In a paper published January 31 in the journal Molecular Psychiatry, researchers at Sanford-Burnham Medical Research Institute (Sanford-Burnham) reveal how antipsychotic drugs interfere with normal metabolism by activating a protein called SMAD3, an important part of the transforming growth factor beta (TGFbeta) pathway.

The TGFbeta pathway is a cellular mechanism that regulates many biological processes, including cell growth, inflammation, and insulin signaling. In this study, all antipsychotics that cause metabolic side effects activated SMAD3, while antipsychotics free from these side effects did not. What’s more, SMAD3 activation by antipsychotics was completely independent from their neurological effects, raising the possibility that antipsychotics could be designed that retain beneficial therapeutic effects in the brain, but lack the negative metabolic side effects.

“We now believe that many antipsychotics cause obesity and diabetes because they trigger the TGFbeta pathway. Of all the drugs we tested, the only two that didn’t activate the pathway were the ones that are known not to cause metabolic side effects,” said Fred Levine, M.D., Ph.D., director of the Sanford Children’s Health Research Center at Sanford-Burnham and senior author of the study.

In a previous study aimed at developing new insights into diabetes, Dr. Levine and his team used Sanford-Burnham’s high-throughput screening capabilities to search a collection of known drugs for those that alter the body’s ability to generate insulin, the pancreatic hormone that helps regulate glucose. That’s when they first noticed that many antipsychotics alter the activity of the insulin gene.

In this current study, the researchers set out to connect the dots between antipsychotics and insulin. In doing so, experiments in laboratory cell-lines showed that antipsychotics known to cause metabolic side effects also activated the TGFbeta pathway—a mechanism that controls many cellular functions, including the production of insulin—while the drugs without these side effects did not.

Wondering whether their initial laboratory observations were relevant to the human experience, the researchers reanalyzed previously published gene expression patterns in brain tissue from schizophrenic patients treated with antipsychotics. What they found supported their earlier findings—TGFbeta signaling was activated only in those patients receiving antipsychotic treatment. Looking further, they found that the extent to which each antipsychotic drug activated the TGFbeta pathway in human brains correlated very closely with the extent to which those same drugs activated SMAD3 and affected the insulin promoter in their cell culture experiments.

The TGFbeta pathway also plays an important role in metabolic disease in people who don’t take antipsychotic medications. “It’s known that people who have elevated TGFbeta levels are more prone to diabetes. So having a dysregulated TGFbeta pathway—whether caused by antipsychotics or through some other mechanism—is clearly a very bad thing,” said Dr. Levine. “The fact that antipsychotics activate this pathway should be a big concern to pharmaceutical companies. We hope this new information will lead to the development of improved drugs.”

A research group led by Giulio Maria Pasinetti, MD, PhD, Professor of Neurology, and Psychiatry, at Mount Sinai School of Medicine, explored whether dietary supplementation with a standardized decaffeinated coffee preparation prior to diabetes onset might improve insulin resistance and glucose utilization in mice with diet-induced type 2 diabetes. The researchers administered the supplement for five months, and evaluated the brain’s genetic response in the mice. They found that the brain was able to more effectively metabolize glucose and use it for cellular energy in the brain. Glucose utilization in the brain is reduced in people with type 2 diabetes, which can often result in neurocognitive problems.

“Impaired energy metabolism in the brain is known to be tightly correlated with cognitive decline during aging and in subjects at high risk for developing neurodegenerative disorders,” said Dr. Pasinetti. “This is the first evidence showing the potential benefits of decaffeinated coffee preparations for both preventing and treating cognitive decline caused by type 2 diabetes, aging, and/or neurodegenerative disorders.”

Coffee intake is not recommended for everybody due to the fact that it is associated with cardiovascular health risks such as elevated blood cholesterol and blood pressure, both of which lead to an increased risk for heart disease, stroke, and premature death. These negative effects have primarily been attributed to the high caffeine content of coffee. Nonetheless, these novel findings are evidence that some of the non-caffeine components in coffee provide health benefits in mice. Dr. Pasinetti hopes to explore the preventive role of decaffeinated coffee delivered as a dietary supplement in humans.

“In light of recent evidence suggesting that cognitive impairment associated with Alzheimer’s disease and other age-related neurodegenerative disorders may be traced back to neuropathological conditions initiated several decades before disease onset, developing preventive treatments for such disorders is critical,” he said.

