Abstract Physical activity, and specifically exercise, has been suggested as a potential treatment for drug addiction. In this review, we discuss clinical and preclinical evidence for the efficacy of exercise at different phases of the addiction process. Potential neurobiological mechanisms are also discussed focusing on interactions with dopaminergic and glutamatergic signaling and chromatin remodeling in the reward pathway. While exercise generally produces an efficacious response, certain exercise conditions may be either ineffective or lead to detrimental effects depending on the level/type/timing of exercise exposure, the stage of addiction, the drug involved, and the subject population. During drug use initiation and withdrawal, its efficacy may be related to its ability to facilitate dopaminergic transmission, and once addiction develops, its efficacy may be related to its ability to normalize glutamatergic and dopaminergic signaling and reverse druginduced changes in chromatin via epigenetic interactions with BDNF in the reward pathway. We conclude with future directions, including the development of exercise-based interventions alone or as an adjunct to other strategies for treating drug addiction.
Is this the breakthrough we’ve been searching for?
I first got drunk at 12 years old.
Young perhaps, but it was Soviet Moscow, where my dad was stationed as an American journalist in the 1980s. I wasn’t very good at drinking, though I tried. When I was 15, I was arrested three times for public drunkenness, twice in one day. Back in the States, while I was still in high school, a litany of drug and alcohol violations got me kicked out of boarding school—with the final incident just hours before my graduation ceremony, my father the keynote speaker (nope, no daddy issues there). In college, the morning I was scheduled to clock in for a new job, I woke up behind the wheel, on a highway in another state, facing the wrong way. Several years later, a DWI and drug charges landed me in the crime log of the newspaper where I worked as a reporter. And so it went.
Fast-forward 17 years and I’m catching my breath near the 14,115-foot summit of Colorado’s Pikes Peak, my race bib fluttering in the wind. Bracing myself at the halfway mark of the grueling mountain marathon, taking in the countless jagged switchbacks I’d just picked across, I couldn’t help but think about the distance I’d put between Then and Now. And the irony: that after nine marathons and thousands of miles, this is how I get high. Standing on a vast rooftop shingled with mountain peaks, the thin air fizzing my brain, I was feeling pretty buzzed. And grateful. I largely have running to thank for my transformation. After years of face-plants (literal and figurative) and a self-image curdled by guilt and self-loathing, a simple pair of running shoes had returned momentum, even joy, to my life and allowed me to evolve into a capable person—a genuine human being… And I wasn’t alone.
About five years into my running life—mostly solitary back-country road work—I started to come across stories about other troubled souls who had traded in chaos for running shoes: a meth-head-turned-Ironman-competitor; a recovering crack addict who once ran 350 miles in a week; an ex-convict alcoholic who would tackle the equivalent of almost six back-to-back marathons across the Gobi Desert. Later, I’d read about a treatment center in East Harlem that trains rock-bottom people suffering from addiction to finish the New York City Marathon (http://www.runnersworld.com/nyc-marathon) and another in Canada that mandates running, complete with a natural track area on the premises and an annual race named the “Redemption Run.” I wrote a recovery memoir in that time, and when it was released, my in-box swelled with messages from around the country: from other drunks-turned-runners, sober marathoners, freshly quit opioid addicts, the imprisoned, psychiatrists, and drug counselors. Other than some skeptical 12-steppers arguing I’d substituted one addiction for another (I didn’t go the Alcoholics Anonymous route), all were firm believers in the healing power of the run. In something as simple as hitting the road, they, too, had felt a loosening of addictive thoughts and a sparking of positive changes in the brain, and in the heart. But was there much to it beyond our personal stories and a would-be “swapping of vices”?
May 15, 2013: 9:03 AM ET The epic inside story of long-term criminal fraud at Ranbaxy, the Indian drug company that makes generic Lipitor for millions of Americans. By Katherine Eban
1. The assignment FORTUNE
On the morning of Aug. 18, 2004, Dinesh Thakur hurried to a hastily arranged meeting with his boss at the gleaming offices of Ranbaxy Laboratories in Gurgaon, India, 20 miles south of New Delhi. It was so early that he passed gardeners watering impeccable shrubs and cleaners still polishing the lobby’s tile floors. As always, Thakur was punctual and organized. He had a round face and low-key demeanor, with deep-set eyes that gave him a doleful appearance.
His boss, Dr. Rajinder Kumar, Ranbaxy’s head of research and development, had joined the generic-drug company just two months earlier from GlaxoSmithKline, where he had served as global head of psychiatry for clinical research and development. Tall and handsome with elegant manners, Kumar, known as Raj, had a reputation for integrity. Thakur liked and respected him.
Like Kumar, Thakur had left a brand-name pharmaceutical company for Ranbaxy. Thakur, then 35, an American-trained engineer and a naturalized U.S. citizen, had worked at Bristol-Myers Squibb (BMY) in New Jersey for 10 years. In 2002 a former mentor recruited him to Ranbaxy by appealing to his native patriotism. So he had moved his wife and baby son to Gurgaon to join India’s largest drugmaker and its first multinational pharmaceutical company.
