimated 100 million Americans suffer from chronic pain.

 Pain causes stress and suppresses immune responses, which make medical problems worse. The use of opiates to manage pain has increased. Unfortunately, along with the rise in opiate prescriptions is the increase in abuse. By 2012, 2.1 million Americans were addicted to prescription opiates.

 Opiates for pain relief were involved in 14,800 drug overdose deaths in 2008 versus 11,500 in 2007.

To combat opiate abuse and its dire consequences, drug makers developed many strategies. Some formulations allow active medicine for pain relief while blocking excessive blood levels at receptors. Other strategies alter opiate availability in a physical manner, so that drugs can no longer be snorted, injected, or dissolved.

Opiates act on specific receptors that evolved to respond to endogenous opiates such as dynorphin and enkephalin. Receptors include Î¼, Î´, and Î, distributed at Î³-aminobutyric acid (GABA)-releasing axons. They can inhibit GABA release onto dopamine-producing neurons in the nucleus accumbens, increasing dopamine-induced pain relief. Unfortunately, in addition to relieving pain, dopamine is also heavily implicated in addiction. Many newer opiate formulations are designed to achieve a balance at receptors, relieving pain but blocking excessive levels associated with abuse and addiction.

Approved in 2002 for opiate dependence, Suboxone is a combination of buprenorphine and naloxone in a 4:1 ratio. In addition to treating abuse, it is used as therapy for chronic pain. Buprenorphine is a partial opioid agonist at Î¼-opioid receptors and an antagonist at Îº-opioid receptors. By itself, buprenorphine relieves pain, but because it is an antagonist at higher doses, it can prevent abuse. The addition of naloxone adds further abuse prevention, as an opioid antagonist with no agonist activity.

Embeda, a morphine/naltrexone analgesic, is a gelatin capsule of the Î¼-opioid antagonist naltrexone within a morphine-containing pill. The naltrexone is released if the tablet is crushed, blocking the opiate effects of morphine. If the pill is taken as intended, naltrexone has a minimal effect.

Another medication, under development with Elite Pharmaceuticals, is ELI-216, which is a combination of oxycodone and naltrexone. ELI-216 is similar to Embeda in that naltrexone is only released when the medication is crushed, dissolved, or otherwise extracted. Naltrexone in this case is sequestered within small beads placed inside the gel capsule.

Drug manufacturers have developed several different technologies that allow for pain management but deter abuse on the basis of their physical properties alone. For example, Opana ER, marketed by Endo Pharmaceuticals, is a controlled-release oxymorphone in a drug matrix called INTAC Technology, created by the company GrÃ¼nenthal. INTAC makes a drug resistant to crushing, dissolving, cutting, and chewing. Even when the medication has been tampered with, release properties stay the same. According to an informational brochure released by GrÃ¼nenthal, this is based on “polyethylenoxide (PEO) of high molecular weight and a proprietary hot-melt extrusion process that combines the two factors of heat and pressure.”

With similar intentions to prevent pill manipulation, Acura Pharmaceuticals has developed Aversion technology. Three different strategies prevent abuse, although all are not incorporated into one medication. For example, if the medication is crushed, it turns into nasal cavity irritating chunks. When mixed with liquid, it becomes a difficult-to-inject gel. The third strategy is the addition of niacin to an opiate, which causes itching, headache, and chills when too much is ingested. Symptoms go away after about 90 minutes.

As an example, Acuracet uses Aversion technology. It is an immediate-release oxycodone/acetaminophen combination, with deterred nasal inhalation and intravenous injection. However, in a recent phase 2 trial, the technology did not elicit a negative enough response in users who snorted the medication, and the FDA requested further information from Acura. Vycavert is another opioid analgesic developed by Acura, which contains hydrocodone and acetaminophen. It also uses Aversion technology to prevent nasal inhalation and intravenous injection.