Metabolic syndrome is a cluster of conditions that are risk factors for cardiovascular disease. The study showed a close association with two conditions in particular: high blood pressure and elevated fasting blood sugar levels, which is a precursor to diabetes. The research is published today in the medical research journal Translational Psychiatry.

“This is the first report of an underlying biological factor predisposing children to complications associated with second-generation anti-psychotic medication use,” says Dr Dina Panagiotopoulos, study co-author, clinician scientist at the Child & Family Research Institute (CFRI), pediatric endocrinologist at BC Children’s Hospital, and assistant professor, Department of Pediatrics, University of British Columbia (UBC).

“It’s concerning because these children take medications to treat a chronic disease – mental illness – and then develop risk factors for a second chronic disease,” says Dr. Angela Devlin, study co-author, CFRI scientist and assistant professor in the UBC Department of Pediatrics.

Second-generation anti-psychotics are prescribed to approximately 5500 children and youth in British Columbia for psychotic disorders, mood and anxiety disorders, attention deficit hyperactivity disorder, autism spectrum disorders, adjustment disorders and substance abuse. Of these medications, the two most commonly prescribed in B.C. are quetiapine (Seroquel®) and risperidone (Risperdal®).

For the study, researchers assessed 209 children who were inpatients between April 2008 and June 2011 at the Child & Adolescent Psychiatry Department at BC Children’s Hospital, an agency of the Provincial Health Services Authority. Their average age was 13 years, and 105 of the children were treated with second-generation anti-psychotics while 112 did not use these drugs. DNA analysis showed that eight per cent of children from both groups had a genetic variation called C677T on the MTHFR gene. Children with the MTHFR C677T variant who used these medications were six-times more likely to have metabolic syndrome.

The researchers targeted the MTHFR C677T variant because it is known to be associated with metabolic syndrome in adults who have schizophrenia, and with cardiovascular disease in adults who don’t have psychiatric illness.

Dr. Devlin and Dr. Panagiotopoulos say their discovery is an important step to preventing and managing metabolic complications associated with second-generation antipsychotic medications. It is critical to reduce these risks in childhood because adults with mental illness have a 19 per cent increased mortality rate that is largely due to cardiovascular disease risk.

The MTHFR gene is involved in metabolizing the B-vitamin folate.

“We now plan to assess B vitamin status and dietary intake in children who take these medications to gain a better understanding of this association,” says Dr. Panagiotopoulos.

However, white women who consumed 200 milligrams or more of caffeine a day had slightly lower estrogen levels than women who consumed less. Black women who consumed 200 milligrams or more of caffeine a day were found to have elevated estrogen levels, but this result was not statistically significant.

Total caffeine intake was calculated from any of the following sources: coffee, black tea, green tea, and caffeinated soda.

Findings differed slightly when the source of caffeine was considered singly. Consuming 200 milligrams or more of caffeine from coffee mirrored the findings for overall caffeine consumption, with Asians having elevated estrogen levels, whites having lower estrogen levels, and the results for blacks not statistically significant. However, consumption of more than one cup each day of caffeinated soda or green tea was associated with a higher estrogen level in Asians, whites, and blacks.

The changes in estrogen levels among the women who took part in the study did not appear to affect ovulation. Studies conducted in animals had suggested that caffeine might interfere with ovulation.

The study was published online in the American Journal of Clinical Nutrition.

“The results indicate that caffeine consumption among women of child-bearing age influences estrogen levels,” said Enrique Schisterman, Ph.D., of the Division of Epidemiology, Statistics and Prevention Research at the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the NIH institute where some of the research was conducted. “Short term, these variations in estrogen levels among different groups do not appear to have any pronounced effects. We know that variations in estrogen level are associated with such disorders as endometriosis, osteoporosis, and endometrial, breast, and ovarian cancers. Because long term caffeine consumption has the potential to influence estrogen levels over a long period of time, it makes sense to take caffeine consumption into account when designing studies to understand these disorders.”

The study authors noted that 89 percent of U.S. women from 18-34 years of age consume the caffeine equivalent of 1.5 to two cups of coffee a day.

The study’s first author was Karen C. Schliep, Ph. D., M.S.P.H., from the University of Utah, Salt Lake City, who conducted the study during a research appointment at NICHD. Dr. Schliep undertook the research with Dr. Schisterman and colleagues at the University of Utah, the NICHD and the State University of New York at Buffalo.