When he stepped into Kumar’s office that morning, Thakur was surprised by his boss’ appearance. He looked weary and uneasy, his eyes puffy and dark. He had returned the previous day from South Africa, where he had met with government regulators. It was clear that the meeting had not gone well.
The two men strolled into the hall to order tea from white-uniformed waiters. As they returned, Kumar said, “We are in big trouble,” and motioned for Thakur to be quiet. Back in his office, Kumar handed him a letter from the World Health Organization. It summarized the results of an inspection that WHO had done at Vimta Laboratories, an Indian company that Ranbaxy hired to administer clinical tests of its AIDS medicine. The inspection had focused on antiretroviral (ARV) drugs that Ranbaxy was selling to the South African government to save the lives of its AIDS-ravaged population.
Use B-Complex Vitamins and DHA to Keep Your Brain Sharp as You Age
If you want to keep your marbles as you grow older, it may be worthwhile focusing on two nutrients: B-complex vitamins and docosahexaenoic acid (DHA), one of the omega-3 fats found in fish oils. Three recent studies have found that these nutrients play major roles in keeping the brain sharp.
In the first study, A. David Smith, PhD, of Oxford University, England, and his colleagues analyzed data from 168 men and women they treated with either B-vitamins or placebos. The subjects’ brain changes were also tracked with MRIs (magnetic resonance images) of the brain.
The supplements consisted of 800 mcg of folic acid, 500 mcg of vitamin B12, and 20 mg of vitamin B6 daily, which the subjects took for two full years. The study participants had been diagnosed with mild cognitive impairment and brain atrophy – problems likely to develop into Alzheimer’s disease. Smith also measured the subjects’ blood levels of homocysteine, one of the markers of B-vitamin deficiency and a risk factor for cardiovascular disease and Alzheimer’s. People taking the B vitamins experienced an average of 30 percent less brain shrinkage, but some of the patients had more than a 50 percent reduction in brain shrinkage, compared with those in the placebo group. Homocysteine levels also decreased significantly among those taking B vitamins, and the rate of response was related to initial homocysteine levels. People with higher homocysteine levels were more likely to benefit from the B vitamins.
In the second study, Giuseppe Astarita, DSc, of the University of California, Irvine, and his colleagues compared brain and liver levels of DHA in 37 people with Alzheimer’s and 14 without the disease. All of the tissues samples were obtained post mortem. People with Alzheimer’s had lower levels of DHA, which is a precursor for neuroprotective compounds. “There were statistically detectable differences in DHA content in all [brain] regions examined,” Astarita wrote.
Astarita determined that the low levels of DHA were related to a defect in the liver’s ability to convert tetracosahexaenoic acid (THA) to DHA. THA is the immediate metabolic precursor to DHA, and the conversation requires “D-bifunctional protein.” People with Alzheimer’s appear to lack the ability to make this particular protein. The finding “led us to hypothesize that the alteration in brain DHA might result from a systemic deficiency in the biosynthesis of this fatty acid,” Astarita wrote. Although Astarita did not explicitly suggest it, his research left open the possibility of using DHA supplements to bypass this defect.
Finally, Matthew F. Muldoon, MD, of the University of Pittsburgh in Pennsylvania and his colleagues measured blood levels of three omega-3 fats – alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), and DHA – in 280 people between the ages of 35 and 54 years. None of the subjects had been taking omega-3 supplements.
People with higher levels of DHA performed better on tests given to gauge reasoning, mental flexibility, memory, and vocabulary. Muldoon wrote that the omega-3s are “emerging as important nutrients for optimal brain development and for possible protection against brain senescense…it is plausible that insufficient dietary intake is related to relatively poor cognitive abilities or performance throughout the lifespan…”
SOURCE: Nutrition Reporter, Jack Challem. Nov. 2010 Vol.21 No.11
References: Smith DA, Smith SM, de Jager CA, et al. Homocysteine-lowering by B vitamins slows the rate of accelerated brain atrophy in mild cognitive impairment: a randomized controlled trial. PLoS One, 2010;5:e12244. Astarita G, Jung KM, Berchtold NC, et al. Deficient liver biosynthesis of docosahexaenoic acid correlates with cognitive impairment in Alzheimer’s disease. PLoS One, 2010;5:e12538. Muldoon MF, Ryan CM, Sheu L, et al. Serum phospholipid docosahexaenoic acid is associated with cognitive functioning during middle adulthood. Journal of Nutrition, 2010;140:848-853. !
Assurex Health recently sent me an email inviting me to dine at Legal Seafood to learn about “Clinical Applications of Psychiatric Pharmacogenetics.†I didn’t go, but increasingly I am hearing from colleagues about their experiences at these dinner programs: “What do you think about this GeneSight test? The data looked pretty impressive at this dinner.â€
Clearly, the field of pharmacogenetic testing is growing up when companies can afford this kind of promotional money nation-wide. There are now several companies marketing such tests—including Assurex, Genomind, Genelex and others.
