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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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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Pharmacological options to help recovery from stroke as well as physical brain injury are limited. Patients are often left paralyzed after a stroke. One approach, to get around the fact that only a small number of post hoc curative options are available in this area of medicine, has been to pre-condition the physiological system to withstand trauma. Several plant-derived substances as well as synthetic ones have been tried out to help the brain adjust to adverse environmental conditions (very cold and very hot) as well as to physiological insults like deprivation of oxygen. These “adaptogens” or molecules that help to adapt have been known as nootropic molecules or simply nootropics. Some nootropics like an extract from Bacopa monnieri also help to enhance memory and cognitive functions even in the absence of brain trauma.

The list of known nootropics is growing and the latest molecules to join the club are Cerebrolysin and GYKI-52466. Cerebrolysin is a mixture of neuropeptides that promotes growth of neurons, thereby diminishing the impact of environmental insults. GYKI-52466 is an anti-convulsant drug.

Exposure to very hot conditions has been shown to induce neurological and behavioral changes in experimental animal models. Rats exposed to whole body hyperthermia (4 hours at ambient temperature of 38C displayed behavioral changes and impaired motor functions. Neurotransmitters like glutamate and aspartate were elevated in these rats whereas the levels of glycine and GABA had reduced under these conditions. Anatomical studies also revealed damage to neurons as well as glial cells and a breakdown of the blood-brain barrier. Usually, the blood-brain barrier in cranial blood vessels is stringently permeable to very few substances. A breakdown in the blood-brain barrier signifies greater chances of permeation of blood borne toxins and viruses into neural tissue.

These effects of exposure of the whole body to extremely hot conditions can be reversed by administration of Cerebrolysin, if it is given within one hour of exposure. In experiments carried out by Drs. Sharma, Sharma, Mossler and Muresanu, damage to brain cells could be prevented if the animals were given Cerebrolysin 30 minutes prior to exposure to high heat or within one hour post exposure. Delayed administration of Cerebrolysin did not help recovery from brain damage resulting from these conditions.

These findings are important in light of the fact that exposure of people to such temperatures is possible. Consider the daytime temperatures in places like hot deserts where temperatures of 49 degrees Celsius (Thar Desert, India), 40C (Great Victoria Desert, Australia), 58C (Sahara Desert, Libya), 50C (Gobi Desert, Mongolia) have been recorded in summer. The Afar depression in Ethiopia, which incidentally is inhabited by humans, has daytime temperatures of 48C in summer with the highest recorded temperature being 64.4C. In steel mills, in some of the hottest sections, workers may be exposed to ambient temperature of 56C.

Nootropics like Cerebrolysin may help to recover from the damage caused by whole body hyperthermia in these situations, particularly in the manufacturing industry. People from endemic cultures of hot desert regions have presumably adapted to living under these conditions and the effects of administration of nootropics to such people is probably a whole new area of investigation. However, if occasional exposure is indicated for people who otherwise would remain in a comfortable ambiance, then treatment with cerebrolysin would perhaps help to reduce the damage caused by whole body hyperthermia.

GYKI-52466 is an antagonist of the glutamate receptor which is primarily used to treat convulsions and acts as a skeletal muscle relaxant. In a recent paper, Drs. Nayak and Kerr have described experiments conducted on rats where administration of low doses of GYKI-52466 helped to reduce the extent of brain damage resulting from an induced stroke. Loss of brain tissue was lesser in animals pre-treated with GYKI-52466 than that seen in control animals which were not given the drug. Behavioral traits were also less affected in rats treated with GYKI-52466 as compared to animals not exposed to the drug.

Research into both these nootropics is in progress and accumulation of more data is certainly warranted. However, there seems to be evidence that favors prophylactic prescription of such drugs to people who are at greater risk of suffering from hyperthermia or stroke.

References

Masliah E, & Díez-Tejedor E (2012). The pharmacology of neurotrophic treatment with Cerebrolysin: brain protection and repair to counteract pathologies of acute and chronic neurological disorders. Drugs of today (Barcelona, Spain : 1998), 48 Suppl A, 3-24 PMID: 22514792

Nayak PK, & Kerr DS (2012). Low-dose GYKI-52466: Prophylactic preconditioning confers long-term neuroprotection and functional recovery following hypoxic-ischaemic brain injury. Neuroscience PMID: 23246617

Sharma HS, Sharma A, Mössler H, & Muresanu DF (2012). Neuroprotective effects of cerebrolysin, a combination of different active fragments of neurotrophic factors and peptides on the whole body hyperthermia-induced neurotoxicity: modulatory roles of co-morbidity factors and nanoparticle intoxication. International review of neurobiology, 102, 249-76 PMID: 22748833

Image via VladisChern / Shutterstock.

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Although news bulletins focused on his legal efforts to be permitted to commit assisted suicide, Nicklinson’s tragic disability — seven years of what his wife called a “living nightmare” — also bears upon stroke awareness and the availability of the emergency treatment that too few people know about or receive — the clot-busting drug, tissue plasminogen activator (tPA). Locked-in syndrome has something to say to everyone at risk for stroke. So does tPA.

In 2005, Stephan Mayer MD, together with colleagues at the Columbia University College of Physicians and Surgeons, reported on a unique case of heroic treatment to prevent locked-in syndrome in a stroke victim.

tPA and a Case of Locked-In Syndrome

Mayer’s patient, the pastor of a well-known church in Manhattan, suffered from a “stuttering course” of brainstem ischemia that lasted days. He first went to the emergency room some 10 hours after he began to experience facial numbness and right-side weakness. A history of neck pain suggested a vertebral dissection, or tear in the lining of the main artery that supplies blood to the brain. Transferred to the neurointensive care unit (Neuro-ICU), his symptoms were varied and ominous. First the left arm would become weak, afterwards the right; then one side of his face would become paralyzed. To insure he could breathe, he had to be intubated.