More than 250 women from 18 to 44 years old participated in the study between 2005 and 2007. On average, they consumed 90 milligrams of caffeine a day, approximately equivalent to one cup of caffeinated coffee.

Most of the participants in the study reported to the study clinic one to three times a week for two menstrual cycles. Their visits were scheduled to correspond with specific stages of the menstrual cycle. At the visits, the women reported what they had eaten in the last 24 hours and answered questions about their exercise, sleep, smoking and other aspects of their lifestyle and reproductive hormone levels were measured in blood. The study authors noted that collection of these details during multiple time points across two menstrual cycles produced more precise information about the link between caffeine and hormones than was possible in earlier studies. The researchers also noted that the study participants were more racially diverse than those who took part in previous studies.

Mephedrone is a synthetic stimulant — a ‘designer drug’ — that became widely used in the UK from 2008 to 2010. Its rise in popularity may have been caused by its legality and ready availability (typically sold online as ‘plant food’), and also to the reduced purity of street cocaine and ecstasy during the same period. In 2010, because of its similarity to amphetamines and frenzied media reporting of the harmful effects of the drug, mephedrone was made illegal in the UK and scheduled as a Class B drug. The drug is still available through street dealers and online.

Research published online today in the journal Addiction shows that after taking mephedrone, users showed impaired working memory as well as the typical stimulant drug effects of euphoria, self confidence and buzzing.

While intoxicated, they also experienced marked craving for mephedrone and typically binged on the drug, taking it repeatedly for an average of eight hours. When drug-free, this group showed higher levels of depression and poorer long term memory compared to controls using drugs other than mephedrone.

When asked what factors might influence them to try a new legal high, the same users said they would be drawn to a new drug that was pure and had few short-term or long-term harms. While they would be attracted by positive reports from friends and on the Internet, lack of scientific research on the drug and its legal status were less important factors.

Mephedrone has been the most publicized ‘legal high’ in recent years, but there are many new compounds currently emerging on Internet markets. In 2010, 41 new substances were detected in the EU, compared with 24 in 2009 and 13 in 2008. Of those 41 new substances, 15 are synthetic stimulants, just like mephedrone. One of these may become the new ‘legal high’ that current mephedrone users want.

Says lead researcher Tom Freeman of University College London, “Drug users today are attracted to new substances that are pure and have few adverse effects. Lack of scientific research on the effects and risks of new legal highs might explain why young people rely on subjective reports from friends or the Internet when deciding whether to try a new substance. Internet reports may be biased and offer an opportunity for drug vendors to promote their products. As well as encouraging new research, an important harm reduction strategy is for the media and advice websites such as FRANK to provide balanced and up-to-date information on these drugs.”

The scientists recreated a surgical procedure in vivo in which pain fibres were stimulated under controlled conditions. Says Sandkühler: “Although deep anaesthesia prevents any sensations of pain, we were able to reserve long-term synaptic potentiation in the spinal cord. Despite anaesthesia, there appears to be a memory trace for pain and a pain amplifier has engaged.”

High doses of intravenous opioids over the course of an hour – normally opioids are delivered at moderate doses over a longer period – were able to completely resolve the potentiation. Says Sandkühler: “The memory trace for pain was therefore deleted again and the pain amplifier switched off.”

The memory trace, as it is termed, is triggered by a variety of mechanisms, including the potentiation of signal transmission at the contact points (synapses) between the nerve cells. This is known as long-term synaptic potentiation. This pain memory can result in the sensation of amplified pain lasting much longer than the actual cause of the pain, even leading to a condition known as chronic pain syndrome.

A paradigm shift in pain therapy?

The project, which is sponsored by the Vienna Fund for Science, Research and Technology (WWTF), is currently investigating how this discovery can be put to use in clinical settings. To this end, test subjects or patients with pain syndrome are being given a high dose of an opioid over a period of 60 minutes.

“If our approach turns out to be effective under clinical conditions, this would herald a paradigm shift in pain therapy. It would mean moving away from the temporary, purely symptom-based pain therapy to a long-term removal of the cause of pain based on pain mechanisms using opioids.”