We covered this topic last fall (TCPR, October 2014) and concluded that there was not enough good evidence for using genetic testing in routine practice. In the following, I’ll zero in specifically on GeneSight to review the data—so that you’ll be more informed if you choose to dine courtesy of Assurex. Good food and wine tend to dull your critical faculties, and you don’t want a company to hypnotize you into adopting a very expensive test unless it will really help your patients.
The Context of Pharmacogenetic Testing
Humans vary genetically—not only in eye and hair color but in more obscure ways, such as how we metabolize drugs. While the majority of our patients metabolize drugs normally, a small percentage do not. Using the most important enzyme, 2D6, as a benchmark, roughly 5–10% of Caucasians are poor metabolizers, and 1% are ultra-rapid metabolizers (Ingelman-Sundberg, M, Pharmacogenomics J 2005;5(1):6–13). Of the remainder, the majority are “extensive†(or normal) metabolizers. You should know that these frequencies vary among ethnic groups—for example, only about 1% of Asians are slow metabolizers.
Before I discuss GeneSight, an important but often overlooked point is that the recent GeneSight studies were preceded by decades of disappointing clinical studies in this field. Two large reviews of the literature on pharmacogenetics in mood disorders—one in 2007 (Genet Med 2007;9(12):819–825) and one in 2013 (CNS Spectr 2013;18(5):272–284)—could find no association between metabolizer status and response of depressed patients to SSRIs. Tricyclics are a different story, with evidence-based guidelines recommending dosage adjustments based on P450 testing (Hicks JK et al, Clin Pharmacol Ther 93(5):402–408, 2013). But most psychiatrists are not using the new genetic tests for tricyclics, which we rarely prescribe.
The take home point is that there’s a long history of negative or inconclusive studies in the field—so GeneSight’s evidence had better be pretty convincing before we decide to change our clinical practice based on it.
The GeneSight Test
The basic GeneSight test as evaluated in their clinical trials analyzes patient DNA for genes encoding three metabolic enzymes and two serotonin-related proteins. The three enzymes are 2D6, 2C19, and 1A2—all of which are located in the liver and are involved in metabolizing various medications. The other two molecules are SLC6A4 (the serotonin transporter gene) and HTR2A (the serotonin 2A receptor gene). (GeneSight has expanded its testing panel since the clinical trials—you can find the current list on its website, www.genesight.com).
The metabolic enzymes are clearly relevant for metabolism—no surprises there. But why did they include the serotonin genes in the assay? Presumably because they can theoretically affect the antidepressant response. However, there’s no scientific consensus that we have found the right genes yet. The most definitive meta-analysis found no consistent evidence of a relationship between serotonin genes and response to any antidepressant (Am J Psychiatry 2013;170(2):207–217). So GeneSight’s adding these genes appears to serve little use other than to make their assay appear more robust than a simple test of P450 enzymes.
The testing process is quite simple: you use cotton cheek swabs to collect the DNA, the samples are overnighted to Assurex, and results are provided within 36 hours. As a doctor, you’ll be sent a report classifying a list of 38 psychiatric drugs into three possible categories: green bin (“use as directedâ€), yellow bin (“use with cautionâ€) and red bin (“use with caution and with more frequent monitoringâ€). An easy example is Paxil, which is metabolized primarily by 2D6. Paxil will presumably show up in the red bin in two cases: if your patient is a poor metabolizer (because Paxil doses could go too high) or if he is an ultra-rapid metabolizer (the dose could be too low).
It all makes sense theoretically. But what about in actual practice?
The GeneSight Evidence
Three clinical studies have been conducted thus far. See the chart on this page for a brief summary of the main findings. There have been two open label studies, and one randomized, “double-blind†study (I’ll explain why I put quotes around that in a second). The methods of the studies are similar. Patients who are taking medications for depression are recruited from a clinic. They are assigned to one of two groups. In the guided group, patients are given the GeneSight test, the prescriber sees the results, and is free to make changes in the patients’ meds based on the results of the test. In the unguided group, patients get the test, but the results are sealed until after the study is over. Patients are periodically evaluated with standard depression scales, and the study length was eight weeks in the open label trials, 10 weeks in the randomized trial. The main outcome is whether patients assigned to the guided group improve more than those assigned to the unguided group.
Open Label Results
The open label studies found a statistically significant effect of using GeneSight to guide treatment. Open label studies are easy to conduct, and they’re great for generating hypotheses, but we shouldn’t rely on them to make clinical decision. Remember gabapentin? Open label studies found it apparently effective for bipolar disorder—but subsequent double-blind studies did not.
GeneSight’s open label studies are vulnerable to various possible biases that might render the results meaningless. Here are some potential problems.
Patients were not assigned to groups randomly, but were chosen based on conversations with doctors and researchers. One potential source of bias: doctors may have preferentially assigned more complicated patients to the guided group on the theory that they would be most helped by genetic testing. If so, we wouldn’t really know if the results are applicable to all the patients we see, or just some undefined subset.
Patients assigned to the guided group knew they were getting a cutting-edge genetic test that could predict which medication would work best for them. Patients in the other group knew the test results would not be used for their treatment. Clearly, those in the guided group would be more optimistic about their treatment, which is a key component of the non-specific placebo effect.
