Brain Blogger » Drugs & Clinical Trials http://brainblogger.com Health and Science Blog Covering Brain Topics Thu, 16 Jul 2015 15:00:27 +0000 en-US hourly 1 http://wordpress.org/?v=4.2.2 The Most Popular Psychiatric Drugs Alter Decisions to Cause Harm http://brainblogger.com/2015/07/15/the-most-popular-psychiatric-drugs-alter-decisions-to-cause-harm/ http://brainblogger.com/2015/07/15/the-most-popular-psychiatric-drugs-alter-decisions-to-cause-harm/#comments Wed, 15 Jul 2015 15:00:10 +0000 http://brainblogger.com/?p=20112 Citalopram (Celexa®) and levodopa (Larodopa®), considered to be the most commonly prescribed antidepressant and Parkinson’s drug respectively, have been shown in a new study to alter how healthy individuals make moral decisions to harm both oneself and other people. Conducted by researchers from UCL and Oxford University the research investigated how taking citalopram or levodopa altered participants’ decisions to inflict pain on themselves or strangers in exchange for money…the results are both concerning and promising.

The experiment involved 175 healthy adults, 89 of which were randomized to receive serotonin-boosting citalopram or placebo and the remaining 86 randomized to receive dopamine-boosting levodopa or placebo. The participants had to make choices in a harm aversion experiment regarding giving both themselves and other participants electric shocks for financial gain.

Entering separate testing rooms without seeing each other, the participants were given the drugs and waited until the peak drug absorption time was reached, 3 hours or 60 minutes for citalopram and levodopa respectively. With the drugs influence at its peak the harm aversion experiment began.

86 times the participants were asked to decide between receiving a lower amount of money for less shocks to themselves or more money for more shocks. Likewise, they also had to make choices 86 times for shocking anonymous strangers, where the participant had to decide on which tradeoff was better, receive more money for themselves by inflicting a greater number of shocks to a stranger, or receive less money for themselves in order to electrocute the stranger a fewer number of times.

The researchers had previously published a study of the harm aversion experiment that revealed that most people show a greater aversion to inflicting pain on others than towards themselves, which they coined being a hyperaltruistic disposition.

However, in the present experiment the participants in the test condition were given commonly prescribed drugs that influence the levels of common, multifunctional neurotransmitters in the brain that are involved in a myriad of cognitive functions, namely serotonin (citalopram) and dopamine (levodopa).

For those who had a pharmacological enhancement of serotonin by taking citalopram, they were more likely to avoid harming both themselves and others, choosing to receive less money rather than inflict pain compared with drug-free controls. This is promising news considering reduced harm aversion is a risk factor for both preplanned and in the moment reactive aggression that are both common features of the mental illnesses and disorders that citalopram and similar serotonin reuptake inhibitors are prescribed to treat.

Whereas those who had a pharmacological enhancement of dopamine by taking levodopa had their hyperaltruism reduced, and were more likely to inflict pain on others than themselves compared with control. Ultimately, this means that taking levodopa increases selfishness for monetary reward, which is backed by other studies.

Interestingly, these decision altering affects of both drugs were dose dependent, meaning that the higher quantity of the drug that was taken, the stronger the effect on moral decision making.

Looking at how quickly decisions were made on both drugs was also enlightening when considering other research on uncertainty. With citalopram it took longer for the participants to make their decision which the researchers interpreted as erring on the side of caution to avoid imposing unwanted levels of shocking pain on others.

However, it is also important to note that citalopram enhanced the participants’ negative affect, which includes negative emotions like anger, contempt, disgust, guilt, fear and nervousness. It may be that enhanced worry and nervousness caused by healthy people taking citalopram and abnormally enhancing seretonin levels promotes harm aversion and cautious behavior, which may not be useful for overly harm avoidant, fearful and withdrawn psychiatric patients.

With levodopa on the other hand the authors suggest a mechanism by which levodopa reduces hyperaltruism through boosted dopamine levels reducing the variability of neural representations of other people, making the decision to cause pain a quicker and easier than without levodopa, in line with the current neuroscientific perspective on empathy.

Dr Molly Crockett, lead author of the study reminds us that psychiatric drugs influencing moral decisions in healthy people has serious ethical implications of pharmacological interventions however,

“It is important to stress…that these drugs may have different effects in psychiatric patients compared to healthy people. More research is needed to determine whether [and how] these drugs affect moral decisions in [different groups of people] that take them for medical reasons.”

References

Main DOI: http://dx.doi.org/10.1016/j.cub.2015.05.021

Previous research: 10.1073/pnas.1408988111

Aggression and psycopath: 10.1016/0010-0277(95)00676-P

dopamine and selfishness: 10.1007/s00213-013-3210-x

empathy neuroscience: 10.1038/nn.3085

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Cartoon – Antibiotic Overuse in America http://brainblogger.com/2015/06/17/cartoon-antibiotic-overuse-in-america/ http://brainblogger.com/2015/06/17/cartoon-antibiotic-overuse-in-america/#comments Thu, 18 Jun 2015 01:30:39 +0000 http://brainblogger.com/?p=19899 Reference

Hicks LA, Bartoces MG, Roberts RM, Suda KJ, Hunkler RJ, Taylor TH Jr, & Schrag SJ (2015). US outpatient antibiotic prescribing variation according to geography, patient population, and provider specialty in 2011. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 60 (9), 1308-16 PMID: 25747410

Image created by Jerry King for Brain Blogger.

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Prescription Drug Monitoring Programs – Much Promise But Limited Progress http://brainblogger.com/2015/03/22/prescription-drug-monitoring-programs-much-promise-but-limited-progress/ http://brainblogger.com/2015/03/22/prescription-drug-monitoring-programs-much-promise-but-limited-progress/#comments Sun, 22 Mar 2015 12:54:34 +0000 http://brainblogger.com/?p=19208 The Problems of Opioids

During roughly the past two decades there have been significant increases in the prescription of opioid analgesics for helping millions of patients with pain disorders. At the same time, the United States is in the midst of an epidemic of misuse of these drugs and related abuse, addiction, overdose, and deaths.

For example, the prescribing of opioid analgesics has more than doubled since the 1990s. At the same time, sales of opioids quadrupled and there was a 6-fold increase in admissions to substance abuse treatment programs. Most importantly, opioid-related deaths have more than tripled, with unintentional deaths due opioid overdose exceeding those of heroin and cocaine combined.

As one tool for addressing the problems associated with opioid analgesics, prescription drug monitoring programs (PDMPs) have been developed over the years. These programs are intended to medically benefit patient care, and also as a tool for law enforcement and other agencies concerned with stemming the tide of opioid-related threats to the public health.

PDMPs: Simple in Concept, Complex in Execution

Fundamentally, a PDMP is a central repository of prescribing and dispensing records pertaining to medications classified as scheduled, controlled substances by the U.S. Drug Enforcement Administration, but a PDMP may include any drug/substance of interest or determined to have abuse potential. These days, the information is stored in online electronic databases allowing easy access to authorized individuals or agencies, such as law enforcement and drug control agencies, practitioner licensure boards, medical examiners, drug courts and criminal diversion programs, addiction treatment programs, public and private third-party payers, medication dispensers (e.g., pharmacies) and prescribers, and other healthcare providers. States vary widely in which categories of users are permitted to request and receive prescription history reports and under what conditions.

Individual state PDMPs also differ as to required prescribing information — such as, drugs of interest, dose/quantity, date dispensed, and dispenser, prescriber, and patient information, etc. — and time of entry into the database. Only one state, Oklahoma, collects data in real time — that is, at the same time that a prescription is filled — whereas, most states allow up to a week or longer for submission of data to the PDMP.

In using the data, PDMPs may be categorized as being a) reactive, b) proactive, or c) a combination of the two. A reactive approach passively relies on inquiries (solicitations) from authorized agencies or individuals before generating reports; for example, a physician might query the PDMP database prior to prescribing an opioid for a patient. Or, PDMPs may be more proactively designed to watch for patterns of prescribing or dispensing that raise red flags and then provide unsolicited reports to authorized agencies or individuals for further action. In some cases, state PDMPs use a combination of both approaches.

A Long Evolution of PDMPs

According to research conducted for the Pew Charitable Trusts, PDMPs are not a new concept. In fact, as of 1990 there had been 9 PDMPs developed, dating from the earliest in California in 1939. Most of the programs were initiated by law enforcement and/or regulatory agencies and all of them only collected data on Schedule II prescriptions (i.e., opioids) using multi-page, serialized prescription forms requiring manual data entry at the PDMP. There was an emphasis on controlling illicit channels of opioid purchase or distribution and these early PDMPs provided reports on request (solicited) as well as unsolicited reports to law enforcement personnel, regulatory agencies, or professional licensing agencies; no reports were provided to prescribers or pharmacists.

Beyond 1990, and with support from the U.S. Drug Enforcement Administration (DEA), PDMP administrators formed an alliance for mutual support and information exchange, and to help promote expansion of PDMPs to other states. At this time, PDMPs also started to extend data collection beyond Schedule II drugs; although, each state was free to select the drugs included. This also marked a new generation of PDMPs using electronic technology for prescription information collection, largely abandoning the need for serialized prescription forms. Initially, reports were transmitted by fax, but online systems soon allowed more expedient inquiries.

Continued interest at the federal level, and focusing on reducing opioid-related problems, resulted in various economic support programs; e.g., Harold Rogers Prescription Drug Monitoring Program Grants and the National All Schedules Prescription Electronic Reporting (NASPER) Act. The U.S. Bureau of Justice Assistance helped to form PDMP assistance and training programs with a special emphasis on evidence-based practices. Through the years, other government agencies (e.g., ONDCP, CDC, etc.) and private industry (Purdue Pharma) provided additional assistance and support for program development.

According to the most current information, by the end of 2014 all 50 states and the District of Columbia (Washington DC) had or were nearing realization of a PDMP; Washington DC enacted legislation but did not have an operational program and Missouri was nearing legislative authorization of a PDMP. Still, there are many inconsistencies across state programs, for example:

  • Many, but not all, programs allow sharing of their information with other state PDMPs; however, in many cases there are problems with data formatting and transmission that are barriers to such sharing.
  • In 5 states, PDMPs are still housed in law enforcement agencies.
  • When it comes to proactively sending unsolicited reports, there are many differences in who is contacted, whether it be prescribers, pharmacists, law enforcement, or licensing entities.
  • Less than a quarter of states (12) require that patients are notified when or if their prescription information might be accessed.