“We realized he was in the early stages of an evolving basilar artery syndrome,” recalls Mayer, “the final result of which, in the worst case, you infarct your whole pons and become locked-in.” Patients who end up in a complete locked-in state remain conscious but are completely paralyzed save for the vertical gaze. The condition is widely recognized as a fate worse than death.

Over two days Mayer presided over the patient’s disrupted “low flow state” in the occluded basilar artery of his brainstem. He administered heparin, an anticoagulant, and artificially raised his blood pressure but neither measure had any appreciable effect. An angiogram showed blood seeping into the basilar artery and small fragments of clotted blood. Occlusion of both vertebral arteries shut down the possibility of a mechanical solution such as angioplasty.

Suddenly, on the second day in the ICU, the patient became totally quadriplegic. Efforts to reverse it failed. Mayer went to the patient’s wife.

“I said, ‘We’re losing him. He’s going to develop this locked-in syndrome. We’ve got to try something.” He added: “The one thing I can think of doing is giving tPA.”

Were circumstances less than extraordinary, that meant breaking all the rules. “Forget the three hour [time window for giving tPA]; this ischemic process had been going on for two days.” Mayer was purposely keeping blood pressure high, at around 220 systolic, another contraindication. So was the anticoagulant he administered. Finally, a diagnosis of arterial dissection was not an approved use for tPA, which raised genuine concern for catastrophic hemorrhage.

“Look,” Mayer told the patient’s wife. “It’s high risk. But I don’t know what else to do. It’s a total roll of the dice and probably won’t work. But otherwise you’re going to just stand around and watch this guy become locked-in.”

With her approval, he administered tPA.

“I’ll be damned,” Mayer recalls. “About an hour later, he started to improve. He started to move both sides.” Sensation and movement fully returned. Within days he would walk out of the hospital.

“From a biological point of view, he was thrombosing [developing blood clots],” recalls Mayer. “By giving the tPA, it was just enough to open everything up.”

Mayer and his colleagues went on to write up the case, published in Neurocritical Care. They hoped to illustrate and underscore that, “Sometimes, when you’re facing certain doom, you can roll the dice, break the rules, as long as you have eyes wide open about the risks and benefits.”

The contrast in outcomes between Mayer’s case and that of Tony Nicklinson also points to the importance of stroke awareness and knowing about the use of tPA to treat stroke, now recommended within 3-4.5 hours of symptom onset.

“I’m already dead – don’t mourn for me,” were Tony Nicklinson’s last words before he died after seven years of unmitigated suffering. When Stephan Mayer’s patient, who was about 60 years old at the time of his stroke, left the hospital after beating incipient locked-in syndrome, he took up a new email address. Its username: notdeadyet.

References

Janjua N, Wartenberg KE, Meyers PM, & Mayer SA (2005). Reversal of locked-in syndrome with anticoagulation, induced hypertension, and intravenous t-PA. Neurocritical care, 2 (3), 296-9 PMID: 16159079

Zivin JA, Simmons J. tPA for stroke: the story of a controversial drug. New York: Oxford University Press; 2011.

Image via olly / Shutterstock.

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Although appropriate for almost 9 in 10 strokes — those that are ischemic, or due to blood clots — only a small fraction of potentially eligible patients, not more than about 4-8%, receive tPA.  Consider this:

It’s safe and effective…so few patients get it. As a drug for a major and life-threatening disorder, tPA was shown to be effective with a 11-13% absolute benefit (cancer drugs that provide a 2% absolute benefit are routinely approved).

It’s a one-time drug…yet so became the target of a muckraking campaign. Unlike drugs such as Vioxx, which were prescribed for daily use to masses of patients only to show unanticipated adverse effects, tPA for stroke is usually given once, intravenously. But its approval nevertheless incited journalists to campaign against it as dangerous and ineffective. Such charges lingered for years after post-approval studies confirmed the original results of randomized trials, which were supported not by the drug industry but by a branch of the National Institutes of Health.

Neurologists never had a drug to treat stroke before…so they were reluctant to use this one. Many neurologists might have been expected to be early adopters but initially only a few were enthusiastic. Neurologists were not accustomed to treating strokes as the emergencies they demonstrably are, and  many remained skeptical for years. Most have been by now been convinced, but tPA has been the most controversial drug ever used in neurology.

Emergency physicians were accustomed to using tPA… yet with stroke they didn’t want to. When the drug was first FDA-approved, ER doctors often used it for heart attack (most commonly due to clots, like stroke). But when it came to a brain disease, many (despite their reputation as cowboys in the ER) were fearful and concerned about their diagnostic acumen. A few created and many bought into the efforts to impugn tPA as overhyped by its manufacturer, Genentech, presumably in cahoots with the American Heart Association.

Stroke victims don’t know about tPA. Although controversies over the drug are now largely past, their legacy has been persistent lack of stroke awareness among the general public, with only a small minority of potential patients and their families or colleagues knowing the symptoms of stroke,  the importance of time-to-treatment, or the simple instruction (Call 911). So it is that, although FDA-approved for stroke since 1996, tPA today reaches only a fraction of nearly 800,000 new stroke victims annually in the United States. About 50% are potentially eligible.