Prescribers knew which patients were being guided by the test, potentially leading to the “cheerleader effect.â€
The symptom raters knew which patients were in which group, potentially leading to biased ratings, since the raters may have vested interests in GeneSight being successful.
The bottom line is that the open label studies can tell us very little other than that GeneSight appears to have potential—and that it’s time to do the more expensive randomized double-blinded tests.
Randomized Results
The randomized double blind study was not “double†blind in the way drug trials are. The idea behind the double blind is that neither the researchers nor the patients know which group they are assigned to, so that there is no possibility of various biases or placebo effects creeping in. The GeneSight double blind study was blinded only to patients and symptom raters, and not to prescribers, who might have been cheerleading their patients to wellness.
Nonetheless, the results of that study showed a numerical superiority of guided treatment, but it was not statistically significant. For example, the difference in the Ham-D scores had a p value was 0.29—which means that there was a 29% chance that this difference was due to chance. The usual cut-off for statistical significance is 5%, so this result was not close to being significant. It’s possible that if they had recruited more patients, they might have found a significant difference. But for now we have to conclude that there is no convincing evidence that the GeneSight test helps us prescribe more effective medications for our patients
However, there is a bit of a silver lining for GeneSight in this study. In a subanalysis, the author focused on the 13 patients who entered the study taking antidepressants that were classified in the red bin—in other words, “use with caution and with more frequent monitoring.†Six of these were randomized to the guided group, and their doctors used the results to adjust the meds of all of these patients, who ended the study with a 33.1% Ham-D improvement. On the other hand, the seven patients who were assigned to the unguided group were less likely to have their meds changed, and they improved by only 0.8% on the Ham-D. This is intriguing, and raises the possibility that GeneSight might be useful for some patients. But remember—this is based on a subanalysis of 13 patients from an already tiny study.
If we were to hold the GeneSight test to the usual standards we require for making medication decisions, we’d conclude that there’s very little reliable evidence that it works. On the other hand, some of you will probably want to try it out, especially for those patients who have insurance that will cover the cost of the test. If you do order it, reserve it for patients who are most likely to benefit, including patients who have failed to respond to multiple medications (which could be caused by ultra-rapid metabolism, causing drug levels to be too low), and patients who have had lots of side effects (potentially caused by slow metabolism, causing drug levels to he too high).
“Personalized medicine†is a buzzword in healthcare and stems from the idea that treatments can be designed specifically for a patient, based on his or her own biological characteristics.
In psychiatry, personalization is largely based on “,†the selection of medications based on genetic factors associated with drug response and tolerability. Could your patient’s genetic code predict which medications you prescribe?
It’s important to point out that some genes affect pharmacokinetics while others involve pharmacodynamic processes. Pharmacokinetics refers to how quickly and efficiently a drug reaches its target and how quickly it leaves the body: drug absorption, distribution, metabolism, and excretion. Clinically, the most important contributor is the cytochrome P-450 (CYP450) system, which accounts for the metabolism of approximately 60% of prescribed drugs.
Multiple CYP450 enzymes exist and are classified according to a standardized nomenclature. The major enzymes of interest in clinical psychopharmacology are 1A2, 2B6, 2C9, 2C19, 2D6, and 3A4. For instance, fluoxetine is a substrate of 2D6; increased activity of this enzyme means lower blood levels of fluoxetine, while decreased activity corresponds to higher blood levels.
Pharmacodynamics, on the other hand, refers to the mechanism of action of a drug at its particular target(s). Whenever you prescribe a psychotropic drug, you are (most likely) thinking about the drug’s targets: receptors, transporters, or enzymes. Each of these directly or indirectly regulates the synthesis, transmission, or degradation of neurotransmitters such as serotonin and dopamine. Similar to the enzymes mentioned above, pharmacodynamic targets exist as proteins produced by different genes. Slight variations in the coding for a particular gene are referred to as polymorphisms, and these can alter the amount, structure, binding, or function of these proteins. In turn, these differences in the protein targets can influence the therapeutic or adverse effects of the drugs you prescribe.
For a well-known example of pharmacodynamic variation, consider the serotonin reuptake transporter (SERT). SERT regulates the reuptake of serotonin into neurons, and is the main site of action of selective serotonin reuptake inhibitor (SSRI) antidepressant drugs. Multiple genetic polymorphisms in SERT have been identified. Some research suggests that patients carrying certain SERT polymorphisms (such as the S or “short†allele) may respond less well to SSRI drugs and may experience more adverse effects of SSRIs, but the correlation is not absolute.
Polymorphisms of other genes involved in the pharmacodynamics of drug response, such as serotonin (5-HT) receptors, dopamine receptors, and other transporters, have been studied. But no single genetic difference, as of now, is significant enough to predict an outcome when you prescribe a drug.