As a newly added concern, the recent hacking of online, electronic databases threatens the integrity of PDMP programs and the security of confidential patient information. According to news reports, hacker attacks in Oregon and South Carolina exposed social security numbers and other personal information housed in state databases. Last August, a collective of activist hackers known as “Anonymous” brought the Missouri state database servers to a halt temporarily, which may threaten passage of PDMP legislation in the state.

Serving Multiple Roles

The early and ongoing development of PDMPs has been principally driven by concerns about opioid-related problems — e.g., diversion, abuse, deaths — so the programs were designed foremost to serve regulatory and law enforcement agencies. For example, the database can be used at the individual-patient level to identify those obtaining prescriptions for drugs of concern from multiple prescribers and/or pharmacies during a brief timeframe (known as “Doctor Shoppers”); in response, the prescribers can be proactively alerted. On a larger scale, PDMP records can help to identify medical practices or clinics that appear to over-prescribe controlled substances of concern (“Pill Mills”), which may trigger investigations leading to regulatory or law enforcement actions. In other cases, PDMP records may be used to identify insurance fraud in billing for certain drugs and possible drug diversion within a particular locale.

Of greatest interest currently is having medical professionals use PDMPs as a tool for reducing the abuse, addiction, and diversion of opioid analgesics and other prescription drugs. For example, prescribers are urged to proactively use the database to detect alleged “Dr. Shoppers” so such behavior can be deterred at the point-of-care. Another potential benefit of PDMPs is the improved patient care and safety afforded by prescribers knowing of all controlled substances patients are being prescribed by all healthcare providers, since patients may not report complete information in their health history. Ideally, PDMP reports would include data on all prescription medications, beyond just CII opioids, but most PDMPs are not designed to capture such extensive information.

Although PDMPs have significant potential to improve public health and patient care outcomes, they remain a substantially underutilized resource. Reasons for this include differences in the data individual state PDMPs collect, whether and how data quality is ensured, the kinds of data analyses and reports that are produced, and to which users and under what conditions data are made available. Furthermore, while it is claimed that PDMPs do not infringe on the legitimate prescribing of controlled substances and simply make it possible to spot potential problems in patients deserving a closer look, an end result often has been a “chilling effect” on the prescribing of opioids overall.

Evidence Lacking to Support PDMPs

Early PDMPs in the pre-electronic era had limited effects due to the lag time inherent in reporting information via paper documentation, the minimal data collected, the need for manual data entry, the absence of off-hours access to data, and the voluntary nature of reporting. Since 2001, with the advent of newer and improved PDMPs, there still have been no federally-mandated rules to enforce consistency and compatibility among those programs, which makes doing research across programs more challenging.

Several dozen published and unpublished empirical studies on PDMP effectiveness have been summarized in the Pew report, which more than anything points to the difficulties of such investigations. At best, studies have been observational in nature, but most have been case reports of select aspects of PDMPs (e.g., increases in user satisfaction); the vast majority of studies reported favorable outcomes related to PDMP applications and practices. It is important to note, however, that none of the studies were of high quality and none examined improvements in patient care or health outcomes as a result of PDMP implementation and use.

The few broader-scope comparisons of all states with versus states without PDMP programs did not show outcomes favoring PDMPs. For example, an observational study by Paulozzi, Jones, et al. (2011) of early program effectiveness, spanning 1999 through 2005, found that states with PDMPs demonstrated unfavorably increased trends in drug overdoses and mortality, along with significantly greater consumption of hydrocodone. Interestingly, the only states showing improvements in overdose deaths and opioid consumption at the time included 3 states with PDMPs still using special prescription forms rather than newer electronic approaches. This suggested there were many challenges still to be overcome in developing electronic PDMPs and, while it cannot be stated that PDMPs themselves caused negative outcomes, the researchers concluded that, “…it can be said unequivocally that PDMP states did not do any better than the non-PDMP states in controlling the rise in drug overdose mortality.”

Further studies are needed to assess individual state programs as well as PDMPs grouped on a regional and nationwide basis. Along with that, however, many potentially confounding factors must be considered. For example, several government agencies have been developing and promoting educational and regulatory programs that impact some of the same outcome variables measured for PDMP programs. For example, reductions in opioid-related overdoses and deaths during recent years might be attributed to successes of the FDA’s REMS (Risk Evaluation and Mitigation Strategies) programs for opioid analgesics.

Prescriber Dilemmas

Prescribers have not widely embraced the use of PDMPs, even though there could be some advantages of PDMPs for patient care. For example, a comprehensive and accurate history of pharmacotherapy-management is essential for clinical evaluation of a new patient with chronic pain. While reliance on the patient’s self-reported history is generally considered acceptable, it may lead to dangerous misprescribing. A PDMP might help to identify patients who are receiving multiple legitimate prescriptions for opioids or benzodiazepines, from different healthcare providers, and are at risk for complications from polypharmacy — but only if the PDMP tracks more than class CII opioids.

Online electronic PDMPs help to solve many of the problems that restrained earlier, paper-based systems, but they also raise new concerns. In one survey of prescribers, the respondents cited time restraints and access difficulty issues as barriers to using PDMPs. A newly-reported nationwide survey, by researchers at the Johns Hopkins Bloomberg School of Public Health, found that among the 420 randomly-selected eligible physicians questioned more than one-fifth (22%) were not aware of their state’s PDMP and only 53% had actually used the program.

The researchers suggest that usage might be improved if more states allow physicians to appoint a proxy such as a staff member who can do the work of accessing the database. Another problem noted is that, in some state databases, the information is not clearly presented, making it difficult to interpret. Furthermore, only 21 states presently require prescribers to register with their PDMP and only 16 states require that prescribers use PDMP information.

In that regard, a cross-sectional study of 33 PDMP programs found that only slightly more than half of clinicians on average within the states were registered to use the PDMP, with many who did register using it infrequently. In states with PDMPs administered by law enforcement agencies, usage by healthcare providers was lower than in states with PDMPs managed by health or pharmacy boards.

In a recent survey of PDMP users in Oregon, almost all (95%) reported accessing the database when they suspected drug abuse or diversion in a patient, but fewer than half checked it routinely for every new patient or every time they prescribed a controlled drug. Clinicians also reported a variety of problems that arose when a PDMP report included “worrisome” information: patients often reacted with anger or denial (at least 88% reacted this way sometimes); nearly three-quarters of clinicians (73%) said that those patients sometimes did not return; less than a quarter (22%) reported that the confronted patients asked for help with drug addiction or dependence problems.

Overall, the data at hand suggest that prescribers generally do not perceive PDMPs as an essential tool for improving patient care in their practices, and the detriments may overshadow advantages. While most practitioners believe that they can detect “problem patients” on their own, research has shown this to be untrue. Additionally, accessing PDMPs incurs extra time in busy healthcare practices, whether by the clinician or a proxy staff member, without added compensation. Plus, the uncovering of “worrisome” data opens a proverbial “can of worms,” requiring further uncompensated time with patients to discuss information that may not be accurate, that may be upsetting to patients and damaging to practitioner-patient relationships, and that the clinician may be uneducated to manage.

Many Challenges Ahead

There still seem to be questions about whether PDMPs successfully serve the interests of public health (e.g. to stem opioid abuse, drug trafficking, deaths) or better patient care (e.g., to avoid harmful drug interactions and help guide opioid prescribing) or both objectives. Clinicians are facing the challenge of caring for an increasing number of patients with chronic pain who may benefit from opioid therapy. At the same time, increased opioid prescribing has correlated with soaring rates of abuse, diversion, addiction, overdose and deaths. PDMPs are no panacea for addressing the problems.

There are realistic concerns that PDMPs can be burdensome for prescribers and dispensers, and a “chilling effect” of these programs may inappropriately reduce the amount of opioid analgesics prescribed as an unintended consequence. Many clinicians are still unaware of the PDMPs in their states and those who are aware also realize that their prescribing practices are being monitored by law enforcement, regulatory, and licensing agencies. Concerns about punitive action for falsely-perceived misprescribing or overprescribing practices may foster apprehensions among prescribers and medical boards to adopt and use PDMPs. This, in itself, may alter prescribing habits in ways that adversely affect patient care.

Online database security and patient confidentiality also are of concern, particularly when PDMP databases expand to include multiple state programs or are consolidated nationally and inadvertently become appealing targets for hackers. The costs of implementing secure PDMPs are significant and, beyond infrastructure and administrative costs, the time and effort required to use PDMPs effectively must be considered.

Research examining outcome effects of PDMPs has been hampered by the variations in individual state’s program designs. As states develop, expand, or retool their PDMPs, the most successful characteristics of existing programs must be identified and applied to enhance the future impact and effectiveness of all PDMPs. Along with that, there must be a common goal of facilitating the legitimate prescription of controlled substances for patient well-being while mitigating the prescription drug abuse epidemic and associated public health problems via appropriate uses of PDMPs and their data.

References

Clark T, Eadie J, Kreiner P, Strickler G. Prescription Drug Monitoring Programs: An Assessment of the Evidence. The Prescription Drug Monitoring Program Center of Excellence; Heller School for Social Policy and Management, Brandeis University; September 20, 2012. A report for the Pew Charitable Trusts.

CMS (Centers for Medicare and Medicaid Services). The Role of a Prescription Drug Monitoring Program in Reducing Prescription Drug Diversion, Misuse, and Abuse. U.S. Department of Health and Human Services; June 2014.

DEA (U.S. Drug Enforcement Administration). Drug Schedules. Undated.

Fleming ML, Chandwani H, Barner JC, et al. Prescribers and pharmacists requests for prescription monitoring program (PMP) data: Does PMP structure matter? J Pain Palliat Care Pharmacother. 2013;27:136-142.

Frenk SM, Porter KS, Paulozzi LJ. Prescription Opioid Analgesic Use Among Adults: United states, 1999–2012. National Center for Health Statistics; NCHS Data Brief. 2015(Feb):189.

Goldberg S. Missouri House Bill Seeks Prescription Drug Monitoring. Business Insurance; February 27, 2015.

Irvine JM, Hallvik SE, Hildebran C, et al. Who uses a prescription drug monitoring program and how? Insights from a statewide survey of Oregon clinicians. J Pain. 2014;15(7):747-755.

NAMDSL (National Alliance for Model State Drug Laws). Compilation of Prescription Monitoring Program Maps. NAMDSL, Charlottesville, VA; 2015.