The effect of opioids (morphine or morphine-like substances) is based on their ability to bind to specific binding sites, known as µ-opiate receptors (MOR) which are found on nerve cells and which process pain-related information. Until now, it has been assumed that opioids are only able to alleviate pain while they are bound to the MOR and therefore suppress stimulation in the pain-processing system. Says Drdla-Schutting: “As soon as the medication is stopped, the pain-relieving effect disappears too.”

In clinical practice, opioids are therefore given continuously in moderate doses in order to achieve permanent binding to the MOR. This may relieve pain very effectively, but its cause cannot be eliminated. The new, high-dose, short-term therapy with opioids, on the other hand, causes a reversal of cellular changes that play an important role in pain memories, therefore possibly eliminating one of the causes of chronic pain.

The study, published in the January issue of Neurogastroenterology and Motility, looked at 226 patients seen at the Mayo Clinic in Rochester, New York, USA, over a 13-year period.

These were broken into three groups. Eighty-two patients with CVS were randomly matched with 82 patients with Irritable Bowel Syndrome (IBS) based on age, gender and geographic referral region. Researchers also examined the records of 62 patients with functional vomiting (FV), recurrent vomiting that cannot be attributed to a specific physical or psychiatric cause.

“Our study showed that CVS and FV had very similar clinical features, apart from marijuana use” says Dr G Richard Locke III from the Division of Gastroenterology and Hepatology at the Clinic.

Key findings of the study included:

• Members of the CVS group were younger than members of the FV group (30 versus 36 years) and more likely to be male (53% versus 46%).

• No statistically significant association was detected between membership of the CVS and FV groups and marital status, education level, body mass index, employment status, alcohol use or smoking history.

• 37% of the CVS group had used marijuana (81% male), together with 13% of the FV group (equally split between male and female) and 11% of the IBS group (73% male).

• Marijuana users were 2.9 times more likely to be in the CVS group than the FV group. When this was adjusted for age and gender, males using marijuana were 3.9 times more likely to be in the CVS group and women using marijuana were 1.2 times more likely.

The research team also looked at gastrointestinal symptoms and migraine as these have previously been associated with CVS. They found that

• The prevalence of gastrointestinal symptoms, including abdominal pain and nausea, was similar in CVS and FV patients, with the exception of retching, which was more common in patients with CVS (69% versus 31%).

• Patients in the CVS group were more likely to have headaches and migraines than patients in the FV group, but the difference was not statistically significant. Migraine headache and psychiatric disorders did not appear to commonly co-exist in CVS patients, unlike in the IBS group.

• The researchers also measured rapid gastric emptying, which is when undigested food enters the small bowel too quickly causing nausea, vomiting and other symptoms. This showed that there were much higher rates of fast gastric emptying in patients in the CVS and FV group (45% and 46% respectively), compared with the IBS group (8%). A novel finding was that the patterns of fast, normal and delayed gastric emptying were similar in the CVS and FV groups.

“Our study confirms that cyclic vomiting syndrome occurs most often in young males and is significantly associated with marijuana use, unlike functional vomiting” says Dr Locke. “The current treatment options for this condition remain challenging and are limited by the lack of randomised controlled trials. Further research is clearly needed.”

“Investigation of food items consumed by ancient people offers insight into the traditions and customs of a particular civilization,” explains Jennifer Loughmiller-Newman from the University at Albany in New York. “Textual evidence written on pottery is often an indicator of contents or of an intended purpose, however actual usage of a container could be altered or falsely represented.”

Many of the Mayan flask vessels from the Kislak collection of the Library of Congress examined in this study were filled with other substances, such as iron oxide used in burial rituals, making it difficult to detect the original content.

The most indisputable evidence of a container’s usage is obtained when hieroglyphic text or pictorial illustrations on the exterior of a container is consistent with the chemical analysis of interior residues. For the current investigation, researchers analyzed samples extracted from the Late Classic Maya period (600 to 900 AD) using gas chromatography mass spectrometry (GCMS) and liquid chromatography mass spectrometry (LCMS).

Nicotine—the signature alkaloid in tobacco—was identified as the major component of the extracts from one of the 150 vessels in the collection. The flask was determined to be made in southern Campeche, Mexico and dates to around 700 AD.

Prior to the current discovery, the only existing evidence showing a Mayan vessel to have the same content as indicated by hieroglyphic text was the identification of theobromine, an alkaloid found in cacao, more than 20 years ago.