Pharmacogenetic Tools
In recent years, numerous products have come on the market to analyze genetic polymorphisms. The first commercially available product was the AmpliChip CYP450 Test, developed by Roche Diagnostics and approved by the FDA in 2004. Using a small blood sample from the patient, it analyzes genetic polymorphisms associated with two metabolizing enzymes (2D6 and 2C19). Based on the patient’s 2D6 and 2C19 polymorphisms, his or her 2D6 metabolic activity is characterized as poor, intermediate, extensive, or ultra-rapid, and 2C19 activity as poor or extensive. This information can theoretically be used to make clinical decisions about drugs that are 2D6 or 2C19 substrates.
Many newer pharmacogenetic tests, based on similar technology, are currently available on the market. The most popular ones include Genecept and GeneSight. These tests analyze the majority of the known 450 enzyme polymorphisms, as well as various combinations of pharmacodynamic genes.
Laboratory Tests are Under-regulated by FDA
Despite their ready availability, does pharmacogenetic testing make sense for your patient? Does it really matter whether the patient in front of you is a “fast†or a “slow†metabolizer of a drug you are prescribing?
The answer to these key questions comes down to data, which I’ll review later in this article. But first, it’s important to know a bit about how these tests are regulated (or, more accurately, under-regulated). We are all familiar with the standards used by the FDA to approve medications: companies must submit double-blind, placebo-controlled trials and the FDA carefully scrutinizes the data before finally rendering a decision about approval.
Not so with laboratory tests. In fact, there are no specific federal requirements for laboratories to establish or verify the clinical validity of their tests, and laboratories generally do not have the capability to develop evidence of clinical utility. The bottom line is that the availability of a test should not be assumed to be proof that it has been proven to enhance clinical outcomes. Partly because of this problem, the FDA is currently developing draft guidelines on the regulation of laboratory tests, which would include pharmacogenetic test products.
What Does The Data Show?
Seven years ago, the federal Agency for Healthcare Research and Quality (AHRQ) reviewed existing studies to determine if testing for 450 polymorphisms in patients taking SSRIs leads to improvement in outcomes or  if testing results are useful in medical, personal, or public health decision-making (Thakur M et al, Genet Med 2007;9(12):826–835). The review revealed few high-quality, clinical studies. Several studies included non-randomized design, small numbers of subjects, and a failure to account for other genetic factors that may influence SSRI response or tolerability. There were no prospective studies of P450 genotyping and its relationship to clinical outcomes. There was no correlation between P450 polymorphisms and SSRI drug levels, efficacy, or tolerability. There were no data regarding whether testing leads to improved depression outcomes; whether testing influences medical, personal, or public health decision-making; or whether any harms are associated with testing itself or with subsequent management decisions. A more recent study found no clear benefit of testing for pharmacodynamic targets (de Leon J, Pharmacol Res 2009;59(2):81–89).
All this negative data has not dissuaded testing companies from marketing their products to us, sometimes aggressively so. The “GeneSight Psychotropic†test, offered by Assurex Health, detects genetic polymorphisms associated with six metabolic enzymes (1A2, 2B6, 2C9, 2C19, 2D6, and 3A4) and two pharmacodynamic genes (5HT2A and SERT). They claim that the results are potentially relevant to the use of 22 antidepressant drugs and 16 antipsychotic drugs.
The testing process is quite simple: blood samples or mouth swabs are sent to a central laboratory for analysis, and the results (available in 36 hours) categorize each of these 38 drugs into one of three groups: 1) little or no gene-drug interaction; 2) moderate gene-drug interaction; and 3) severe gene-drug interaction. For a particular patient, the use of drugs within each group is characterized as “use as directed†(referred to as “green bin†drugs), “use with caution†(“yellow binâ€), and “use with caution and with more frequent monitoring†(“red binâ€). The “green bin†drugs require no special dosing considerations for the patient. For drugs within the yellow and red “bins,†additional comments about their potential use are provided in the laboratory report. These comments might explain expected changes in drug blood levels (such as too high or too low) or expected clinical effects (such as reduced efficacy or increased side effects).
Does this information lead to better clinical outcomes? Two open-label studies have reported that GeneSight Psychotropic was effective for managing patients with depression (Hall-Flavin DK et al, Transl Psychiatry2012;2:e172; Hall-Flavin DK et al, Pharmacogenet Genomics 2013;23(10):535–548). In each study, a pharmacogenetic testing report was used to guide the selection and dosing of medication for one patient cohort, but not for the other cohort. The guided group in each study had greater depression symptom improvements. However, there were methodological problems. Patients were not randomly assigned to the groups. Also, prescribers and patients in each group were not fully blinded—potentially leading to a placebo effect that could artificially improve the outcomes for those who got the testing. Moreover, although these studies were funded by Mayo Clinic research grants, most of the authors have significant financial relationships with Assurex Health, which could have further biased the outcomes.
The company subsequently funded a prospective double-blind randomized trial, comparing the use of GeneSight Psychotropic to treatment without these test results. There was a slightly greater improvement in depression scores with guided treatment, but the difference between groups was not statistically significant (Winner JG et al, Discov Med 2013;16(89):219–227). The overall likelihood of medication switches, augmentations, or dose-adjustments did not differ between groups. However, a subanalysis showed that GeneSight subjects taking a “red bin†medication at baseline were significantly more likely to have this medication changed and, afterward, had significantly improved depression scores than unguided subjects taking a “red bin†medication. Overall, not very impressive results.