ONDCP (Office of National Drug Control Policy). Epidemic: responding to America’s prescription drug abuse crisis. Washington, DC: Office of National Drug Control Policy, 2011.

Paulozzi LJ, Jones CM, Mack KA, Rudd RA. Vital Signs: Overdoses of Prescription Opioid Pain Relievers — United states, 1999-2008. MMWR. 2011(Nov 1);60. Available at:

Paulozzi LJ, Kilbourne EM, Desai HA. Prescription Drug Monitoring Programs and Death Rates from Drug Overdose. Pain Med. 2011:12(5):747-754.

Paulozzi LJ, Kilbourne EM, Shah NG, et al. A history of being prescribed controlled substances and risk of drug overdose death. Pain Med. 2012;13:87-95.

Perrone J, Nelson LS. Medication Reconciliation for Controlled Substances — An “Ideal” Prescription-Drug Monitoring Program. N Engl J Med. 2012;366:2341-2343.

Rutkow L, Turner L, Lucas E, et al. Most primary care physicians are aware of prescription drug monitoring programs, but many find the data difficult to access. Health Aff. 2015(Mar);34(3):484-492.

Stukey A. House Budget Committee Cuts State’s IT Budget, Despite Cyber Threats. St. Louis Post Dispatch; March 9, 2015.

Image via David Smart / Shutterstock.

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Opioids for Chronic Pain – An Interview with Dr. Webster, Pain Guru http://brainblogger.com/2015/01/30/opioids-for-chronic-pain-an-interview-with-dr-webster-pain-guru/ http://brainblogger.com/2015/01/30/opioids-for-chronic-pain-an-interview-with-dr-webster-pain-guru/#comments Fri, 30 Jan 2015 12:00:54 +0000 http://brainblogger.com/?p=18330 With chronic pain has come a debate on how to treat it, and some controversy on whether opioid use is effective or not. Lynn R. Webster, M.D., is one the nation’s leading researchers and experts in the field of chronic pain management.

Dr. Webster is the Vice President of Scientific Affairs of PRA Health Sciences and immediate past president of the American Academy of Pain Medicine. Practicing medicine for over three decades, Dr. Webster has authored Avoiding Opioid Abuse While Managing Pain: A Guide for Practitioners. As developer of the Opioid Risk Tool (ORT), he is considered a world authority on how to assess patients for abuse risk with opioid medications, and in trying to help physicians safely treat pain patients while actively working within the industry to develop safer and more effective therapies for chronic pain and addiction. Here, I interview Dr. Webster on prescription opioids for pain.

Lakhan: What are the indications for long-term opioid prescriptions?

Lynn WebsterWebster: Chronic opioid therapy should be reserved for patients who have pain severe enough to warrant a strong analgesic and no other options to effectively relieve the pain. The precise number of people in this category is unclear and is often determined by what a payer is willing to cover, because most alternative treatments are unaffordable to most patients. Chronic opioid therapy can produce side effects, including sexual dysfunction, constipation, hyperalgesia and sleep apnea. Of course exposure to an opioid may also lead to abuse or addiction in a subset of the population with genetic and environmental vulnerabilities.

Lakhan: Are there certain individuals who should NOT be prescribed opioids?

Webster: As with all medications, a risk-benefit analysis is necessary to determine the potential benefit versus harm. People at high risk of harm would be people with an active opioid addiction, significant genetic risks for opioid addiction, abuse of or addiction to other psychoactive drugs, morbid obesity, serious mental health disorders and individuals who are unreliable or who have a history of poor adherence to medical direction. Opioids may be necessary for these people during an acute injury or surgery with appropriate monitoring, but chronic opioid use should be avoided in these populations.

Lakhan: What are the dangers on long-term opioid use?

Webster: “Dangers” implies serious adverse outcomes like addiction or overdose death rather than a common side effect like constipation or sexual dysfunction. The most serious outcome is respiratory depression leading to death. This risk is heightened when combining an opioid with a benzodiazepine or other central nervous system depressant. Respiratory depression can occur if more opioid is circulating when a concomitant medication is added that slows the metabolism of the opioid. Respiratory infections can reduce the pulmonary reserve, increasing the risk of hypoxia and respiratory failure leading to death. That said, even the more common side effects like constipation or sexual dysfunction can cause serious difficulty if not managed.

Conflicting reports have assessed the risk of long-term opioid use in the development of addiction. In general, long-term use of opioids has not been associated with an increased risk of addiction per se. That is because the dose of an opioid and duration of exposure are not necessarily risk factors for opioid addiction. People can be harmed at a low dose or a high dose and with short-term exposure as well as long-term exposure to opioids.

Lakhan: How do patients become addicted to opioids?

Webster: Addiction is a brain disease. Opioid addiction, in contrast to some other types of addiction, has approximately two equal contributions to its expression: 50% genetic and 50% environmental. This means that most people who develop an addiction to an opioid have some genetic vulnerability and an environment that allows or induces the vulnerability to be expressed. There are many single nucleotide polymorphisms (SNPs) that appear to contribute to the genetic vulnerability.

Most people have some of the SNPs, but even those who have a strong genetic vulnerability could be spared an opioid addiction if they live in a protective environment. The environmental factors that contribute to the expression of an addiction are multiple, but stress appears to be one of the more significant contributing factors. Unfortunately, severe pain is one of the most stressful conditions that exists and can trigger the expression of addiction in a genetically vulnerable person. A quick survey of a person’s family can provide some insight into the possible genetic risks to an opioid addiction.

The number of people who are prescribed an opioid and develop addiction is hotly debated. Studies suggest anywhere from 3% to 40% of people prescribed opioids develop an abuse or addiction problem. The reason for such a large range is that the definitions used to define abuse and addiction vary tremendously depending upon who is speaking. There are many biases and prejudices toward people who use opioids for pain. Often, any deviation in expected behavior with using opioids is documented on the spectrum of behaviors associated with addiction.

Lakhan: Where are people sourcing opoids from?

People with opioid addictions can get their supply from a number of different sources. Most opioids obtained for non-medical use are obtained from family or friends who have been prescribed opioids for a legitimate medical purpose. These drugs are either stolen by, sold to, or given to the abuser. Only about 10-15% of opioids used for non-medical purposes are prescribed directly to the abuser.

Lakhan: What measures can be taken to prevent opioid abuse and addiction?

Webster: I think the first step is to understand that as long as any rewarding substance is prescribed, a subset of the population will abuse or become addicted to that substance. This is part of our biology and applies to opioids and many other rewarding drugs used in medicine. However, there are many things we can do to mitigate the harm and reduce the risk of opioid-related aberrant behaviors. In general, prescribers and patients need to understand the risk and be cognizant of the signs of addiction. This requires rudimentary education.

To develop an addiction, a person must be exposed to the drug. Avoiding the use of opioids whenever possible decreases exposure. Decreasing exposure reduces the chance for the disease of addiction to be expressed. Since we cannot know for sure a prioi who is genetically vulnerable, we should only use opioids long term when other alternatives are ineffective or unavailable.

If an opioid is to be prescribed, an assessment for risk factors should be performed followed by close monitoring for aberrant behavior. Addiction can be triggered with the first dose or develop after prolonged exposure. People with a “loaded” genome may express an addiction earlier than those who are spared many of the genetic risks. People who develop an addiction later may have less of a genetic vulnerability, but the stress associated with chronic pain can tip toward destructive use behaviors. Using urine drug testing and prescription drug monitoring is essential to detecting non-adherence, which could be a sign of addiction.

For more on how to prevent opioid addiction see my book, Avoiding Opioid Abuse While Managing Pain

Lakhan: What are the “eight principles” for safer opioid prescribing?

Webster: The most serious adverse outcome from prescribing an opioid is an unintended death from overdose. The eight principles are an evidence-based guide on how to reduce the risk of unintended overdoses if an opioid is prescribed. There are many causes for overdoses, but the eight principles identify the factors that appear to contribute often. If all prescribers understood the eight principles, the number of opioid-related deaths should be reduced.

Lakhan: How do opioid abusers circumvent the deterrent properties of the abuse-deterrent opioid formulations? What is promising in this arena?

Webster: Abuse-deterrent formulations are meant to prevent a manipulation of the formulation that would increase the speed of delivery or amount of the drug to an individual for use in an unintended way. The intention is to decrease the user’s ability to crush and thereby extract the opioid molecule from the formulation, making it more difficult to snort or inject. In an extended-release formulation, the abuse-deterrent properties prevent the conversion to an immediate-release formulation. In other words, they prevent a dose dumping or a bolus of drug to be delivered.

There is debate about whether all extended-release formulations should have abuse-deterrent properties. I personally believe that the FDA should set a deadline for when all ER formulations must meet a minimum standard of abuse-deterrent properties to remain on the market. If this were to occur, the cost of ER formulations would likely increase, but this may be a reasonable trade-off for potentially safer products. Of course, this move will not eliminate all dangers; people can still overdose if they take multiple pills of an abuse-deterrent formulation.

Promising research indicates that some new formulations could be inert if injected, snorted or crushed, meaning the opioid would only be active when taken as directed. If someone takes a higher dose than prescribed, the technology is designed to deactivate the molecule, thereby preventing an overdose. There is even more promising research in development investigating an opioid without rewarding properties or respiratory-depressant effects within the therapeutic range. This would be a major advance in analgesic drug development.

Lakhan: Should prescription drug monitoring, which is currently done on a state level, be nationalized?

Webster: All states but Missouri have prescription drug monitoring programs or plans to develop one. The programs are operated differently from state to state, so criteria for using them will vary. Access to timely information is variable as well. It is important that prescribers have access to interstate data sharing because patients can easily move from one area to another if they intend to deceive the prescriber. In some cases, physicians can access data from prescription monitoring programs in surrounding states by contacting those states, but this takes more time and work than is desirable.

For years there has been a push for a nationally centralized database of prescriptions. However, funding has been lacking to make that happen. States have seen the value in sharing their information with physicians in surrounding areas, so some “exchanges” for states to share their databases have been set up. Ultimately, utilization of the databases is what is important. In most states less than a third of physicians use the databases when prescribing an opioid. This needs to change if we are going to identify most of the “doctor shoppers” and curb the epidemic of drug abuse.

Lakhan: What is the future of opioid research?

Webster: The future of opioid research is exciting. In the not-too-distant future we should be able to replace the current mu agonists with opioids that are not nearly as addictive or associated with the same magnitude of adverse effects. This is a field that is only beginning to produce candidates for further development, but there is real optimism and hope that we will one day have a class of opioid drugs that is closer to the Holy Grail of powerful analgesics without addictive properties than anyone could have dreamed possible.