“Our study provides rare evidence of the intended use of an ancient container,” concludes Dr. Dmitri Zagorevski from the Rensselaer Polytechnic Institute in Troy, New York. “Mass spectrometry has proven to be an invaluable method of analysis of organic residues in archaeological artifacts. This discovery is not only significant to understanding Mayan hieroglyphics, but an important archaeological application of chemical detection.”

A recent study by Dr. Timothy E. Wilens and colleagues, published in the January 2012 issue of the Journal of the American Academy of Child and Adolescent Psychiatry(JAACAP), is the first randomized placebo-controlled trial designed to assess efficacy and safety of guanfacine extended release (GXR) as an adjunct to psychostimulants in children and adolescents diagnosed with ADHD who had a suboptimal response to a psychostimulant alone.

As reported in the article “A Controlled Trial of Extended-release Guanfacine and Psychostimulants for Attention-deficit/hyperactivity disorder,” Wilens and colleagues conducted a nine week multicenter, double-blind, placebo-controlled, dose-optimization study, with participants in 59 study sites who continued their stable dose of psychostimulant given in the morning and were randomized to receive GXR in the morning, GXR in the evening, or placebo.

For both morning and evening administration of GXR, subjects receiving GXR plus a psychostimulant showed significantly greater improvement from baseline to endpoint, as measured by the ADHD-Rating Scale IV total score, compared with subjects receiving placebo plus a psychostimulant. In particular, the inattention subscale rating and the hyperactivity/ impulsivity subscales of the ADHD-RS-IV showed significantly greater improvements from baseline in subjects receiving GXR with a psychostimulant compared with subjects receiving placebo plus psychostimulant. Significant benefits of adjunctive administration were observed whether GXR was administered in the morning or evening.

No new safety signals emerged after adjunctive administration of GXR with psychostimulants compared with psychostimulants alone.

Reflecting on their research findings, Wilens and colleagues stated, “The results of this study support the hypothesis that adjunctive administration of the selective alpha2A-adrenoceptoragonist, GXR, to a psychostimulant in subjects with suboptimal response to psychostimulants reduces ADHD symptoms over placebo with a psychostimulant.”

Although the causal pathway between injecting methamphetamine and suicidal behavior requires further investigation, study authors suggest that it likely involves a combination of neurobiological, social, and structural mechanisms, at least in the population studied.

The study results are published in the December issue of Drug and Alcohol Dependence.

“Compared to other injection drug users, it is possible that methamphetamine users are more isolated and have poorer social support systems,” said lead author Brandon Marshall, PhD, a postdoctoral fellow at the Mailman School of Public Health and research coordinator for the Urban Health Research Initiative in British Colombia. “The high rate of attempted suicide observed in this study suggests that suicide prevention efforts should be an integral part of substance abuse treatment programs,” said Dr. Marshall. “In addition, people who inject methamphetamine but are not in treatment would likely benefit from improved suicide risk assessment and other mental health support services within health care settings.”

The Vancouver Injection Drug Users Study is part of the ongoing British Columbia Centre for Excellence in HIV/AIDS’ Urban Health Research Initiative, which focuses on the effects of substance use, infectious diseases, and the urban environment on the health of urban populations. Vancouver’s Downtown Eastside is known as a center for illicit drug use, and fatalities from drug overdoses and drug-related violence are common. A large outbreak of HIV infection reported there in 1997 was among the fastest spreading HIV epidemics in the developed world.

Participation in the seven-year study, which ended in May 2008, was through word of mouth, street outreach, and referrals and included an interviewer-administered questionnaire on sociodemographic characteristics, drug use, treatment utilization, and HIV risk behaviors. The researchers evaluated 1,873 participants whose median age was 31, while 36.2% of participants were female, and 32.1% were of Aboriginal ancestry. In total, 8% percent of study participants reported a suicide attempt.

“This is one of North America’s largest cohorts of injection drug users, and the research is among the first longitudinal studies to examine attempts of suicide by injection drug users,” said Dr. Marshall. “Most of these 5,000 users are concentrated in a very small neighborhood, making it a logical environment for this type of study. Because our study is one of the main points of access to health care for this population, this is a very well utilized study with a high rate of follow-up.”

Dr. Marshall and colleagues also discovered that infrequent methamphetamine injection was a predictor of attempting suicide, while frequent methamphetamine injection was associated with the greatest risk of attempting suicide.