Remoxy is an oxycodone developed by Durect, Pain Therapeutics, and Pfizer. It is resistant to injection and snorting because of its Oradur technology. In a statement on their Web site, Durect states that Oradur “uses a high-viscosity base component such as sucrose acetate isobutyrate to provide controlled release.” They further claim that this component makes it more difficult to abuse medications containing Oradur technology by crushing or dissolving them. Remoxy is currently in phase 2 clinical trials.

Maintaining gradual, consistent drug release properties is another way to keep opiates from being abused. NkTR-181 is a Î¼-opioid agonist for chronic pain currently in phase 2 trials with Nektar Therapeutics. Its reduced abuse potential is based on slower entry into the CNS, because it is conjugated to small polymers. Slower entry also reduces euphoric effects and potential for respiratory depression.

Exalgo contains hydromorphone and is delivered via the OROS (osmotic extended-release oral delivery system). The slow controlled-release mechanism and crush-resistant nature of the tablet and makes it difficult to abuse. The ALZA company developed OROS, and tablets consist of a rigid shell with one or more holes drilled into them. After ingestion, water enters the tablet. Osmotic force gradually pushes the active drug through holes in the tablet.

COL-003 is an oxycodone that uses DETERx technology, which maintains the medication’s extended-release qualities even if the medication has been crushed or dissolved. Collegium Pharmaceutical developed both the medication and the technology. The medication consists of beads within a capsule. Active molecules are contained within a matrix, in a fatty acid-ionic complex. The matrix contains the extended-release mechanism at a microscopic level, so crushing a pill does not change release, even when the medication is sprinkled on food.

Dr Barry Setlow of the University of Florida College of Medicine Center for Addiction Research and Education commented on the new opiate formulations. He states, “Addiction is a heterogeneous disorder, and different prevention approaches will be effective in different individuals. Just as reducing easy access to prescription opiates has proven effective in reducing abuse, minimizing the abuse liability of opiates once they are prescribed should further reduce abuse, allowing for safer and more effective pain management.”

July 9, 2014, marked the release of the President’s drug policy blueprint. In contrast to waging a war on drugs, it emphasizes understanding addiction as a brain disease. Perhaps consistent with this idea, current opiates contain roadblocks to actively stop addiction from developing, rather than leaving it up to human will alone.

 Institute of Medicine. Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research. Washington, DC: National Academies Press; 2011. http://books.nap.edu/openbook.php?record_id=13172&page=1. Accessed August 19, 2014.

 National Institute on Drug Abuse. National RX Drug Abuse Summit. April 21, 2014. http://www.drugabuse.gov/about-nida/noras-blog/2014/04/national-rx-drug-abuse-summit. Accessed August 19, 2014.

 Centers for Disease Control and Prevention. Vital signs: overdoses of prescription opioid pain relievers-United States, 1999-2008. M

 Moorman-Li R, Motycka CA, Inge LD, et al. A review of abuse-deterrent opioids for chronic nonmalignant pain. 

To combat opiate abuse and its dire consequences, drug makers have developed a number of strategies--which are detailed here.

Roadblocks to Opiate Abuse

Age may bring wisdom-but it frequently comes with cognitive decline. This can be mild, due to normal aging, or severe, as in Alzheimer disease. Research is increasingly important as life expectancy increases. Aging has numerous brain effects, including decreases in many processes that contribute to plasticity.

Blood exchange to restore vigor seems like a Victorian medical treatment. The technique, parabiosis, was in fact first tested in the 1860s, according to an article that was published in 1956 by McCay and colleagues

 of Cornell University. They found that stitching 2 rats together so that their circulatory systems were joined, restored cartilage in the older animal. Recently, there has been renewed interest in parabiosis, along with the goal of determining exactly what in the blood causes youthful resurgence.

Three simultaneously published reports of mouse studies on parabiosis showed that young blood may benefit the old. Researchers observed regeneration of brain and muscle, seemingly via effects on stem cells. The exchange also improved function in the hippocampus: old mice who received young blood became more adept at memory and exercise tasks.