Lakhan: Any final remarks for our readers?

Webster: The reason we have a problem with opioids is because of the prevalence of severe pain and lack of alternative therapies. Nearly one-third of all Americans have chronic pain. Chronic pain is the most prevalent medical problem today, but we spend less than 1% of the National Institutes of Health research budget on finding safer, more effective therapies. To ultimately solve the opioid problem we will need to find better ways to treat pain. This will require an unprecedented commitment of resources.

We need something like a Manhattan Project. We cannot ignore the millions of Americans whose lives are torn apart by pain or accept the large number of people who are harmed from opioids. After all, each reader of this article is likely to experience chronic pain or be close to someone who does. As of now, chronic pain has the power to alter lives forever. We need a societal commitment to find safer and more effective therapies for mankind’s primal enemy – pain.

Image via Michal Kowalski / Shutterstock.

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Memory Enhancement – Nootropics and Electromagnetic Stimulation http://brainblogger.com/2014/11/18/memory-enhancement-nootropics-and-electromagnetic-stimulation/ http://brainblogger.com/2014/11/18/memory-enhancement-nootropics-and-electromagnetic-stimulation/#comments Tue, 18 Nov 2014 12:00:21 +0000 http://brainblogger.com/?p=17379 Memories naturally degrade with the passing of time. Although the information is initially registered and stored, after a couple of days, weeks, or even years, it is simply erased from storage. The decline of memory function, be it due to normal aging or due to specific medical conditions, greatly affects one’s day-to-day life. Consequently, it is no surprise that the search for ways of improving memory has thousands of years of history.

The vast majority of the retrieval processes (i.e. most of remembering) happens without us even realizing. It is automatic and requires little to no effort or planning. Interestingly, the information that our subconscious identifies as being important or truly relevant tends to be kept in storage for as long as we need it. This can range from a transient need, like the information that you studied for a school exam, to a permanent, primary need, like recognizing your family’s faces and names.

Memory improvement strategies that have been employed throughout the centuries range from simple cognitive exercises and diet modifications to actual pharmaceutical products which influence the molecular pathways at play in memory processes. While many of these strategies have failed to produce any desirable effects, some substances have actually provided with interesting results in different settings.

Nootropics

Nootropics are a group of such substances which show evidence of positively affecting one or more aspects of memory functions. These substances includes not only drugs, but also supplements, “nutraceuticals”, and functional foods.

Notwithstanding the diversity of nootropic compounds, it is possible to summarize their mechanisms of action as follows:

  • increasing circulation to the brain
  • providing precursors to neurotransmitters
  • improving neuronal function
  • preventing oxidative neuronal damage
  • providing energy sources to the brain.

Perhaps the most famous type of nootropics are racetams, which include various structurally similar compounds, such as piracetam and oxiracetam. Little is known about their precise actions at the molecular level, but there are a few clinical studies indicating their potential when prescribed to individuals with specific memory problems.

For instances, in a study of oxiracetam therapy in patients with senile dementia of Alzheimer type (SDAT) and multi-infarct dementia (MID) of mild to moderate degree, significant improvements were observed. Nootropics are also very popular for being available over-the-counter and for having virtually no undesirable side effects.

Dietary supplements, such as vitamins and omega-3, are considered nootropics as well, thanks to their influence on memory, learning, concentration and decision-making.

Other popular classes of nootropics include:

  • stimulants, such as amphetamines and xanthines (e.g. caffeine)
  • dopaminergics, affecting the neurotransmitter dopamine or the components of the nervous system that use dopamine. Attributable effects of dopamine are enhancement of attention, alertness, and antioxidant activity
  • cholinergics, including acetylcholine precursors and cofactors, and acetylcholinesterase inhibitors
  • nutraceuticals, including Bacopa monnieri, isoflavones and Gingko biloba.

One of the nootropic substances that has sparked a lot of scientific curiosity is nicotine. Famously known for its carcinogenic potential and a myriad of other adverse effects on smokers’ health, researchers have long been aware of the ability of nicotine to influence cognitive performance.

For example, difficulty in concentrating is one of the symptoms of nicotine withdrawal, but for a long time this was regarded as a mere relapse factor. Still, as smokers repeatedly reported that one of the reasons they smoke is for the perceived cognitive improvement that smoking gives them, experiments have been attempting, for more than 40 years, to validate these claims and to delineate the conditions under which nicotine might enhance the various domains of human performance.

Biologically, there is a basis for the influence of nicotine in cognitive processes. Nicotine binds to presynaptic nicotinic acetylcholine receptors in the brain, facilitating the release of acetylcholine, dopamine, serotonin, glutamate, and other neurotransmitters known to be involved in these processes.

A meta-analysis of the acute and long-term effects of nicotine on human performance, which looked at the results of a number of studies on the topic, revealed impressive results. Nicotine appears to actually have a significant, positive impact on six domains: fine motor, alerting attention-accuracy, response time (RT), orienting attention-RT, short-term episodic memory-accuracy, and working memory-RT.

Despite these positive effects, it is important to stress that nicotine should not be the nootropic of choice for anyone seeking to improve their memory functions, due to the numerous medical issues it potentiates and the dependence it causes.

As one would expect, like all pharmaceutical products, nootropics have risks as well as benefits. Most of these enhancers are being used with little scientific data to support them, and while some compounds are known to have a good safety profile, others have a risk of unintended side effects that is both high and consequential. It is also important to stress that having an acceptable safety profile is actually dependent on the circumstances under which the product is administered. For example, a drug that restored good cognitive functioning to people with severe dementia but caused serious adverse medical events might be deemed reasonable to prescribe to these patients under the light of its great benefits, but not to healthy individuals who are only seeking enhancement.

Even in terms of practical efficacy, there is much to be said about nootropics. Despite the fact that some studies have shown impressive results, the truth is that there is a lot of heterogeneity (not to mention transiency) in response.

But science is an ever moving field, and recent studies have provided some insight into what might be a revolution in the area of cognitive enhancement. A groundbreaking investigation, published just this year in the renowned journal Science, suggests that there might be a more effective, alternative strategy to stimulate and improve the processes underlying memory formation.

Electromagnetic stimulation

We have known for quite some time now, mainly in the aftermath of very select cases of severe brain injuries which are illuminating by virtue of the impairments they produce, that the hippocampus plays a decisive role in the works of memory. Naturally, the hippocampus does not work on its own, and a team of American researchers took advantage of these complex interactions to test its function.

Using the technique of noninvasive electromagnetic stimulation – never tested in humans before – researchers altered the interactions between the networks of hippocampal and cortical neurons and registered the effects of such modulation on memory. After multiple sessions of electromagnetic stimulation, there was a clear functional increase in the transmission of neural impulses between those neurons. Concomitantly, associate memory performance of the subjects involved improved significantly, persisting about 24 hours after stimulation.

While these results are promising and may constitute a new window into the mechanics of memory formation and memory enhancement, they are also preliminary findings that still leave many questions unanswered. Further investigations, both in healthy individuals and in people with medical issues associated with memory formation, will be necessary for the scientific community to really understand the benefits and risks of electromagnetic stimulation.

References

Greely, H. (2013). Some First Steps Toward Responsible Use of Cognitive-Enhancing Drugs by the Healthy The American Journal of Bioethics, 13 (7), 39-41 DOI: 10.1080/15265161.2013.795823

Gruneberg, M. and Morris, P.E. (1994). Theoretical Aspects of Memory, Volume 2, Routledge.

Heishman SJ, Kleykamp BA, & Singleton EG (2010). Meta-analysis of the acute effects of nicotine and smoking on human performance. Psychopharmacology, 210 (4), 453-69 PMID: 20414766

Rosenbaum RS, Gilboa A, & Moscovitch M (2014). Case studies continue to illuminate the cognitive neuroscience of memory. Annals of the New York Academy of Sciences, 1316, 105-33 PMID: 24871381

Villardita C, Grioli S, Lomeo C, Cattaneo C, & Parini J (1992). Clinical studies with oxiracetam in patients with dementia of Alzheimer type and multi-infarct dementia of mild to moderate degree. Neuropsychobiology, 25 (1), 24-8 PMID: 1603291

Wang JX, Rogers LM, Gross EZ, Ryals AJ, Dokucu ME, Brandstatt KL, Hermiller MS, & Voss JL (2014). Targeted enhancement of cortical-hippocampal brain networks and associative memory. Science (New York, N.Y.), 345 (6200), 1054-7 PMID: 25170153

Image via Africa Studio / Shutterstock.

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Why Are We Still Developing Brain Drugs? http://brainblogger.com/2014/02/11/why-are-we-still-developing-brain-drugs/ http://brainblogger.com/2014/02/11/why-are-we-still-developing-brain-drugs/#comments Tue, 11 Feb 2014 12:00:59 +0000 http://brainblogger.com/?p=15909 The social stigma surrounding the pharmaceutical industry has gotten pretty bad lately. The business of saving lives is now rated positively by only 32% of the public, tucked neatly between oil and banking in consumer confidence polls – down eight places since 1996. Without dwelling too much into the reasons for pharma’s tumbling social status, one can sense an undeniable skepticism surrounding the intentions of the industry, and, most frighteningly, the effectiveness of its drugs.

It would be bitterly unfair to agree with the hardline pharma critics in that drugs simply do not work. After all, antibiotics, HIV retrovirals, chemotherapy and heart disease drugs continue to attest to just the opposite. Survival prognosis for infection, atherosclerosis or even cancer is so great today, that 95% more people reach the age of 80 than they did a century ago.

But with longer-living populations come older-age diseases, and the therapeutic landscape begins to dramatically shift towards diseases like dementia, Alzheimer’s and Parkinson’s, and diseases which have remained poorly treated, such as schizophrenia, bipolar disorder and depression.

Brain Drugs: 50 years later, we still can’t tell you how they work

Note that the common denominator of all “modern” disorders is that they are all diseases of the brain. These ailments bear an economic burden of more than $2 trillion in the US and EU and rake in upwards of $80 billion a year for the pharmaceutical industry.

But nearly all brain medications have come about serendipitously — through observation that certain chemicals improved certain symptoms, rather than through research tailored to the disease. An overwhelming majority of today’s Thorazines, Valiums, Prozacs and Xanaxes are still characterized by widely unknown mechanisms of action 60 years after their market debuts. Even more frighteningly, in recent clinical trial re-runs involving Prozac and Xanax the drugs fared hardly better than placebo.