Assurex Health has commercialized two other pharmacogenetics products: GeneSight ADHD (released in May 2012) and GeneSight Analgesic (released in April 2014). Using the three-bin categorization scheme described previously, GeneSight ADHD classifies eight stimulant and non-stimulant drugs used for treating ADHD and GeneSight Analgesic classifies 22 opioid and non-opioid drugs. I am unaware of any published literature on clinical outcomes associated with the use of these tests.
Larger multi-center studies of genetic testing are currently underway. Cost-effectiveness will need to be assessed, as these tests are not cheap (eg, GeneSight Psychotropic is approximately $3,800) although they are sometimes covered by insurance. Forthcoming FDA guidelines will likely encourage, if not require, the assessment of clinical validity and utility of these tests before future tests go to market.
TCPR’s Verdict: Pharmacogenetic testing is intriguing, expensive, and unlikely to be clinically useful. Until we see better evidence, buyer beware!
Giving long-term high doses of docosahexaenoic acid to carriers of the apolipoprotein E ε4 (APOE4) allele before the onset of Alzheimer’s disease (AD) dementia may reduce the risk for AD, or delay the onset of symptoms, and should be studied, according to an expert review.
While the review of landmark observational and clinical trials that assessed supplementation with ω-3 fatty acids such as docosahexaenoic acid (DHA),revealed it was not beneficial in symptomatic AD, several observational and clinical trials of ω-3 supplementation in the pre-dementia stage of AD suggested it may slow early memory decline in APOE4 carriers, reported Hussein Yassine, MD, of the Keck School of Medicine at the University of Southern California in Los Angeles, and colleagues.
Results were mixed in patients with mild or no cognitive impairment, they wrote in JAMA Neurology.
DHA is critical to the formation of neuronal synapses and membrane fluidity, the authors explained.
“We hypothesize that DHA supplementation in APOE4 carriers can result in beneficial outcomes if the timing of the intervention precedes the onset of dementia. Given the safety profile, availability, and affordability of DHA, refining an interventional prevention study in APOE4 carriers is warranted,” they noted, adding that advanced brain imaging techniques could be used to identify optimal timing of DHA supplementation and treatment efficacy could be evaluated using specific biomarkers.
Their review of original articles, systematic reviews, and meta-analyses of ω-3 studies in AD showed that most associated higher levels of seafood, ω-3 consumption, or ω-3 blood levels with decreased incidence of AD, better cognitive measures, or preserved brain volume in AD-vulnerable regions.
One summary of 21 studies in a meta-analysis of of 181,580 participants, with 4,438 dementia cases identified over follow-up of 2 to 21 years, concluded that a single weekly serving of fish was associated with significantly lower risk for AD dementia.
A 2015 meta-analysis concluded that ω-3 supplementation significantly improved episodic memory in cognitively healthy older individuals.
“These studies indicate that APOE4 is a modifiable AD risk factor, and that the effect of APOE4 on AD pathologic changes can be attenuated with DHA supplementation,” Yassine’s group said.
Individuals with a single ε4 allele are three to four times more likely to develop AD as those without an ε4 allele, and people with two ε4 alleles have a 12-fold higher risk of developing AD, the researchers pointed out.
In an email to MedPage Today, Yassine stressed that the review was not intended to act as a recommendation for DHA supplementation. It was done “to stimulate interest in refining the role of high-dose DHA supplementation in a population at increased risk of AD using appropriately designed interventions. We think that long-term high-dose DHA supplementation in APOE4 carriers who are not avid seafood consumers may result in reducing AD incidence. This is evident from some of the epidemiology studies, but was difficult to demonstrate in randomized clinical trials given the limitations of trial designs.”
His group proposed that APOE4 carriers be classified into three stages based on disease severity.
In the earliest pre-dementia phase of the disease (stage I), participants would have evidence of brain imaging changes in areas vulnerable to AD. However, no cognitive changes, or only subtle ones, would be detectable.
“In this stage, brain DHA metabolism is altered by APOE4, and brain imaging or CSF biomarkers can be used to select at-risk individuals and monitor the efficacy of supplementation,” they explained.
It is for patients in an early prodromal stage of disease (stage II) that long-term high dose DHA supplementation could slow cognitive decline, the researchers stated. Patients in this group would have evidence of memory and/or executive decline but no significant impairment in activities of daily living.
Stage III would represent clinical AD with impairments in multiple cognitive domains. DHA supplementation would probably not be beneficial in this group.
Steven DeKosky, MD, of the McKnight Brain Institute in Gainesville, Fla., agreed that “it is almost surely correct that DHA won’t help much if at all in people with full-blown disease.”
But he cautioned that “the jury is still out on pre-AD. There isn’t much to say to clinicians about how they should act on this information other than to know that we somehow have to get a trial going to prove if it does help or not,” he told MedPage Today.
“This frequently gets translated into ‘My doctor said I should take DHA supplements,'” noted DeKosky, who was not involved in the review.