 Aged animals were connected to young mice at the abdomen. The connected pairs are called parabionts. The researchers compared parabionts that were both old (for mice that is 18 months) with old mice connected to young mice. The pairs shared their circulatory systems for 5 weeks.

Following this strange conjunction, the researchers used microarray analysis, a method for examining the expression of several genes at the same time. They specifically isolated the hippocampus. What they found was compelling. In old animals exposed to young blood, there was more expression of genes associated with brain plasticity than is normally seen in old animals that have not received transfusions. Specifically, cells expressed “immediate early genes” in the hippocampus. This may indicate more brain activity and improved memory processing. When the scientists measured hippocampal activity using electrodes (long-term potentiation [LTP], an indicator of memory), they also found increases in LTP in the old animals that had received young blood but not in old animals that had not.

The scientists then looked at the anatomy of cells in the hippocampus of old mice that had received young blood. They found that dendrites were more complex, a possible sign of increased learning. They measured aged mice in standard tests of memory, such as fear conditioning and a water maze, and compared a group of old mice that had received injections of blood plasma with a group of old mice that had not. Both fear learning and spatial memory improved in the group that received the plasma injections.

According to lead author and University of San Francisco Professor Saul Villeda, the finding was partially unexpected: “We knew that there were factors in blood that could rejuvenate stem cells . . . the idea of cognition was surprising.”

The investigators used viral vectors, which can block specific genes, to eliminate signaling via CREB (cyclic adenosine monophosphate responsive element binding protein)-a factor that can bind DNA and regulate gene expression. CREB is well known to regulate neural plasticity and memory processes in the brain. They found blocking CREB reduced changes in dendritic spines. Memory improvements also diminished in infused old animals when CREB was blocked. CREB seemed to be highly important for the young blood–induced spine increases and for memory improvements. Although CREB is likely a “master regulator,” for these processes, Villeda noted that other factors could be involved as well, since “when you block CREB activity you still get a benefit, it’s just not as strong.”

Jennifer Bizon, PhD, a Professor of Neuroscience at the University of Florida, was intrigued by the study. She remarked, “This is an exciting finding with potentially important implications for human aging. The challenge moving forward is how to translate this work to humans.” When asked whether the findings could lead to treatments for memory loss, Bizon responded, “As with any research emerging from rodent models, it takes time to appreciate the potential risks and determine efficacy in humans.”

According to Villeda, this study provides a good example of how basic research in animals can possibly benefit humans. He stated, “At the end of the day our goal is to improve health.” He hopes that the general public will be patient with scientists and understand that the process takes time.

A group at Harvard has also studied the benefits of young blood for the old. They focused on a specific protein, GDF11, present in young animals but reduced with age. The researchers, led by Professor Lee Rubin and Dr Lida Katsimpardi, found that GDF11 changed blood vessels in the brains of older mice and led to the production of new brain cells.

 According to Katsimpardi, “I expected the young blood to help the old brain because it makes sense. What surprised me extremely were the blood vessels. I didn’t expect that.”

New neurons can generate in several regions in the adult brain, including the hippocampus, subventricular zone, and olfactory bulb. Many factors decrease neurogenesis, including age, stress, and reduced blood flow. The scientists were interested in understanding whether neurogenesis can be reestablished in aged animals, specifically through effects on the circulatory system.

They first used parabiosis, attaching 15-month-old mice to young ones for 5 weeks, which increased blood vessel branching in the old animals. The blood exchange also induced neurogenesis in several brain regions, including the subventricular zone and the olfactory bulb. Parabiosis improved smell in the old animals, which makes sense because the olfactory bulb processes scents. When very old mice (21 months) were attached to 2-month-old mice, there was a decrease in subventricular zone neurogenesis in the young mice. Something in the old blood was having a detrimental effect. Katsimpardi stated, “Some factors increase with aging and they are toxic. So we know it goes both ways.”