Is Big Pharma shying away from CNS drugs?

Because the brain remains so poorly understood, Big Pharma are having a bad time developing pharmaceuticals which act upon the central nervous system (CNS). After a number of very loud and painful CNS clinical trial failures in recent years, GSK, AstraZeneca and Novartis have announced total closures of neuroscience divisions globally. Meanwhile Pfizer, Sanofi, Janssen and Merck have begun to significantly downsize CNS operations.

Few remain in the race. And who can blame them, when CNS drug development can cost billions more than any other therapeutic area, yet has a 45% higher chance of failure than drugs targeting other disorders?

Electricity and chemistry rule the brain in equal measure

The complexity of the brain is unrivaled. The intricate network of neuronal connections (the “connectome”), the densely populated molecular environment, and the electric behavior of brain cells, all in addition to the vast individual genomics and metabolomics of any given brain are difficult to ponder even in a single sentence. Unlike the peripheral nervous system, where molecules govern tissues, the central nervous system is just as much ruled by the binary patterns of electrical stimulation as by the neurotransmitter molecules which carry brain messages throughout the body.

And this is the crucial point: chemicals and electricity share a 50:50 responsibility in the brain. A chemical release between two neurons will cause the downstream neuron to “electrically detonate”, sending the message forward, yet electric stimulation of the upstream neuron will succeed to do just the same, albeit without collateral damage to much of the neuronal neighborhood (chemicals spread multridirectionally, whilst electricity does not).

The future is electric

Scientists have known of the effectiveness of neuro-electric brain therapy for decades, and many such systems are already in use today. Deep Transcranial Magnetic Stimulation (Deep TMS), for instance, is a novel, non-invasive, FDA-approved therapy to-date found effective for the treatment of Parkinson’s disease, depression, chronic pain and schizophrenia.

Deep TMS involves magneto-electric activation of regions deep (up to 7cm) within the brain. The stimulation can be applied at virtually any 3D brain coordinates. Thus the more we map the brain, the more useful the treatment becomes.

Pill lovers needn’t get disheartened by the prospect of an electric future, either. Meticulous brain mapping and advances in drug delivery systems could potentially culminate in the birth of a highly lucrative pharmaceutical — the electroceutical — or, rather more bluntly, electricity in a pill.

Electroceuticals may eventually take the form of electro-charged nano-robots we ingest in a pill, which would, with military precision, deliver electric current to any desired brain coordinates. In the era of electroceuticals, chemical “cross-contamination” of tissues and brain areas, along with unwanted side effects and liver toxicity would become a figment of the past.

How close are we to the electric future?

An often surprising fact is that electric therapy is already very widely used in the hospital, even in what would be considered traditional surgical settings. According to Itzhak Fried — Israel’s leading brain surgeon famed for his 22-hour separation surgery on Siamese twins literally sharing a brain — many procedures performed at his department already require an electric element.

In a breakthrough surgery two years ago, Fried’s team implanted tiny electrodes into the brain of an epilepsy patient. The electrodes, much like a tape recorder, listened to and recorded the activity of neurons in an area suspected of generating seizures. The “playback” of the recorded cell activity then gave clues as to the exact location of where the seizures originated. This turned out to be a tiny brain area next to the speech center of the brain which then was safely and successfully excised. Just a millimeter in the wrong direction could have rendered the patient forever unable to speak. All hail electricity.

Obama thinks the future is electric, too

And here is why all the electricity talk is not just cuckoo clairvoyance. Firstly, there is an unmissable brain project frenzy scurrying across the world. Projects like the “Brain Research through Advancing Innovative Neurotechnologies” (BRAIN), initiated by President Obama in the U.S., The Human Brain Project in Europe and Israel Brain Technologies are all aimed at electrically mapping the brain. Some lab projects have gone so far as to make mouse skulls completely transparent or to implant fiber optics into rat brains.

An equally telling development is the injection (or diversion from previous CNS research and development) of funds into electroceutical research done by Big Pharma themselves. In August 2013, GSK unveiled a $50 million bioelectrics venture fund aimed at sponsoring projects “that begin detailing how nerves in the body are related to particular diseases, understand the firing patterns of those nerves, and explore new technologies that will enable us to interface with multiple individual nerve fibres”. As CNS departments are ubiquitously shutting down, other players are left with no choice but to shortly follow suit.

It certainly seems that there is one thing neurosurgeons, neuroscientists and Big Pharma all finally agree on: neuro-chemistry is just so 2004.

Image via Palau / Shutterstock.

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Ambien Zombies, Murder, and Other Disturbing Behavior http://brainblogger.com/2014/01/25/ambien-zombies-murder-and-other-disturbing-behavior-2/ http://brainblogger.com/2014/01/25/ambien-zombies-murder-and-other-disturbing-behavior-2/#comments Sat, 25 Jan 2014 21:12:23 +0000 http://brainblogger.com/?p=15821 Ambien is one of a number of Controlled Schedule 4 agents designed as sedative hypnotics. Like other sedative hypnotics they are usually effective for about two weeks, largely to relieve persisting insomnia. These agents, especially Ambien, are linked to sleep-driving, eating, and even sex.

Sedative hypnotics impact mostly the neurotransmitter, GABA, which is inhibitory in its psychokinetic impact. As with other psychotropics, there is a darker side of the experience, though rare.

On March 29, 2009, Robert Stewart, 45, stormed into the Pinelake Health and Rehab nursing home in Carthage, North Carolina and opened fire, killing eight people and wounding two. Stewart’s apparent target was his estranged wife, who worked as a nurse in the home. She hid in a bathroom and was unharmed.

Stewart was charged with eight counts of first-degree murder; if convicted, he could face the death penalty. Even though there was evidence that Stewart’s actions were premeditated (he allegedly had a target), Stewart’s defense team successfully argued that since he was under the influence of Ambien, a sleep aid, at the time of the shooting, he was not in control of his actions. Instead of the charges sought by the prosecutors, Stewart was convicted on eight counts of second-degree murder. He received 142 – 179 years in prison.

After its approval, Ambien quickly rose to dominance in the sleep aid market. Travelers swore by it to combat jet lag. And women, who suffer more insomnia than men, purchased it in droves. Sanofi, Ambien’s French manufacturer, made $2 billion in sales at its peak. In 2007 the generic version of Ambien was released, Zolpidem, and at less than $2 per pill, it still remains one of the most prescribed drugs in America, outselling popular painkillers like Percocet and prescription strength ibuprofen.

Not all prosecutors will consider the Ambien defense, and its position within established criminal rules is tenuous. It does not really fall under “voluntary intoxication,” in which someone is responsible for his own intoxication and any events that occur as a result of that intoxication.

Image via Corepics VOF / Shutterstock.

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Medical Marijuana – A Magic Bullet for Treating PTSD? http://brainblogger.com/2013/12/07/medical-marijuana-a-magic-bullet-for-treating-ptsd/ http://brainblogger.com/2013/12/07/medical-marijuana-a-magic-bullet-for-treating-ptsd/#comments Sat, 07 Dec 2013 12:00:52 +0000 http://brainblogger.com/?p=15638 A new battle has been waged on Capitol Hill surrounding the much-debated legalization of medical marijuana. As research continues solidifying the positive effects of using cannabis to treat certain clinical symptoms, some research is focusing on the possible effects it may have on treating Post Traumatic Stress Disorder (PTSD).

Since the 1990s, organizations including the Multidisciplinary Association for Psychedelic Studies (MAPS) have attempted to further the development of research protocols surrounding the use of medical marijuana.

It was not until March 2011 that the National Cancer Institute acknowledged the viability of using marijuana in various treatment protocols. MAPS has continued its work to initiate further research and legislation requiring the National Institute on Drug Abuse and the Drug Enforcement Administration to loosen its reins and allow scientific organizations to grow their own cannabis for research purposes.

Viable research continues to evidence the positive impact medical marijuana has had on the lives of those suffering from cancer, glaucoma, multiple sclerosis, and other symptomatic disorders and diseases. It is also widely recognized that some individuals suffering from PTSD already use recreational drugs, including the illegal use of marijuana, to offset symptoms of the disorder. A 2012 case study focusing on a male patient with a variety of PTSD symptoms, severe in nature, revealed some symptoms were significantly reduced “by smoking cannabis resin.”

Further studies have focused on the molecular etiology of PTSD in reference to elevated brain cannabinoid CB1 receptors, along with endocannabinoid signaling systems. Research implies that the increased CB1 receptor-mediated anandamide signaling may play a role in some PTSD symptoms. As such, this research may provide evidence-based opportunities for drug therapies by utilizing a neurobiological model as presented in positron emission tomography studies.

The field of psychiatric medicine recognizes the distinct commonality of specific symptoms associated with PTSD, including severe flashbacks as well as uncontrollable panic attacks. How and why do memories of traumatic events affect the biological nature of the brain with such intensity? Evidence continues to support the theory that the endocannabinoid system holds primary influence over the regulation of memory and emotional behavior. Therefore it is reasoned that the evidence-based research focusing on the affects that THC and medical marijuana have had in other case studies may provide the same results with some symptoms exhibited in patients suffering from the PTSD.

Many social and political barriers continue to plague the future of not only the research of possible treatment options for medical marijuana, but also the legalization and use of its byproducts. It is difficult for society to erase the visual memories of soldiers smoking marijuana depicted through media sources throughout the Vietnam War. Vivid memories of young “hippie-garbed” individuals dancing in the rain while listening to rock-and-roll music and smoking “reefer” often wash over the eyes of many Americans who struggle with the concept of legalizing medical marijuana. Many politicians recognize the possible fall-out that may occur in supporting the legalization of medical marijuana, along with the difficulties involved in management of the sale and use of a perceived controlled substance.

There is no cut and dried solution to overcoming the possible negative implications of complete legalization of a product, such as marijuana, for medical purposes. Many government agencies are cautious of approving less restrictive regulations surrounding prescribed treatments using cannabis.

Yet, the number of individuals suffering from PTSD continues to grow. Many of these people maintain an active search for treatments that provide even the slightest bit of relief from often debilitating symptoms. The addition of military personnel suffering from PTSD is likely to lend greater support for continued research and legalization of medical marijuana as a viable treatment option.