Calling the hypothesis “thoughtful,” DeKosky predicted that getting “evidence [of DHA supplementation’s value] for the jury” would not be easy. Such a study would have to run long enough to demonstrate the DHA supplementation is effective in delaying onset or emergence of signs or symptoms of AD, he stated.
“Given that DHA is not patented, no pharma will fund a study that long since many companies could sell it,” DeKosky said. “But that would be the evidence we would need.”
Yassine’s group plan to identify whether APOE4 carriers in the pre-dementia stage have measurable changes in brain DHA homeostasis, using novel imaging methods or cerebrospinal fluid DHA levels as an index of brain DHA. Then they will test to see whether high-dose DHA supplementation can offset these changes before the onset of AD dementia, Yassine explained.
The study was supported by the National Heart, Lung, and Blood Institute, the Alzheimer’s Association, the National Institute on Aging, the LK Whittier Foundation, and Huntington Medical Research Institute.
Yassine disclosed no relevant relationships with industry. One co-author disclosed relevant relationships with Baxter, Eli Lilly, Forum, Lundbeck, Merck, Novartis, Roche/Genentech, TauRx, and Biogen, AC Immune, Accera, Avraham, Boehringer Ingelheim, Cerespir, Cognition, Forum, Merck, Neurim, Roche, Stemedica, Takeda, TauRx, vTv, and Toyama/FujiFilm.
Unipolar major depressive disorder is a common, pervasive, and debilitating disease. Nearly one in five people will experience at least one episode of depression during their lifetime. In the United States alone, 16 million Americans – or, approximately 6.7% of the total population – will experience a depressive episode over the next 12 months(1). The symptoms of depression, which are akin to hibernation, negatively impact the lives of patients and their families, causing significant burden. Worldwide, depression causes more years lost to disability than any other disease(2). This is because depression usually impacts people early in their lives, and presents with a relapsing-remitting or a chronic course over their lifetime. Financially speaking, around $200 billion dollars a year is spent on the societal burden of depression in the United States(3). This total is higher than the burden of most other disorders. For comparison, the annual societal cost for cancer is around $131 billion dollars, and the cost for diabetes is around $173 billion dollars. Treatment-resistant depression, in particular, disproportionally accounts for a very large portion of the financial burden of depression, costing upwards of $48 billion yearly(3). Patients with depression, and especially those with treatment-resistant depression, will have decreased productivity in the workplace and at home, increased morbidity and mortality for medical conditions, as well as increased costs to the health care system through specialized treatment and services. This burden underscores the crippling effect of depression – especially treatment-resistant depression – on both patients and society, as a whole.
Kessler, R.C., et al., Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry, 2005. 62(6): p. 617-27.
Smith, K., Mental health: a world of depression. Nature, 2014. 515(7526): p. 181.
Mrazek, D.A., et al., A review of the clinical, economic, and societal burden of treatment-resistant depression: 1996-2013.Psychiatr Serv, 2014. 65(8): p. 977- 87.
Giving long-term high doses of docosahexaenoic acid to carriers of the apolipoprotein E ε4 (APOE4) allele before the onset of Alzheimer’s disease (AD) dementia may reduce the risk for AD, or delay the onset of symptoms, and should be studied, according to an expert review.
While the review of landmark observational and clinical trials that assessed supplementation with ω-3 fatty acids such as docosahexaenoic acid (DHA),revealed it was not beneficial in symptomatic AD, several observational and clinical trials of ω-3 supplementation in the pre-dementia stage of AD suggested it may slow early memory decline in APOE4 carriers, reported Hussein Yassine, MD, of the Keck School of Medicine at the University of Southern California in Los Angeles, and colleagues.
Results were mixed in patients with mild or no cognitive impairment, they wrote in JAMA Neurology.
DHA is critical to the formation of neuronal synapses and membrane fluidity, the authors explained.
“We hypothesize that DHA supplementation in APOE4 carriers can result in beneficial outcomes if the timing of the intervention precedes the onset of dementia. Given the safety profile, availability, and affordability of DHA, refining an interventional prevention study in APOE4 carriers is warranted,” they noted, adding that advanced brain imaging techniques could be used to identify optimal timing of DHA supplementation and treatment efficacy could be evaluated using specific biomarkers.
Their review of original articles, systematic reviews, and meta-analyses of ω-3 studies in AD showed that most associated higher levels of seafood, ω-3 consumption, or ω-3 blood levels with decreased incidence of AD, better cognitive measures, or preserved brain volume in AD-vulnerable regions.
One summary of 21 studies in a meta-analysis of of 181,580 participants, with 4,438 dementia cases identified over follow-up of 2 to 21 years, concluded that a single weekly serving of fish was associated with significantly lower risk for AD dementia.
A 2015 meta-analysis concluded that ω-3 supplementation significantly improved episodic memory in cognitively healthy older individuals.
“These studies indicate that APOE4 is a modifiable AD risk factor, and that the effect of APOE4 on AD pathologic changes can be attenuated with DHA supplementation,” Yassine’s group said.