The researchers wanted to understand what might be contributing to youthful renewal. In previous studies, they had identified the protein GDF11 in the blood of young animals but not in the blood of old animals. And, GDF11 was seen in old animals that had received blood from young mice. They decided to inject old mice with either GDF11 or a sham treatment.

The GDF11 acted on the capillary endothelial cells that are needed for blood vessel generation, specifically through the SMAP2/3 pathway. GDF11 also increased neurogenesis in the old animals. The effects were not as dramatic as those seen with parabiosis, which could have to do with the dose that was used. According to Katsimpardi, GDF11 is able to induce half the biological effect of parabiosis. Increasing the dosage of GDF11 might increase its effect.

There may also be other factors at work. According to Katsimpardi, “There are some other candidates and there are some molecules that increase with aging.” More experiments are needed to test this.

Dr Nicole Berchtold, of the UC Irvine Institute for Memory Impairment and Neurological Disorders, speculated about the effects of GDF11 in young animals. She said, “It would be interesting to see if GDF11 injections do the same thing to cognitive function, synaptic genes, etc, as parabiosis did in the aged animals.” Katsimpardi has yet to conduct those experiments.

Another study led by Professor Amy Wagers tested the effects of parabiosis on muscle stem cells. Connecting the circulatory systems from young to old transformed muscle from an aged state to one characteristic of a younger animal.

 The improved muscle quality increased strength and endurance.

Older mice that were injected with GDF11 were able to run longer on a treadmill than were control mice. However, GDF11 is not a performance-enhancing protein per se, since younger mice did not become super athletes when injected with it-they ran at the same pace as usual.

Last year the same group published a study showing that GDF11 can rejuvenate heart tissue when injected into older animals, so the effects on running ability could also have to do with having a more vigorous heart and circulatory system.

Now that GDF11 and CREB-mediated processes have been identified, will drugs that act on them become the new fountains of youth? Katsimpardi feels that the real potential lies in the treatment of neurodegenerative diseases. She states, “The idea is to have a drug that could either prevent or slow neurodegenerative diseases. The most interesting thing for us is not to rejuvenate everyone on the planet, it’s more to focus on age-related diseases or vascular diseases.”

According to Villeda, researchers are “figuring out a way to translate this into humans. There’s a lot more to be done.” However, these studies bring promise that science has revealed more about aging and age-related disease.

 McCay CM, Pope F, Lunsford W. Experimental prolongation of the life span. 

 Villeda SA, Plambeck KE, Middeldorp J, et al. Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice. 

 Katsimpardi L, Litterman NK, Schein PA, et al. Vascular and neurogenic rejuvenation of the aging mouse brain by young systemic factors. 

 Sinha M, Jang YC, Oh J, et al. Restoring systemic GDF11 levels reverses age-related dysfunction in mouse skeletal muscle. 

 Loffredo FS, Steinhauser ML, Jay SM, et al. Growth differentiation factor 11 is a circulating factor that reverses age-related cardiac hypertrophy. 

Is there something in young blood that holds the key to preventing or reversing cognitive decline and/or dementia associated with aging? The answer to that question is the subject of intense recent research. Details here.

Blood Revival: Young Mice Reverse Aging in the Old

It’s hard to believe that 40 years ago it was proposed that Alzheimer disease (AD) is caused by brain aluminum. Some people even threw out their cookware, in fear of acquiring the memory-impairing disease. The aluminum hypothesis has long since been discounted, and research has marched forward: Î²-amyloid (AÎ²) protein was identified in 1984 in brain plaques of patients with AD, and hyperphosphorylated Ï protein was identified in 1986.

 These are true AD markers; possible culprits behind neuronal death and memory impairment.