References

Akirav I. (2013). Targeting the endocannaabinoid system to treat haunting traumatic memories. Frontiers in Behavioral Neuroscience 7: 124. PMCID: PMC3776936

Neumeister A, Normandin MD, Pietrzak RH, Piomelli D, Zheng MQ, Gujarro-Anton A, Potenza MN, Bailey CR, Lin SF, Najafzadeh S, Ropchan J, Henry S, Corsi-Travali S, Carson RE, & Huang Y (2013). Elevated brain cannabinoid CB1 receptor availability in post-traumatic stress disorder: a positron emission tomography study. Molecular psychiatry, 18 (9), 1034-40. PMID: 23670490

Passie T, Emrich HM, Karst M, Brandt SD, & Halpern JH (2012). Mitigation of post-traumatic stress symptoms by Cannabis resin: a review of the clinical and neurobiological evidence. Drug testing and analysis, 4 (7-8), 649-59 PMID: 22736575

Image via Yarygin / Shutterstock.

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Are Psychoactive Drugs a Thing of the Past? http://brainblogger.com/2013/11/01/are-psychoactive-drugs-a-thing-of-the-past/ http://brainblogger.com/2013/11/01/are-psychoactive-drugs-a-thing-of-the-past/#comments Fri, 01 Nov 2013 11:00:46 +0000 http://brainblogger.com/?p=15547 Before I actually get started on this article, I would like to immediately answer the question I posed in the title: no. Psychoactive drugs are alive and well. But they might not be for long.

In a recent article titled “Changing brains: why neuroscience is ending the Prozac era”, The Observer reports that large pharmaceutical companies have, for the most part, significantly slowed research on new drugs.

We already have drugs meant to treat pretty much any problem, and it has been a long time since the era of discovering revolutionary new prescription medications on a regular basis. Now, the occasional new drug has the same effects as a previous one, but it provides fewer side effects. Better, yes, but hardly exciting. And because of this, Big Pharma has largely ceased funneling major research dollars into new psychoactive drugs.

But that does not mean they are slowing their research. Pharmaceutical companies are still investing billions of dollars every year in new technologies and methods for treating various diseases.

So what are they working on now? One of the major up-and-coming areas is optogenetics, a term that you’ll likely be hearing about quite a bit over the next several years. Optogenetics is a fascinating neuroscientific field that may soon allow scientists to stimulate specific networks of neurons — a far more fine-grained approach than altering neurotransmitters, as many current psychoactive drugs do.

Optogenetics is based on a very interesting technological method. First, a virus containing the genetic details for light-sensitive proteins is injected into the brain. This virus “infects” a specific population of neurons, making them reactive to a specific wavelength of light (generally in the blue range). Next, tiny fiber optic cables are implanted in the brain, also targeting specific neurons. When a pulse of light is sent through the cable, the neuron is activated or inhibited.

It sounds like science fiction, but it’s not. In fact, they’ve actually been using a similar strategy to treat Parkinson’s disease for a while now, though they use electrodes instead of fiber-optics. Obviously, the electrodes offer significantly less fine control. And over the next decade or so, you can expect to see billions upon billions of dollars spent on research in this area. They have successfully used this technology in mice, but as of yet, there have been no human trials (at least that I am aware of).

But this kind of research brings with it very important philosophical considerations. Many cognitive scientists — including neuroscientists — have an essentially mechanistic view of the brain-mind-body interface; desires, preferences, and actions are determined by chemical and electrical reactions in the brain, all coming together to make us who we are. There is little room for the idea of a soul or, sometimes, even free will in this kind of view.

If this is the case, what happens to us when we fundamentally alter the brain and use that to affect changes in behavior? The change in behavior could be something as significant and positive as inhibiting suicidal behavior or encouraging compassion. What does this mean for us as people? Does this change who we are? If so, should we allow Big Pharma, an industry known for manipulating medicine and academic research to its own purposes, to dictate how this technology works and is applied?

There are a lot of questions surrounding optogenetics, and these are just a few. Share your thoughts in the comments below, and let us know what you think about optogenetics and its potential future uses.

References

Bell, V. (2013). Changing brains: why neuroscience is ending the Prozac era. The Observer, Sunday 22 September.

Image via Bluerain / Shutterstock.

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Amyvid Alzheimer´s Testing – To Be Or Not To Be? http://brainblogger.com/2013/10/14/amyvid-alzheimers-testing-to-be-or-not-to-be/ http://brainblogger.com/2013/10/14/amyvid-alzheimers-testing-to-be-or-not-to-be/#comments Mon, 14 Oct 2013 11:00:06 +0000 http://brainblogger.com/?p=15428 The FDA approved Amyvid for Alzheimer´s testing in April 2012, yet Medicare and Medicaid denied coverage for it last July. The new brain imaging drug helps detect beta-amyloid neuritic plaques in the brain, which are associated with Alzheimer´s disease. In the past, in order to detect these plaques, a biopsy had to be performed. But the test remains controversial — will it be taken up?

There are about five million Americans suffering from Alzheimer´s disease today, and analysts predict that this number could double by 2050. This constitutes a huge market for pharmaceutical companies trying to develop effective drugs against what remains an incurable condition. Amyvid developer Lilly & Co is one of them, and it is currently working on an experimental drug called Solanezumab. While Amyvid testing is now available in numerous locations around the US, coverage would completely change the landscape of Alzheimer´s diagnosis in the country by clearly identifying the markets for solanezumab and other similar drugs. 

Amyvid is a radioactive agent that is injected into patients prior to performing a 30-minute PET scan. The drug directly highlights amyloid neuritic plaques present in the brain. One of the claims Medicare made against Amyvid testing is that it does not directly establish an Alzheimer´s diagnosis, because there are other conditions associated with cognitive impairment that can cause a high density of neuritic plaques in the brain. However, the new brain imaging technique can reliably rule out Alzheimer´s when the plaques are not present. Studies have shown that 20% to 50% of Alzheimer´s patients in America have been misdiagnosed with the disease, and there seems to be a consensus as to the enormous potential of Amyvid testing to reduce this type of misdiagnosis.

A 2011 survey by the Harvard School of Public Health revealed that 85% of respondents would be willing to be tested for Alzheimer´s if they ever exhibited signs of cognitive impairment, such as memory loss. However, as the test is currently not covered by insurance or Medicare, and its cost of $3000 is rather steep, testing is currently limited to those who can afford it.

As Lilly & Co awaits a final decision about coverage in October 2013, Alzheimer´s patients and researchers associations argue that if the new imaging scan were to be covered by health insurance, the data collected from Alzheimer´s patients worldwide would greatly help researchers develop new treatments for this prevalent disease. Medicare representatives, on the other hand, claim that testing can be of no help so long as Alzheimer´s disease remains incurable.

While results for Solanezumab and other Alzheimer´s treatments in development are still far from commercialization, a definite Alzheimer´s diagnosis would be required in order to treat patients with these drugs. Although there is some truth to Medicare´s argument about neuritic plaques proliferating in the brain in patients with conditions other than Alzheimer´s, the fact is that Amyvid has revolutionized Alzheimer´s diagnosis. Amyvid testing may not be perfect, but it is surely a huge step forward in Alzheimer´s research, and it has great potential to aid the development of new treatments for this prevalent disease.

References

Blendon, R. J. et al. Key Findings from a Five-Country Survey of Public Attitudes about Alzheimer’s Disease. Poster presented at AAIC, July 2011.

Gandhi, H.; Hewing, D.; Botkin, C.; Hubble, W.; Turner, J.; Osman, M. (June 2013). Amyvid: A Review and assessment of clinical implementation. Journal of Nuclear Medicine and Molecular Imaging Meeting.

US Food and Drug Administration. Press Release (April 2012): FDA Approves Imaging Drug Amyvid.

American Academy of Neurology (2011, February 24). Alzheimer’s disease may be easily misdiagnosed. ScienceDaily.

World Health Organization fact sheet (February 2007). The top ten causes of death.

Alzheimer’s Association (2011). Alzheimer’s Disease Facts and Figures

Image via SFAM Photo / Shutterstock.

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The Overlooked Role of Universities in the Drug Discovery Process http://brainblogger.com/2013/06/04/the-overlooked-role-of-universities-in-the-drug-discovery-process/ http://brainblogger.com/2013/06/04/the-overlooked-role-of-universities-in-the-drug-discovery-process/#comments Tue, 04 Jun 2013 11:00:35 +0000 http://brainblogger.com/?p=14730 Drug discovery is the process by which novel therapeutic candidates are discovered and ultimately developed into human-grade medications. These candidates may include compounds ranging from modified or unmodified natural products or extracts and small molecules to biologics. Forbes reports that the average cost of drug development for a major pharmaceutical company is between $4 billion and $11 billion, which is a great deal higher than the more commonly reported $1 billion, as it accounts for failure rates. And in fact, failure rates are an important part of the drug discovery process.

Estimates show there is a 1 in 30 chance for the identification of an initial drug target to result in a product launch. Furthermore, reports indicate that it can take more than 12 years from the initial molecular target discovery to progress through preclinical studies and ultimately to US Food and Drug Administration (FDA) regulated human clinical trials. Costs accrue throughout this lengthy process for various items including personnel, research materials, collaborations, patent filings, clinical trials, and regulatory applications.

Many people tend to associate the development of drugs with the large pharmaceutical companies that sell them including Johnson & Johnson, Pfizer, and Merck & Co., to name a few. However, in most cases the critical initial discovery role of the smaller organization is overlooked.

A recent agreement between Eisai, one of the largest pharmaceutical companies based on revenue, and Johns Hopkins University Brain Science Institute (JHUBSi) represents the current push in university-private sector collaboration for drug discovery. In this arrangement, JHUBSi is tasked with taking the lead in identifying novel compounds to potentially treat neurological disorders and Eisai will have the option to further develop and commercialize these leads through a licensing agreement. The university stands to benefit financially from the potential receipt of up front payments, royalties, and negotiated milestone payments once a licensing agreement is reached.

Interestingly, of the 252 new drugs approved by the FDA from 1998 to 2007, approximately 24% originated from University or biotechnology company research and were subsequently transferred to a pharmaceutical or biotechnology company to further the research and develop a product that could be marketed. These data verify the fundamental role for university research and suggest that technology transfer is an essential component to the development of therapeutics.

In fact, university research has resulted, in part, in the development of many well-known therapeutics including insulin as a treatment for diabetes, various tuberculosis antibiotics, Allegra, and multiple chemotherapeutic agents such as Cisplatin. University research has contributed to the development of other areas of technology transfer and product commercialization, including in the development of various vaccines, medical devices such as the ultrasound and the pacemaker, and everyday items such as the seat belt and Google.