References

Adeoye O, Hornung R, Khatri P, & Kleindorfer D (2011). Recombinant tissue-type plasminogen activator use for ischemic stroke in the United States: a doubling of treatment rates over the course of 5 years. Stroke; a journal of cerebral circulation, 42 (7), 1952-5 PMID: 21636813

Zivin JA, Simmons J. tPA for stroke: the story of a controversial drug. New York: Oxford University Press; 2011.

Image via andkuch / Shutterstock.

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According to the World Health Organization (WHO), depression is one of the leading causes of disability, affecting as much as 121 million people worldwide. Although there are various effective treatments available, some patients register unsatisfactory responses to therapy causing their depression to enter into chronicity. Negative emotions such as anger, fear and sadness are prevalent facial expressions in depression that are associated with activation of the corrugator and procerus muscles in the glabellar region of the face. Injection of BTX-A to this facial region has been previously used to inhibit the activity of the corrugator and procerus muscles for the cosmetic treatment of frown lines. Unexpectedly, recipients of this treatment have also reported an increase in emotional wellbeing beyond the desired cosmetic benefit. Specifically, reduced levels of fear and sadness have been observed.

Taking these findings into account, the capacity for BTX-A to counteract negative emotions may also have clinical implications. To explore whether the attenuation of facial psychomotor features associated with depression may produce alleviation of affective symptoms, Wolmer et al. recently conducted a randomized controlled trial of BTX-A injection to the glabellar region as an adjunctive treatment of major depression. Thirty subjects, both men and women were included into the study and randomly assigned to treatment or placebo group. Subjects were included if their age ranged from ages 25-65 years old, had a diagnosis of on-going major depressive disorder according to the DSM-IV, and exhibited moderate to severe vertical glabellar lines during maximum voluntary frowning.

At baseline, the treatment and placebo group did not differ in any of the collected characteristics.  However, the treatment group showed a significant improvement in depressive symptoms compared to the placebo group at the 16-week follow-up mark, measured by the Hamilton Depression Rating Scale (HAM-D). Even after only one BTX-A treatment at the 6 week mark, BTX-A recipients’ depression scores were reduced on average by 47.1% compared to only 9.2% in placebo-treated participants. The authors concluded that a single treatment of the glabellar region with BTX-A may shortly accomplish a strong and sustained alleviation of depression in patients, although the mechanism of such effect has yet to be elucidated.

Although the mechanisms remain unclear, the authors do not attribute aesthetic benefit as a major contributor to mood improvement as they did not enroll patients into the study who were cosmetically concerned about their frown lines. Notably, treatment response also did not depend on a positive appraisal of the cosmetic change. However, the authors believe that it is possible that a more positive facial expression and improved feedback both from one’s own face in the mirror and from social interaction partners may have contributed to mood enhancement.

What does this mean for the future of BTX-A and its clinical applications? It is possible to extend these findings onto other muscles in the lower sections of the face (e.g. depressor angulis oris and mentalis muscles) and examine any mood-elevating effects.  Modulation of mood states with BTX-A may also be effective in the treatment of other clinical conditions involving negative emotions, like anxiety disorders. If true, findings from these studies would support the concept that facial musculature can not only express, but regulate mood states as well.

References

Gilmer WS, Trivedi MH, Rush AJ, Wisniewski SR, Luther J, Howland RH, Yohanna D, Khan A, & Alpert J (2005). Factors associated with chronic depressive episodes: a preliminary report from the STAR-D project. Acta psychiatrica Scandinavica, 112 (6), 425-33 PMID: 16279871

Lewis MB, & Bowler PJ (2009). Botulinum toxin cosmetic therapy correlates with a more positive mood. Journal of cosmetic dermatology, 8 (1), 24-6 PMID: 19250162

Sommer B, Zschocke I, Bergfeld D, Sattler G, & Augustin M (2003). Satisfaction of patients after treatment with botulinum toxin for dynamic facial lines. Dermatologic surgery : official publication for American Society for Dermatologic Surgery [et al.], 29 (5), 456-60 PMID: 12752511

Wollmer MA, de Boer C, Kalak N, Beck J, Götz T, Schmidt T, Hodzic M, Bayer U, Kollmann T, Kollewe K, Sönmez D, Duntsch K, Haug MD, Schedlowski M, Hatzinger M, Dressler D, Brand S, Holsboer-Trachsler E, & Kruger TH (2012). Facing depression with botulinum toxin: a randomized controlled trial. Journal of psychiatric research, 46 (5), 574-81 PMID: 22364892

Image via PhotographyByMK / Shutterstock.

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The prefrontal cortex in teenagers is in a state of growth and development. Contrary to established notions, brain development continues well into the teenage years and changes in synapses (connections between brain cells that facilitate the transmission of chemical messengers between cells) occur well into adolescence.  Research on adolescent mice and rats shows that exposure to nicotine during this period has long-lasting effects. For starters, nicotine is known to be able to excite neurons bearing nicotinic acetylcholine receptors. In the prefrontal cortex, nicotine has been shown to induce greater expression of a specific subset of nicotinic acetylcholine receptors, by 34%.  In the normal course of development, the number of acetylcholine receptors declines in these cells. This phenomenon is specific to the period of adolescence since a similar increase in the number of receptors is not seen when the initial exposure to nicotine occurs in adulthood, in these animals. Research has also shown that exposure to nicotine in early adolescence enhances the nicotinic ‘reward’ feeling during adulthood. It is therefore surmised that early exposure to smoking is likely to set the stage for long-term addiction and perhaps it also explains why addiction to nicotine is so prevalent, worldwide.