Amyloid precursor protein (APP) is the larger protein from which toxic AÎ² is made. The 

 gene was found on chromosome 21 in 1987, with another risk gene, 

 In the late 1990s, the enzymes Î²-secretase-1 (BACE1) and Î³-secretase were proposed as enzymes that prune APP, with the deadly effect of creating AÎ² as a brain-cell killer.

 Possible ammunition appeared with the discovery of each new AD target.

In the trenches of Alzheimer research, the battle continues . . . but where do we stand? Is the war on AD dementia nearing conclusion, or are we simply in the initial throes of the fight? In interviews with 

, 3 AD experts, Murali Doraiswamy, MD, of Duke Medicine; James Lah, MD, PhD, of Emory University; and Dagmar Ringe, PhD, of Brandeis University weighed in on this important topic.

we now have treatments that target brain neurotransmitters affected by AD. They increase acetylcholine (galantamine, rivastigmine, and donepezil) or block glutamate (memantine). This stalls 

 somewhat, but the disease presses onward. Dr Doraiswamy stated, “there are 4 FDA-approved symptom-relieving therapies that have a modest benefit on cognitive decline. Some of these medications can be used in combination, which may offer some additional benefit over monotherapy. Some people believe that these drugs may also reduce caregiving time and delay institutionalization. The good news is that many of these drugs are now generic and not as expensive as they once were. Unfortunately there has been no new FDA-approved therapy in over 10 years!”

Dr Lah concurred, stating that “current treatments are pretty limited to modestly effective symptomatic medications.”

Drs Doraiswamy, Ringe, and Lah generally agree that it is important to treat AD in its early stages, even before the disease has developed if possible. Much 

According to Ringe, “At the moment there is no treatment for AD, and it’s unclear that there ever will be. We are not looking for a treatment once it has progressed. What we are looking for is a treatment for potential AD patients.”

Doraiswamy agreed, stating, “every prevention trial to date has failed and through them we know a lot more about what doesn’t work. And we have made considerable progress in identifying people at greatest risk as well as the possible timeline for brain changes. So we have a much better chemical road map of what goes wrong in the brain than we did a decade ago. From this has come a sense that we need to begin trials a lot sooner-before people develop full-fledged dementia-to give the drugs the best chance to work.”

Problems have appeared with many clinical trials, starting with the Î²-amyloid vaccine. Mouse AD models offered initial promise, since vaccinated transgenic animals showed 

 Unfortunately, human vaccine trials ended because of 

Lah said, “We know that the most serious side effect for anti-amyloid medications is the possibility of brain swelling. In 2000 this was responsible for the termination of the first vaccine trial.”

Despite initial safety concerns, the development of amyloid vac-cines continues under rigorous safety monitoring. For example, UB-311 passed phase 1 trials and continues to be developed as a vaccine by United Biomedical, Inc.

 Initial studies showed improved brain function in a small group of 

 CAD106 is an anti–Î²-amyloid vaccine co-developed by Novartis and Cytos. An early study indicated that it is safe and produces antibodies, but additional trials are needed to show efficacy in AD.

Lah discussed the development of other anti-amyloid strategies, specifically monoclonal antibodies. These drugs are delivered intravenously every few weeks. Bapineuzumab did not meet clinical trial primary end points, and is not being pursued further.

; however, Lah explained that it “showed more promise in post hoc analyses . . . may have a beneficial effect in patients in the trial with earlier-stage disease.” Therefore, it is being further studied in a prevention trial that will identify susceptible individuals based on genetic markers and brain imaging. He was optimistic about the amyloid antibodies because “there is a lot of hope that when applied earlier . . . they will in fact have a disease-modifying effect.”

In addition to the anti-AÎ² efforts that continue, other approaches focus on the additional AD targets. These include medications that affect the enzymes that are required to produce and release the AÎ² peptides: Î³-secretase and BACE1. Î³-Secretase inhibitor trials have failed thus far; Î³-secretase inhibitors seem unable to lower AÎ² levels when tested in humans. This may have to do with an 

 to enter the brain from the bloodstream.