While the role of large pharmaceutical companies is integral in the development of novel drugs, it is important to also note that universities and biotechnology companies play an important, and often overlooked role as well. Industry-academia collaborations may represent the future of drug development and it is predicted that in years to come, we will see more than 24% of novel drugs originating from technologies developed by universities and biotechnology companies.

References

Bains, W., Drug Discovery World, (Fall 2004). Failure rates in drug discovery and development: will we ever get any better?

Herper, M., Forbes, (October 2012). The Truly Staggering Cost Of Inventing New Drugs.

Kneller, R. (2010). The importance of new companies for drug discovery: origins of a decade of new drugs Nature Reviews Drug Discovery, 9 (11), 867-882 DOI: 10.1038/nrd3251

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Promoting Remyelination in Multiple Sclerosis – an Interview on rHIgM22 http://brainblogger.com/2013/06/02/promoting-remyelination-in-multiple-sclerosis-an-interview-on-rhigm22/ http://brainblogger.com/2013/06/02/promoting-remyelination-in-multiple-sclerosis-an-interview-on-rhigm22/#comments Sun, 02 Jun 2013 11:00:39 +0000 http://brainblogger.com/?p=14968 The Mayo Clinic and Acorda recently enrolled the first patient in their phase 1 clinical trial of a remyelinating antibody that may potentially reverse the damage caused by multiple sclerosis. I recently interviewed Anthony O. Caggiano, MD, PhD, Vice President of Research & Development at Acorda since February 2009. Since joining Acorda in 2001, he has served in various roles in preclinical science and research and development, directing basic research and product development efforts, coordinating external research programs with academic and commercial partners, and collaborating in business development activities.

SL: What is the current state of knowledge on the pathogenesis of multiple sclerosis?

AC: In multiple sclerosis (MS), a person’s own immune system destroys myelin, a substance that insulates nerves and facilitates conduction of nerve impulses that control neurological function such as movement and vision. Without myelin, the neurons in the brain, spinal cord or central nervous system communicate less effectively.

Progressive damage to myelin causes functional impairment in people with MS. Currently there are no approved therapies that stimulate the repair or regrowth of myelin once it has been damaged. Acorda is now studying an antibody called rHIgM22 which has been shown to potentially stimulate remyelination and improve the function of neurons.

SL: How do our current lines of treatment for MS affect the disease course?

AC: There are two main categories of MS treatments. The first involves the use of disease-modifying agents (interferon beta-1a, interferon beta-1b, glatiramer acetate, natalizumab and fingolimod), which have been found to help with relapse management, decrease MRI activity and potentially delay disability. The second category is treatments that target specific symptoms of MS, such as AMPYRA (dalfampridine), which is indicated to improve walking in people with MS.

Disease-modifying agents are an important part of managing MS, and evidence suggests that they can be combined with other treatments to target different aspects of immune response or therapeutic targets such as inflammation or neuroprotection.

SL: How was rHIgM22 identified and what does it target?

AC: rHIgM22 was identified by a team at the Mayo Clinic led by Moses Rodriguez, MD, a neurologist specializing in MS. It is a monoclonal antibody that interested Dr. Rodriguez because of its ability to enhance the repair of the central nervous system (CNS). The cells that make myelin, called oligodendrocytes, can initially repair myelin, but as MS progresses, there is little spontaneous repair. Dr. Rodriguez’s team identified antibodies in mice that promote remyelination and then identified similar antibodies in humans. rHIgM22 is the lead of these human derived antibodies and has been shown to bind CNS myelin, stimulate oligodendrocytes and promote remyelination in animal models.

rHIgM22 is currently being studied in a double-blind, randomized, single ascending dose Phase 1 clinical trial in people with MS. This study will measure the safety and tolerability of rHIgM22 as well as any changes in the MRI results of treated patients. Evaluations of changes in MS symptoms, such as walking ability, will also be conducted.

SL: What is in on the brinks of translating from the benchside to the bedside in MS?

AC: Many researchers are continuing to develop disease modifying therapies and symptom management medications in MS, but research related to remyelination is positioned as a major focus in research in the years ahead. Such therapies have the potential to represent a novel and significant advance in MS care.

References

Rodriguez M, Warrington AE, & Pease LR (2009). Invited article: human natural autoantibodies in the treatment of neurologic disease. Neurology, 72 (14), 1269-76 PMID: 19349608

Watzlawik J, Holicky E, Edberg DD, Marks DL, Warrington AE, Wright BR, Pagano RE, & Rodriguez M (2010). Human remyelination promoting antibody inhibits apoptotic signaling and differentiation through Lyn kinase in primary rat oligodendrocytes. Glia, 58 (15), 1782-93 PMID: 20645409

Watzlawik JO, Warrington AE, & Rodriguez M (2013). PDGF is required for remyelination-promoting IgM stimulation of oligodendrocyte progenitor cell proliferation. PloS one, 8 (2) PMID: 23383310

Image via martan / Shutterstock.

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Treating Acute Ischemic Stroke – The Race Is On http://brainblogger.com/2013/06/01/treating-acute-ischemic-stroke-the-race-is-on/ http://brainblogger.com/2013/06/01/treating-acute-ischemic-stroke-the-race-is-on/#comments Sat, 01 Jun 2013 11:00:27 +0000 http://brainblogger.com/?p=14338 As the fourth leading cause of death in the U.S. and a leading cause of permanent disability, stroke has an incredible impact at both the individual and economic level. According to the CDC, an American dies every 4 minutes as the result of an acute stroke. With 87% of these strokes being ischemic in nature, rapid assessment and diagnosis of patients with stroke symptoms is required in order to ensure that eligible patients receive fibrinolytic therapy within the recommended time frame (around 3 hours). Research has shown that although healthcare providers in the inpatient setting are greatly reducing delays to treatment, there is still much work to be done in the pre-hospital setting to ensure that valuable time is not lost.

Researchers in Finland demonstrated that over a two year period hospitals were able to reduce average delays of treatment initiation by approximately 50%. Similar restructuring has occurred within the U.S. as hospitals started to be designated as ‘stroke centers’ by the Joint Commission — the nation’s leading hospital accrediting body. To achieve stroke center accreditation, hospitals have to meet a set of criteria demonstrating they effectively manage acute stroke based on current medical research. These criteria include having an on call neurologist, the availability of CT imaging, and designated critical care units for stroke patients. These criterions have ensured that more patients are able to receive life-saving thrombolytic therapy. Despite these remarkable efforts, however, there is much yet to be done to improve outcomes for patients with acute stroke.

Kwan and his team of researchers analyzed 54 studies that sought to identify barriers to patients receiving thrombolytic therapy. They found that only 37% of patients in the UK arrived in the hospital within three hours of symptom onset. This would seem to suggest that substantial delays occur in the pre-hospital setting. Such delays were the number one reason cited why patients did not receive rt-PA, with 22-94% of patients being rendered ineligible due to lost time. The number one pre-hospital delay cited in the literature was patient or family delay in requesting medical help due to a lack of knowledge on signs of stroke. The logical next step would seem to be the development of advertisement campaigns with the goal of educating the public on the signs and symptoms of stroke.

Unfortunately, such attempts at education have thus far not been remarkably fruitful. Lecouturier found that education programs directed towards a public audience have been shown to increase the awareness of the signs and symptoms of a stroke, but seem to have had little to no impact on behaviors. One study showed that even after education, contacting emergency medical services (EMS) did not occur until almost 2 hours after symptom onset. This extreme delay makes it unlikely that patients will arrive to an inpatient setting within a 3 hour window to begin thrombolytic therapy.

Earlier research by Moser suggests that perhaps educational opportunities are misdirected. Specific educational programs directed at persons of lower socioeconomic status or those of black or Hispanic descent have not been greatly documented while these groups have among the highest delays in seeking treatment for stroke. Likewise, patients with a prior diagnosis of hypertension are at a significant risk for stroke and may benefit from more directed education.

Additionally, Moser’s findings suggest that the best place to improve education may be within the professional realm. To reduce pre-hospital delay to treatment, the researchers suggest that EMS dispatch teams should rearrange protocols to give a higher priority in dispatching units to suspected stroke victims; some research has suggested that more rural areas do not attribute the same triage priority to stroke as they do to acute coronary syndrome.

Another group that may benefit from further education is paramedics. A nationwide survey showed that paramedics were competent on knowledge of stroke symptoms but were unaware of the treatment window for fibrinolysis. Education and protocol reform may help to ensure more rapid diagnosis and transport of stroke victims by EMS.

Medical literature has made it abundantly clear that the number one factor in reducing morbidity and mortality for patients with acute ischemic stroke is final diagnosis and disposition to the stroke unit in under three hours. This rapid sequence ensures that those patients eligible for rt-PA can receive it within the therapeutic time frame. Much research and interventions must still take place if this is to be achieved for the greatest possible number of patients. Population specific education, restructuring of EMS protocols, and continuing education of paramedics may be the first major steps towards successful mitigation of the devastating effects of stroke.

References

Kwan J, Hand P, & Sandercock P (2004). A systematic review of barriers to delivery of thrombolysis for acute stroke. Age and ageing, 33 (2), 116-21 PMID: 14960425

Lecouturier J, Rodgers H, Murtagh MJ, White M, Ford GA, & Thomson RG (2010). Systematic review of mass media interventions designed to improve public recognition of stroke symptoms, emergency response and early treatment. BMC public health, 10 PMID: 21182777

Moser DK, Kimble LP, Alberts MJ, Alonzo A, Croft JB, Dracup K, Evenson KR, Go AS, Hand MM, Kothari RU, Mensah GA, Morris DL, Pancioli AM, Riegel B, & Zerwic JJ (2006). Reducing delay in seeking treatment by patients with acute coronary syndrome and stroke: a scientific statement from the American Heart Association Council on cardiovascular nursing and stroke council. Circulation, 114 (2), 168-82 PMID: 16801458

Puolakka T, Väyrynen T, Häppölä O, Soinne L, Kuisma M, & Lindsberg PJ (2010). Sequential analysis of pretreatment delays in stroke thrombolysis. Academic emergency medicine : official journal of the Society for Academic Emergency Medicine, 17 (9), 965-9 PMID: 20836777

Image via Rihardzz / Shutterstock.