One might argue that since the teenage years are a short period in the life-span of a person, occasional exposure to nicotine is not likely to leave lasting damage. Here’s the catch. Exposure to nicotine also changes the pattern of synaptic connectivity between neurons in the prefrontal cortex.  The ability of neurons to establish new synaptic connections and develop new firing patterns in response to different stimuli is also known as “synaptic plasticity”. Neuroscientists have shown that all “learning” as well as  information analysis and assimilation in the brain is a net result of the pattern of exchange of neurotransmitter molecules (also referred to as pattern of ‘firing’) between neurons which respond to training stimuli. So, the more you learn, the better you get at learning by stimulating your neurons to make new synaptic connections. However, exposure to nicotine in early adolescence, changes the pattern of firing of neurons in the prefrontal cortex. Now this change reduces the capability of neurons in the prefrontal cortex to make new synaptic connections. Therefore exposure to psychedelic and addictive substances like nicotine results in reduced synaptic plasticity and has a negative impact on cognitive processes in adult life.

All these significant changes take place in early adolescence and perhaps parental guidance may play a huge role in preventing nicotine addiction and associated cognitive deficits.

References

Adriani W, Macrì S, Pacifici R, & Laviola G (2002). Peculiar vulnerability to nicotine oral self-administration in mice during early adolescence. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 27 (2), 212-24 PMID: 12093595

Counotte DS, Goriounova NA, Moretti M, Smoluch MT, Irth H, Clementi F, Schoffelmeer AN, Mansvelder HD, Smit AB, Gotti C, & Spijker S (2012). Adolescent nicotine exposure transiently increases high-affinity nicotinic receptors and modulates inhibitory synaptic transmission in rat medial prefrontal cortex. FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 26 (5), 1810-20 PMID: 22308197

Goriounova NA, & Mansvelder HD (2012). Nicotine exposure during adolescence alters the rules for prefrontal cortical synaptic plasticity during adulthood. Frontiers in synaptic neuroscience, 4 PMID: 22876231

Goriounova NA, & Mansvelder HD (2012). Nicotine exposure during adolescence leads to short- and long-term changes in spike timing-dependent plasticity in rat prefrontal cortex. The Journal of neuroscience : the official journal of the Society for Neuroscience, 32 (31), 10484-93 PMID: 22855798

Kawai HD, Kang HA, & Metherate R (2011). Heightened nicotinic regulation of auditory cortex during adolescence. The Journal of neuroscience : the official journal of the Society for Neuroscience, 31 (40), 14367-77 PMID: 21976522

Kota D, Robinson SE, & Imad Damaj M (2009). Enhanced nicotine reward in adulthood after exposure to nicotine during early adolescence in mice. Biochemical pharmacology, 78 (7), 873-9 PMID: 19576867

Image via william langeveld / Shutterstock.

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Synthetic cathinones are structurally and pharmacologically similar to methamphetamine, Ecstasy, and LSD, which are also considered designer drugs — that is, manufactured versions of controlled substances. Synthetic cathinones pose serious health risks and danger to the public. Side effects include chest pains, increased blood pressure, increased heart rate, agitation, hallucinations, extreme paranoia, and delusions. They are addictive and have been linked to deaths. A number of incidents of bizarre behavior have fueled recent media stories.

But what makes them particularly dangerous is their ease of access — bath salts are available legally via the internet or in drug paraphernalia stores. That’s because the so-called “chemists” who produce them make constant, minor alternations to the drugs’ chemical make-up, dodging Drug Enforcement Administration (DEA) Schedule 1 classification on a technicality — and leading many to claim the drugs provide a “legal high.” Further fueling their popularity, the outlets that sell bath salts often promise that urine drug screens will not detect their presence. Not so…

Ameritox, a uring drug testing company, announced recently the launch of a test for bath salts that not only detects three common synthetic cathinones that the DEA has categorized as controlled substances, but also tests for five other chemical components used commonly in bath salts products.

The battle to keep up with the latest formulations of these designer drugs is truly a game of “cat and mouse.” The DEA placed three specific synthetic cathinones into its Schedule 1 category of controlled substances in October 2011, citing the move as “necessary to avoid imminent hazard to the public safety” due to high abuse potential and lack of medical use.

But there are likely dozens of synthetic cathinones on the street today.

The public safety solution requires effort at multiple levels — with physicians, scientists, communities, law enforcement, and policy makers each playing a collaborative role. As the DEA works tirelessly to categorize these substances, other players are bringing their scientific expertise to bear on the problem.

Specialty laboratories work hard to stay ahead of the game in anticipating new formulations and launching new tests to detect these dangerous substances – and joining forces with the DEA, the physicians conducting these tests, and insurance companies could make our progress even stronger:

• Physicians need to be educated to identify patients suffering from the side effects of bath salts and be able to report increased use in their community. Using techniques like urine drug testing can help.
• Insurance companies need to be encouraged to cover drug screenings, so that data about drug use trends can be provided to the DEA and physicians to help reduce their use.
• The public needs to be educated about this dangerous and unregulated category of drugs, in particular that just because drugs are sometimes legal doesn’t mean they are safe.
• The DEA needs a faster way to outlaw these drugs by class, rather than by substance.

By working together, we can help reduce the threat of “bath salts” to individual’s health and to enhance public safety.

References

Rosenbaum CD, Carreiro SP, & Babu KM (2012). Here today, gone tomorrow…and back again? A review of herbal marijuana alternatives (K2, Spice), synthetic cathinones (bath salts), kratom, Salvia divinorum, methoxetamine, and piperazines. Journal of medical toxicology : official journal of the American College of Medical Toxicology, 8 (1), 15-32 PMID: 22271566

Prosser JM, & Nelson LS (2012). The toxicology of bath salts: a review of synthetic cathinones. Journal of medical toxicology : official journal of the American College of Medical Toxicology, 8 (1), 33-42 PMID: 22108839

U.S. Department of Justice: Drug Enforcement Agency. Federal Register / Vol. 76, No. 204 / Friday, October 21, 2011 / Rules and Regulations.