Individuals with a single ε4 allele are three to four times more likely to develop AD as those without an ε4 allele, and people with two ε4 alleles have a 12-fold higher risk of developing AD, the researchers pointed out.
In an email to MedPage Today, Yassine stressed that the review was not intended to act as a recommendation for DHA supplementation. It was done “to stimulate interest in refining the role of high-dose DHA supplementation in a population at increased risk of AD using appropriately designed interventions. We think that long-term high-dose DHA supplementation in APOE4 carriers who are not avid seafood consumers may result in reducing AD incidence. This is evident from some of the epidemiology studies, but was difficult to demonstrate in randomized clinical trials given the limitations of trial designs.”
His group proposed that APOE4 carriers be classified into three stages based on disease severity.
In the earliest pre-dementia phase of the disease (stage I), participants would have evidence of brain imaging changes in areas vulnerable to AD. However, no cognitive changes, or only subtle ones, would be detectable.
“In this stage, brain DHA metabolism is altered by APOE4, and brain imaging or CSF biomarkers can be used to select at-risk individuals and monitor the efficacy of supplementation,” they explained.
It is for patients in an early prodromal stage of disease (stage II) that long-term high dose DHA supplementation could slow cognitive decline, the researchers stated. Patients in this group would have evidence of memory and/or executive decline but no significant impairment in activities of daily living.
Stage III would represent clinical AD with impairments in multiple cognitive domains. DHA supplementation would probably not be beneficial in this group.
Steven DeKosky, MD, of the McKnight Brain Institute in Gainesville, Fla., agreed that “it is almost surely correct that DHA won’t help much if at all in people with full-blown disease.”
But he cautioned that “the jury is still out on pre-AD. There isn’t much to say to clinicians about how they should act on this information other than to know that we somehow have to get a trial going to prove if it does help or not,” he told MedPage Today.
“This frequently gets translated into ‘My doctor said I should take DHA supplements,'” noted DeKosky, who was not involved in the review.
Calling the hypothesis “thoughtful,” DeKosky predicted that getting “evidence [of DHA supplementation’s value] for the jury” would not be easy. Such a study would have to run long enough to demonstrate the DHA supplementation is effective in delaying onset or emergence of signs or symptoms of AD, he stated.
“Given that DHA is not patented, no pharma will fund a study that long since many companies could sell it,” DeKosky said. “But that would be the evidence we would need.”
Yassine’s group plan to identify whether APOE4 carriers in the pre-dementia stage have measurable changes in brain DHA homeostasis, using novel imaging methods or cerebrospinal fluid DHA levels as an index of brain DHA. Then they will test to see whether high-dose DHA supplementation can offset these changes before the onset of AD dementia, Yassine explained.
The study was supported by the National Heart, Lung, and Blood Institute, the Alzheimer’s Association, the National Institute on Aging, the LK Whittier Foundation, and Huntington Medical Research Institute.
Yassine disclosed no relevant relationships with industry. One co-author disclosed relevant relationships with Baxter, Eli Lilly, Forum, Lundbeck, Merck, Novartis, Roche/Genentech, TauRx, and Biogen, AC Immune, Accera, Avraham, Boehringer Ingelheim, Cerespir, Cognition, Forum, Merck, Neurim, Roche, Stemedica, Takeda, TauRx, vTv, and Toyama/FujiFilm.
Previous studies suggest that depression occurs in youth with attention-deficit/hyperactivity disorder (ADHD) at a higher rate than youth without ADHD, but the effects of ADHD medication on the development of depression are unclear. A study in Biological Psychiatry now suggests that individuals taking ADHD medications may be at reduced risk for subsequent and concurrent depression.
Zheng Chang, Ph.D., of the Karolinska Institutet in Sweden, and colleagues used several population-based registers in Sweden to identify 38,752 patients with ADHD who were born between 1960 and 1998 and were living in Sweden in 2009.
The researchers tracked the individuals from January 2006 through December 2009 to assess the association between ADHD medication (methylphenidate, amphetamine, dexamphetamine, and atomoxetine) and depression. The primary outcome was occurrence of depression between January 1, 2009, and December 31, 2009, including diagnoses from both hospital admissions and outpatient visits for depression. A total of 2,987 patients experienced depression events in 2009.
After adjusting for sociodemographic and clinical confounders, the researchers found that ADHD medication was associated with a reduced risk of depression (hazard ratio = 0.58). For each year an individual was taking ADHD medication during the study period, there was a 21% decrease in the rate of depression in 2009. In addition, the analysis showed that concomitant occurrence of depression was 36% less common during periods when patients received ADHD medications compared with periods when they did not receive medication.
“[O]ur study provided new evidence that ADHD medication does not increase the risk of later depression, but rather is associated with a reduced risk for subsequent and concurrent depression,” the researchers wrote. “Ascertaining the effect of ADHD medication on the development of depression can provide critical information to clinicians treating youths with ADHD.”
Donald Rauh M.D., Ph.D., FAPA
Diplomate of the American Board of Psychiatry & Neurology
Board Certified in General Psychiatry and in Child & Adolescent Psychiatry