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Psychopharmacological Drug Development in A Depression? http://brainblogger.com/2013/05/14/psychopharmacological-drug-development-in-a-depression/ http://brainblogger.com/2013/05/14/psychopharmacological-drug-development-in-a-depression/#comments Tue, 14 May 2013 11:00:47 +0000 http://brainblogger.com/?p=14601 “If you are a mouse and suffer from depression, we can cure you!”.

You may have heard similar statements for other diseases, which is a general reflection on the current state of drug development. After spending billions of dollars in pharmaceutical drug development only about 30 new drugs reached the market last year — a number that is higher than in previous years, but still. It’s not good news for patients, especially those suffering from mental illness, for whom the outlook on new drugs is even bleaker. Why the dry pipeline?

Mental diseases are difficult to treat. Drug development in particular is hampered by the following key obstacles:

Unknown causes

Firstly, the cause of most mental diseases at the molecular level is often unknown, making it difficult to tackle a target with a pill. In oncology for example, molecular targets have been identified and in certain cases, a single point mutation in a gene has been identified as the cause for the disease. Subsequently, specific drugs have been developed against that target and patients are screened for specific mutations to determine whether they are suitable candidates for that treatment or not.

Unfortunately this is not the case for many mental disorders. The first generation of approved antidepressants was found through serendipity by observant physicians. After that, a few more classes of antidepressants emerged, mostly reducing the undesirable side effects associated with first generation drugs. Nevertheless, the exact mode of action of most antidepressants in the human brain remains unclear.

Variable drug response

Secondly, as with any drug, not all patients respond equally to a particular treatment. In a 9-year study investigating the quality of care in patients with depression the percentage of non-responders was around 25%. More pessimistic estimates put the number as high as 50%. It is not uncommon for patients with depression to try several antidepressants before they find one that works or before they give up on it.

Within the last five years, a debate on the efficacy of antidepressants has emerged. One study accused the publishing bias towards positive trial data of skewing our views on the therapeutic effectiveness of antidepressants. The researchers looked back at 74 studies with 12,564 registered patients that were reported to the FDA. 38 of these studies were considered to be positive by the FDA. All of the positive studies were published, except one. In contrast, only a third of the studies, which were considered negative or ambiguous, were published. Even then negative data were misrepresented, according to the investigators.

Similar conclusions were drawn in a recent study on antipsychotic drugs. This is not to say that antidepressants or antipsychotic drugs don’t work. We may have just overestimated their effectiveness. The debate highlights the difficulty in finding effective pills with our current medical knowledge and empirical approach.

The difficulty of using animal models

Thirdly, in the pre-clinical stage of drug development, animal models are used to screen for toxicity and efficacy. The crux here is in the word “model”. No animal model is perfect. There is an inherent risk for failure when the drugs are finally administered to humans. These failures are dramatic for patients, and costly for the industry. Recent failures of late-stage drugs developed against schizophrenia, pain and Alzheimer’s disease are testimony to that statement.

Then what’s the solution?

Changes to the drug development paradigm seem to be required. A better understanding of pathological mechanisms and therapeutic effects is needed. Most notably, “personalized approaches that use biomarkers, including neurophysiological, neuroimaging, genetic, and neuropsychological techniques, are required to guide treatment”. Broadening the scope of clinical trials is already commonplace for drugs in other disease areas. Although costly, such an extension is feasible and of merit.

Also, the Brain Activity Map program seems to have traction. The project is a coordinated effort of government agencies, universities, and the private sector to create a comprehensive understanding of the brain’s function. Similar to the Human Genome Project, the approach would start with the investigation of simple organisms leading up to the human species. Obviously, the challenges are enormous, but one of the outcomes of that project could be a better understanding of the normal brain function leading to better ways of treat mental disease.

Promising technologies such as induced pluripotent stem cells, in vitro neuronal circuits, and connectomics will be discussed in an upcoming workshop at Institute of Medicine of the National Academy of Sciences. The title of this workshop is “Accelerating Therapeutic Development for Nervous System Disorders towards First-in-Human Trials”. Not only scientific tools but also regulatory and ethical issues are key topics of the meeting agenda. The problems have been recognized. The search for solutions is on. There is light at the end of the tunnel.

References

Alivisatos AP, Chun M, Church GM, Deisseroth K, Donoghue JP, Greenspan RJ, McEuen PL, Roukes ML, Sejnowski TJ, Weiss PS, & Yuste R (2013). The Brain Activity Map. Science (New York, N.Y.) PMID: 23470729

Fullerton CA, Busch AB, Normand SL, McGuire TG, & Epstein AM (2011). Ten-year trends in quality of care and spending for depression: 1996 through 2005. Archives of general psychiatry, 68 (12), 1218-26 PMID: 22147841

Mathew, S., & Charney, D. (2009). Publication Bias and the Efficacy of Antidepressants American Journal of Psychiatry, 166 (2), 140-145 DOI: 10.1176/appi.ajp.2008.08071102

Turner EH, Knoepflmacher D, & Shapley L (2012). Publication bias in antipsychotic trials: an analysis of efficacy comparing the published literature to the US Food and Drug Administration database. PLoS medicine, 9 (3) PMID: 22448149

Turner EH, Matthews AM, Linardatos E, Tell RA, & Rosenthal R (2008). Selective publication of antidepressant trials and its influence on apparent efficacy. The New England journal of medicine, 358 (3), 252-60 PMID: 18199864

Image via avarand / Shutterstock.

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On the Path to Preventing Alzheimer’s Disease http://brainblogger.com/2013/03/23/on-the-path-to-preventing-alzheimers-disease/ http://brainblogger.com/2013/03/23/on-the-path-to-preventing-alzheimers-disease/#comments Sat, 23 Mar 2013 11:00:35 +0000 http://brainblogger.com/?p=14256 Nearly 30 million people worldwide are affected by the Alzheimer’s disease (AD) and the most recent estimates indicate that this number will quadruple within the next 40 years. The concern increases as AD is the leading cause of dementia, and, so far, there is no effective treatment to slow the progression or delay the onset of this malady.

It is known that AD is a disease of protein aggregation mainly involving accumulation of beta-amyloid (Abeta) in the brain, a peptide of 36-43 amino acids, mostly in the form of tau fibrils and amyloid plaques.

Currently, 10 genes have been identified as influencers of the AD’s risk. The autosomal dominant mutations in the precursor protein (APP) and presenilin (PSEN) genes encoding amyloid precursor protein and the presenilin proteins are accepted as the causes of the hereditary forms of AD.

Most of these mutations increase total Abeta or Abeta42 production, leading to an increased amyloid plaque formation — a pathological hallmark of AD. Thus, Abeta lowering has become a vital therapeutic goal, with various paths within antibodies against Abeta (anti-Abeta) being tested. Over the past few years, the research has been mostly developed after the detection of disease, pursuing a means of lowering the production of the Abeta by inhibiting the enzymes responsible for the generation of this peptide, preventing the formation of Abeta aggregates, and increasing the rate of Abeta clearance from the brain. Presently, several different anti-Abeta therapies are in clinical trials worldwide. Although some modest reductions in plaque burden have been achieved, no obvious clinical benefit or arrest in the progression of cognitive decline was further confirmed.

Given this lack of success, the Alzheimer’s research community has moved toward a consensus that diagnosing and treating the disease before overt symptoms may be more advantageous to slow the disease’s pathogenic process. Among this novel approach, has been particularly suggested that pre-symptomatic individuals with deterministic mutations in APP, PSEN1, or PSEN2 could undergo treatment with an anti-Abeta agent before the expected age of onset of frank symptoms. Individuals with brain amyloid deposits (detected by positron emission tomography) exceeding normal thresholds, as well as low cerebrospinal fluid Abeta 42 levels, may respond to an anti-Abeta treatment.

The Dominantly Inherited Alzheimer Network (DIAN) investigators showed that the changes in cerebrospinal fluid levels of Abeta42 that accompany Abeta deposition are possible to be detected nearly 25 years before the symptom’s onset. This suggests that, in persons with mutations for dominantly inherited AD, the primary prevention with anti-Abeta agents might need to begin, at least, 25 years before the earliest signs.

Following this lead, a prevention trial with an anti-Abeta in around 300 presymptomatic individuals with presenilin mutations has been approved to be carried out by an academic consortium sponsored in part by the United States National Institutes of Health (NIH) and a biotechnology company. Still in the domain of the autosomal dominant AD, another secondary prevention trial has been proposed to the NIH by the Dominantly Inherited Alzheimer Network, the Alzheimer’s Association and some pharmaceutical companies.

Nevertheless, beyond these prevention trials in presymptomatic participants with rare, dominantly inherited AD, there is an intention to initiate similar studies in presymptomatic persons with common, late-onset (so-called sporadic) AD. Hereupon, another secondary prevention trial of an anti-Abeta in sporadic AD subjects (the A4 trial) will be carried out by a consortium led by the Alzheimer’s Disease Cooperative Study group funded by NIH. They recently announced the selection of Eli Lilly’s monoclonal antibody solanezumab as the first therapeutic drug to be evaluated.

Will this novel approach help overcoming this terrible disease? We shall see.

References

Bateman RJ, Aisen PS, De Strooper B, Fox NC, Lemere CA, Ringman JM, Salloway S, Sperling RA, Windisch M, & Xiong C (2011). Autosomal-dominant Alzheimer’s disease: a review and proposal for the prevention of Alzheimer’s disease. Alzheimer’s research & therapy, 3 (1) PMID: 21211070

Gandy S (2012). Lifelong management of amyloid-beta metabolism to prevent Alzheimer’s disease. The New England journal of medicine, 367 (9), 864-6 PMID: 22931321

Golde TE, Schneider LS, & Koo EH (2011). Anti-a? therapeutics in Alzheimer’s disease: the need for a paradigm shift. Neuron, 69 (2), 203-13 PMID: 21262461

Holtzman DM, Morris JC, & Goate AM (2011). Alzheimer’s disease: the challenge of the second century. Science translational medicine, 3 (77) PMID: 21471435

Holtzman DM, Goate A, Kelly J, & Sperling R (2011). Mapping the road forward in Alzheimer’s disease. Science translational medicine, 3 (114) PMID: 22190237

NIH Fogarty International Center. First-ever Alzheimer’s prevention trial to take place in Colombia. 2012.

Selkoe DJ (2012). Preventing Alzheimer’s disease. Science (New York, N.Y.), 337 (6101), 1488-92 PMID: 22997326

Image via Sebastian Kaulitzki / Shutterstock.

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