European Monitoring Centre for Drugs and Drug Addiction. EMCDDA–Europol 2011 Annual Report on the implementation of Council Decision 2005/387/JHA. April 2012.

Image via yonibunga / Shutterstock.

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Simply put, a vaccine is a mixture of compounds (most often proteins) that are selected for their ability to activate the immune system. These compounds, also known as antigens, are then injected into the body where they prepare the immune system for a future assault. The result of such prophylactic vaccination is either complete immunity to the illness, or at least a significant reduction in disease severity.

While a prophylactic vaccine is administered as a preventative measure, therapeutic vaccines are intended to help fight a disease that has already taken root. For example, a therapeutic vaccine might be given to a patient with cancer in order to enlist the patient’s own immune system in the fight against the disease.

The problem with this kind of approach is ensuring that the antigen used in the vaccine does not induce an immune response against healthy parts of the body. Again, using cancer as an example, diseased cells often contain mutated proteins, or proteins that are not usually expressed in adult tissue (known as onco-fetal genes). This means that vaccines using these antigens specifically target cancer cells.

Recently, a therapeutic vaccine for Parkinson’s disease developed by Austrian pharmaceutical company Affiris entered a clinical trial, a landmark move in the management of a disease that is currently only treated at a symptomatic level.

Patients with Parkinson’s disease suffer from a number of debilitating symptoms that are the result of the loss of a particular class of neurons in the brain. These neurons are involved in the control of muscle function and are particularly sensitive to the neurotransmitter dopamine. It is for this reason that current treatments revolve around modulation of the levels of this chemical.

The underlying molecular cause of the disease is a protein called alpha-synuclein. Ordinarily this protein is found throughout the neocortex, hippocampus, thalamus, substantia nigra, and cerebellum, although its precise function remains unknown. Importantly, this protein is very unusual in that it does not fold up like the majority of proteins. Its “floppy”, unfolded appearance means that it is particularly susceptible to getting tangled up and forming protein aggregates within brain cells, thus sentencing the affected cell to death. The formation of protein aggregates also underlies other brain disorders, including Alzheimer’s disease and Creutzfeld-Jacob disease.

It is the alpha-synuclein protein tangles that are targeted by the vaccine currently in trials, PD01A. The study, funded by the Michael J. Fox Foundation to the tune of $1.5 million, will assess the safety of the vaccine in both men and women with Parkinson’s disease, with the results expected in July of 2014.

Given the prevalence of protein aggregates in brain diseases, therapeutic vaccination might therefore represent a promising future treatment for several neurological conditions.

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The authors used diffusion tensor imaging (DTI), a MRI technique that measures water diffusion, to examine the microstructure of white matter in 59 heavy cannabis users, who used cannabis at least twice a month for three years or longer, as well as 33 non-users. In the human brain, white matter pathways are formed by bundles of axons, which carry the neural signals, and myelin, which coat the axons and speeds up signal transfer. These white matter pathways are crucial for normal brain function as they enable disparate regions of the brain to communicate, and act together.

When the authors investigated white matter microstructure in the cannabis users, they found damage in the white matter pathways of the hippocampus, crucial for memory, and the corpus callosum, which connects the brain’s two hemispheres. Both pathways are critical for normal brain function. The authors suggest that impaired connectivity due to damage in these pathways may be the cause of the cognitive impairment and vulnerability to schizophrenia, depression and anxiety seen in long-term users.

The authors also show an inverse relationship between the amount of white matter damage and the age of first use. That is, participants who started using cannabis younger had more white matter damage and showed poorer brain connectivity. Adolescence is a critical period in the development of white matter in the brain, when the neural connections we rely on in adulthood are being finally formed. The authors point out that white matter cells have cannabinoid receptors (those susceptible to cannabis) during adolescence, which disappear as the brain matures. This new study demonstrates a mechanism that may help explain how cannabis use in adolescence causes long-term changes in brain function. The cannabis users in the study had significantly higher levels of depression and anxiety compared to the non-users.

This important new study suggests that young people’s brains are at risk of white matter injury due to cannabis, and that cannabis exposure during adolescence may permanently damage white matter development. Future research must address the question; can white matter pathways and connectivity recover when a person quits using cannabis?

References

Zalesky A, Solowij N, Yücel M, Lubman DI, Takagi M, Harding IH, Lorenzetti V, Wang R, Searle K, Pantelis C, & Seal M (2012). Effect of long-term cannabis use on axonal fibre connectivity. Brain : a journal of neurology, 135 (Pt 7), 2245-55 PMID: 22669080

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Sixty years ago, research into the effects of psychedelic drugs was accepted — and, dare I say, frequent — among certain institutions and researchers. But, with the rise in the recreational use of drugs and the growth of the anti-drug campaigns, all that was brought to an end by the 1970s. Now, a generation later, scientists are slowly re-opening those doors to find new ways to treat terminally ill patients, who often have paralyzing, debilitating fears about their own mortality.

A study in the Archives of General Psychiatry reported, in 2011, that psilocybin — the active component of magic mushrooms — was safe and effective at reducing anxiety and depression about death when given to terminally ill cancer patients. The psilocybin lead to decreased anxiety and depression for months after the treatment, though it is not clear how the effects lasted so long.