BACE1 inhibitors, however, still hold promise. The Merck BACE1 inhibitor, MK-8931, met safety requirements in a phase 2/3 EPOCH study that included individuals with mild to moderate AD. Merck has therefore started a phase 3 APECS trial that will test MK-8931 in people with 

 There has been some concern that BACE1 generally affects other targets, not just the AÎ² protein, which could cause problems with adverse effects and safety. The advancement of MK-8931 to phase 3 is a major accomplishment.

Hyperphosphorylated Ï is another target for AD treatment. Lah stated, “there’s been some preclinical work suggesting that the Ï approach may be effective as well.” In pre-clinical trials, the anti-Ï drug epothilone D seemed to reduce neuronal death, AD-like cellular effects, and cognitive problems in mice.

 This medication prevents the destabilization of neuron microtubules, which is an effect of hyperphosphorylated Ï. The drug is now in phase 1 clinical trials. Other epothilones are being studied for AD as well.

Therapies that focus on increasing nerve growth factor (NGF), a molecule that can protect brain cells, hold promise. 

is a surgically implanted noninfectious viral system that injects NGF DNA into the brain.

 The idea is to increase the production of protective NGF. Surgeons implant CERE-110 into the nucleus basalis of Meynert, an acetylcholine-producing brain region that degenerates in AD. Findings from phase 1 trials indicate that CERE-110 is well tolerated.

 This approach is currently being tested in a phase 2 trial consisting of about 50 patients with AD. Half of the participants have received CERE-110 while the other half received a mock surgery. Study results are expected in 2015.

Doraiswamy described other treatment approaches: “There are some new strategies being studied, such as nicotinic neurotransmitter modulation, induced stem cell therapies, RNA interference therapy, brain stimulation devices (eg, direct current stimulation, deep brain stimulation) and metabolism-based therapies.” The effects of aerobic exercise and diet are also being studied; for example, the Exercise and NutritionaL Interventions for coGnitive and cardiovascular HealTh ENhancement (ENLIGHTEN) clinical trial at Duke Medicine is looking at these interventions in people with mild cognitive impairment.

Retromer science: a new target for AD therapeutics?

An exciting study, recently published in the journal 

, looked at pharmacological compounds that bind the retromer complex.

 Retromer moves proteins, including APP, from cellular compartments (endosomes) to the Golgi apparatus for processing. It has been suggested that retromer-associated proteins cause APP and the enzyme BACE1 to stay in the endosome, where BACE1 cuts APP, causing AÎ² to form. Inhibiting this process could prevent AD. By increasing retromer levels and bolstering normal processing, less AÎ² may form.

When the researchers tested their retromer-binding compound (R55) in cultured neurons, retromer levels increased and AÎ² decreased. The next step is to test the clinical effects of R55 in mice.

Dr Ringe is one of the authors of this study. She feels that R55 could present a therapeutic approach that would have fewer adverse effects, since “We’re not trying to change the level to something it is not usually . . . we’re restoring a normal physiological state . . . bringing the cell back to the way it should be.” Although this work is in the early stages, targeting retromer represents another approach to be added to the armamentarium of AD treatments.

In 2011, President Obama signed the National Alzheimer’s Project Act (NAPA) that strives for effective treatments by 2025.

 This act, along with current AD research efforts, indicates that although the fight continues, strategies for combating AD may be within sight.

 Glenner GG, Wong CW. Alzheimer’s disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein: 1984. 

 Medina M, Avila J. New perspectives on the role of tau in Alzheimer’s disease: implications for therapy. 

 Wilcock DM, Griffin WS. Down’s syndrome, neuroinflammation, and Alzheimer neuropathogenesis. 

In the trenches of Alzheimer research, the battle continues . . . but where do we stand? Is the war on AD dementia nearing conclusion, or are we simply in the initial throes of the fight? Three experts weigh in.