The research is all part of a larger effort to study the effects of psychedelic drugs under rigorous controlled, scientific processes. MDMA (also known as Ecstasy) has been shown to be effective for severe post traumatic stress disorder and LSD can reduce symptoms of chronic cluster headaches. Psychedelic drugs have also been evaluated in treating addictions, including alcoholism.

Scientists have not identified the precise mechanism of action of psychedelics in anxiety and depression yet, but the effects are probably related to an “unrestrained consciousness” that allows patients to be introspective and a disassociation of sensation and perception. Also, the drugs may deactivate the parts of the brain that are overactive in anxiety and depression, according to functional MRI studies. Further, since the treatments are all administered in a controlled, safe environment, and patients know the expectations and desired outcomes ahead of time, the patients are able to balance experiencing emotions that they would otherwise be unable to face.

Anecdotally, the small numbers of patients who have taken these psychedelic trips report positive outcomes. But, a handful of patients does not make a sufficient scientific sample, especially when it comes to illegal and illicit drugs. While most people — healthcare providers and the lay public – would argue that more can be done to ease end-of-life suffering, both physical and emotional, many would stop short of advocating psychedelic drugs. Arguably, the risk of causing long-term health effects or producing a new drug addict is negligible under these circumstances. And, under these circumstances, there is no risk of contaminated street drugs or pushy drug dealers that terminally ill patients have to contend with. But, that does not mean the drugs should appear in our mainstream armamentarium of anti-anxiety and antidepressant drugs.

Currently, psychedelic and hallucination-inspiring drugs are classified as Schedule I controlled substances by the FDA, meaning that they have no medicinal use and cannot be prescribed or dispensed in the United States. If this were to change, it could open the door to the misuse and abuse of very dangerous drugs. More research into how and why these drugs produce their effects could help scientists develop similar, safer compounds to treat patients with serious conditions refractory to other therapies, but we’re a long way from the Brave New World that Aldous Huxley wanted in which psychedelic experiences are part of our mainstream culture.

References

Bouso JC, Doblin R, Farré M, Alcázar MA, & Gómez-Jarabo G (2008). MDMA-assisted psychotherapy using low doses in a small sample of women with chronic posttraumatic stress disorder. Journal of psychoactive drugs, 40 (3), 225-36 PMID: 19004414

Carhart-Harris RL, Erritzoe D, Williams T, Stone JM, Reed LJ, Colasanti A, Tyacke RJ, Leech R, Malizia AL, Murphy K, Hobden P, Evans J, Feilding A, Wise RG, & Nutt DJ (2012). Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin. Proceedings of the National Academy of Sciences of the United States of America, 109 (6), 2138-43 PMID: 22308440

Grob CS, Danforth AL, Chopra GS, Hagerty M, McKay CR, Halberstadt AL, & Greer GR (2011). Pilot study of psilocybin treatment for anxiety in patients with advanced-stage cancer. Archives of general psychiatry, 68 (1), 71-8 PMID: 20819978

Johansen PØ, & Krebs TS (2009). How could MDMA (ecstasy) help anxiety disorders? A neurobiological rationale. Journal of psychopharmacology (Oxford, England), 23 (4), 389-91 PMID: 19273493

Mithoefer MC, Wagner MT, Mithoefer AT, Jerome L, & Doblin R (2011). The safety and efficacy of {+/-}3,4-methylenedioxymethamphetamine-assisted psychotherapy in subjects with chronic, treatment-resistant posttraumatic stress disorder: the first randomized controlled pilot study. Journal of psychopharmacology (Oxford, England), 25 (4), 439-52 PMID: 20643699

Slater L. How psychedelic drugs can help patients face death. NY Times. April 20, 2012.

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The literature on the addictive properties is still rather sparse and replication of the existing studies would be beneficial. A preclinical study in rodents demonstrated that salv A produced a decrease in dopamine and dopamine transmission, the endogenous neurotransmitter associated with addiction, and no effect on locomotor activity (a common test for the stimulant effects of a drug). These depressive effects would seem to be contrary to the notion of salv A being an addictive drug. Furthermore, these effects may lend value to salv A and its analogs as potential pharmacotherapeutics for neuropsychiatric conditions including addiction and mood disorders.

Other studies have demonstrated the opposite effect, where low doses of salv A increase dopamine efflux, produce a conditioned place preference, and rats examined during intracerebroventricular self-administration will self-infuse the drug. The latter two tests are common preclinical assessments of the rewarding properties associated with a drug. There exists a discrepancy in the literature on whether salv A will substitute for LSD in rodent studies using drug discrimination. On such study in rodents demonstrated that salv A and LSD share similar stimulus properties which is contrary to previous reports.

Recently a controlled behavioral pharmacology investigation was conducted in humans to assess the physiological and subjective effects of salv A. It showed that salv A does not induce changes in blood pressure or heart rate although its subjective effects are similar to other hallucinogenic drugs. Given that salv A produces hallucinogenic effects similar to other known scheduled hallucinogens careful consideration needs to be given to legality of this substance.

References

Braida D, Limonta V, Capurro V, Fadda P, Rubino T, Mascia P, Zani A, Gori E, Fratta W, Parolaro D, & Sala M (2008). Involvement of kappa-opioid and endocannabinoid system on Salvinorin A-induced reward. Biological psychiatry, 63 (3), 286-92 PMID: 17920565

Carlezon WA Jr, Béguin C, DiNieri JA, Baumann MH, Richards MR, Todtenkopf MS, Rothman RB, Ma Z, Lee DY, & Cohen BM (2006). Depressive-like effects of the kappa-opioid receptor agonist salvinorin A on behavior and neurochemistry in rats. The Journal of pharmacology and experimental therapeutics, 316 (1), 440-7 PMID: 16223871

Gehrke BJ, Chefer VI, & Shippenberg TS (2008). Effects of acute and repeated administration of salvinorin A on dopamine function in the rat dorsal striatum. Psychopharmacology, 197 (3), 509-17 PMID: 18246329

Johnson, M., MacLean, K., Reissig, C., Prisinzano, T., & Griffiths, R. (2011). Human psychopharmacology and dose-effects of salvinorin A, a kappa opioid agonist hallucinogen present in the plant Salvia divinorum Drug and Alcohol Dependence, 115 (1-2), 150-155 DOI: 10.1016/j.drugalcdep.2010.11.005

Peet, M., & Baker, L. (2011). Salvinorin B derivatives, EOM-Sal B and MOM-Sal B, produce stimulus generalization in male Sprague-Dawley rats trained to discriminate salvinorin A Behavioural Pharmacology, 22 (5 and 6), 450-457 DOI: 10.1097/FBP.0b013e328349fc1b

Drug Enforcement Administration. SALVIA DIVINORUM AND SALVINORIN A (Street Names: Maria Pastora, Sage of the Seers,
Diviner’s Sage, Salvia, Sally-D, Magic Mint). December 2010.

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The report was recently published in Health Affairs. The authors analyzed data from the National Ambulatory Medical Care Surveys conducted by the Centers for Disease Control and Prevention, which summarize outpatient medical care practices, between 1996 and 2007. Overall, four out of five providers who prescribed antidepressants were not psychiatrists; most of them were primary care physicians. Antidepressants were prescribed in 9.3% of visits to primary care physicians, compared to 3.6% of visits to other nonpsychiatrist providers.

A worrisome finding, according to the authors, is that the proportion of antidepressants prescribed by nonpsychiatrists without a psychiatric diagnosis was 6.4% (increased from 2.5% in 1996). This proportion was highest among primary care physicians, accounting for 7.1% of antidepressant prescribing (up from 3.1%). Among other nonpsychiatrists, the proportion of antidepressants prescribed without a diagnosis was 5.8% (increased from 1.9%). Overall, the proportion of physician visits that resulted in an antidepressant prescription and a psychiatric diagnosis increased only slightly from 1.7% to 2.4%.

The most likely patients to receive antidepressants were non-Hispanic white women over the age of 50 with private health insurance or Medicare coverage. These women were also more likely to have chronic health conditions, including diabetes, high blood pressure, heart disease, excessive fatigue, headaches, nonspecific pain, or trouble sleeping.

A similar study reported that nearly 3 out of every 100 people in the United States received outpatient treatment for depression in 2007, increased from 2.3 people per 100 in 1998. Of these people, 75.3% were treated with an antidepressant, only slightly increased from 73.8% in 1998. At the same time, the proportion of people receiving psychotherapy decreased from 53.6% to 43.1%. Overall, data indicates that more than 10% of children, adolescents, and adults in the United States – roughly 27 million people — are receiving treatment with an antidepressant, with or without a diagnosis of depression.

One driving force of the increase in antidepressant use — other than excessive direct-to-consumer marketing — is the increased acceptance of antidepressant use among Americans. They stigma attached to mental health treatment is decreasing, particularly when it comes to less severe conditions. Many people view antidepressants as little more than enhancers of well-being. Also, some antidepressants are approved for nonpsychiatric conditions, including premenstrual dysphoric disorder, smoking cessation, diabetic neuropathic pain, chronic musculoskeletal pain, and fibromyalgia.

The authors of the current study do not intend to imply that antidepressant prescribing by nonpsychiatrist providers is inappropriate. But, the results do beg the question of who is prescribing what, and why? Antidepressants may not be effective for many of the conditions for which they are prescribed. Simply, more prescriber education and collaborative care might avoid unnecessary prescriptions and promote more appropriate treatments, like psychotherapy, exercise, and other lifestyle or behavioral changes.

Primary care physicians are in a tough spot today. They have too many patients and too little time to spend with them. Primary care physicians lack extensive training in specialized fields of medicine, and, without funding, reimbursement, or referral capabilities, are forced to do their best to take care of their patients, often with little support from other healthcare providers, insurance  companies, or the patients themselves. A paradox related to the findings of these studies is that a large number of patients with mental health disorders still do not receive treatment for their conditions, because primary care physicians are not able to diagnoses their signs and symptoms.  Improved awareness of appropriate prescribing on the part of physicians and patients and increased collaboration with more specialized healthcare providers will lead to better treatment outcomes for mental health disorders.

References

Marcus SC, & Olfson M (2010). National trends in the treatment for depression from 1998 to 2007. Archives of general psychiatry, 67 (12), 1265-73 PMID: 21135326

Mark TL (2010). For what diagnoses are psychotropic medications being prescribed?: a nationally representative survey of physicians. CNS drugs, 24 (4), 319-26 PMID: 20297856

Mojtabai, R., & Olfson, M. (2011). Proportion Of Antidepressants Prescribed Without A Psychiatric Diagnosis Is Growing Health Affairs, 30 (8), 1434-1442 DOI: 10.1377/hlthaff.2010.1024

Olfson M, & Marcus SC (2009). National patterns in antidepressant medication treatment. Archives of general psychiatry, 66 (8), 848-56 PMID: 19652124

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This problem of unwanted drug disposal has created quite a dilemma for patients who need an acceptable and safe alternative to flushing unused medications. According to the National Community Pharmacists Association (NCPA), “Consumer surveys demonstrate that local pharmacies are the most convenient locations where consumers seek to return unused for expired medicines.”

The United States Food and Drug Administration (FDA) has established guidelines for the disposal of unused medicines. They recommend that take-back programs for disposal are the best and primary way consumers should use when discarding expired, unwanted, or unused medicines. When no take-back program is locally available to the consumer, the FDA provides specific guidelines for disposal of medicines in household trash, which include mixing the medication with a substance such as cat litter or used coffee grounds, placing the mixture in a container or sealed plastic bag, and disposing the container in the household trash.

The FDA has published a list outlining specific medications that, due to their especially harmful effects when used by someone other than the patient for whom the medication was prescribed, should be disposed of by flushing when they can not be disposed of via a take-back program. This again poses the concerns over risk of such substances to human health and the environment. The FDA states that, “The majority of medicines found in the water system are a result of the body’s natural routes of drug elimination (in urine or feces). Scientists, to date, have found no evidence of harmful effects to human health from medicines in the environment.” The FDA contends that the few medications disposed of by flushing contribute a small fraction to the overall total amount of drugs found in the water supply and propose that the health and environment risk associated with this method of disposal is exceeded by the possible life-threatening risks from accidental ingestion of these medications.

Apparently drug take-back efforts are having a positive effect and serving as a useful method of unwanted drug collection. The latest national drug take-back day was organized by the Drug Enforcement Administration (DEA) and held on April 30, 2011. According to the DEA, the collection at over 5300 sites brought in 188 tons of unused prescription medicine from the public. The drugs collected by authorities were incinerated.

References

Controlled substance disposal a natural for community pharmacies. Drug Topics E-News, 2011.

Disposal of unused medicines: what you should know. FDA, 2011.

Daughton CG. Drugs and the environment: stewardship & sustainability. National Exposure Research Laboratory, Environmental Sciences Division, US EPA, Las Vegas, Nevada, report NERL-LV-ESD 10/081, EPA/600/R-10/106. 2010 Sept 12.
 

Taylor R. Towards better prescribing. Journal of the Royal College of General Practicioners. 1978 May;28:263-270.

Frolund, F. (1978). Better prescribing. BMJ, 2 (6139), 741-741 DOI: 10.1136/bmj.2.6139.741

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You may get up out of bed while not being fully awake and do an activity that you do not know you are doing. The next morning, you may not remember that you did anything during the night.

Other than alcohol, sleep aids do not regularly cause unconscious behaviors like “driving a car, making and eating food, talking on the phone, having sex, sleep-walking.” That’s quite a list. And that is a lot of activity at night for a drug people are taking to help them sleep longer and deeper without waking making them drowsy the next morning. Seniors are also a prime user group of this type of drug — changes in sleep patterns naturally occur with age, making insomnia more of a problem among the elderly. Roughly 10-15% of the elderly population use hypnotic medications as sleep aids, says a report in Human Psychopharmacology.

According to the New York Times, prescriptions for Ambien made it the top drug in its class by 2006. The Big 3 “hypnosedatives” are closing the gap on benzodiazepines like Valium, the traditional class leader for sleep medication. Physicians wrote roughly an equal number of prescriptions for the newer hypnosedatives as they did for the classic benzodiazepine family by that year. Now a recent study in Psychopharmacology of older prescription drug users has confirmed that there is an additional threat of significant morning-after impairments. French researchers at the University of Caen School of Medicine road-tested a group of seniors using simulated driving scenarios, and found that each morning after taking one of the Big Three hypnotics, the subjects made more mistakes than placebo drivers when it came such measurements as speed and the detection of road exits.

The authors strongly suggest that better patient monitoring and instruction could dramatically cut back on the incidence of traffic accidents due to these prescription medications. But so far, there is no warning sticker for the pills that says:

Do not drive or operate heavy equipment after you wake up (You may have already been doing it in your sleep the night before).

It may seem obvious, but the morning-after impairment among older peole was a bit surprising, given that several earlier studies had not shown major cognitive deficits still at work by the 12-hour mark. The current study was small — 16 subjects over 55 years of age. However, as the first study to document significantly impaired driving in ageing drivers the morning after using Ambien or a similar drug, additional investigations of this effect become even more urgent.

Finally, there is one other matter to bear in mind when using hypnosedative drugs in older populations. A report in CNS Drugs says that common antibiotics like erythromycin, and other drugs like Tagamet (an ulcer drug) and Ketoconazole (a common fungus cream), may interfere with how the drugs work. And, as you probably could have guessed, mixing alcohol with these hypnosedatives is a ticket to even greater sedation and unanticipated interactions.

References

Bocca ML, Marie S, Lelong-Boulouard V, Bertran F, Couque C, Desfemmes T, Berthelon C, Amato JN, Moessinger M, Paillet-Loilier M, Coquerel A, & Denise P (2011). Zolpidem and zopiclone impair similarly monotonous driving performance after a single nighttime intake in aged subjects. Psychopharmacology, 214 (3), 699-706 PMID: 21086117

Hesse, L., von Moltke, L., & Greenblatt, D. (2003). Clinically Important Drug Interactions with Zopiclone, Zolpidem and Zaleplon CNS Drugs, 17 (7), 513-532 DOI: 10.2165/00023210-200317070-000042.

Otmani, S., Demazières, A., Staner, C., Jacob, N., Nir, T., Zisapel, N., & Staner, L. (2008). Effects of prolonged-release melatonin, zolpidem, and their combination on psychomotor functions, memory recall, and driving skills in healthy middle aged and elderly volunteers Human Psychopharmacology: Clinical and Experimental, 23 (8), 693-705 DOI: 10.1002/hup.980

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