Monday, November 24, 2014

Why Do Patients With Schizophrenia Smoke So Many Cigarettes?

For sound neurological reasons, that's why.

(Originally published May 2, 2012, by The Dana Foundation)

For mental health workers, it is well known that an overwhelming majority of psychiatric patients diagnosed with schizophrenia are heavy cigarette smokers. Surveys have shown that at least 60 percent of patients exhibiting symptoms of schizophrenia are smokers, compared with a national average that hovers just above 20 percent. Writing in the New England Journal of Medicine, researcher Judith J. Prochaska, associate professor of psychiatry at the University of California in San Francisco, found that “smokers with serious mental illnesses are dying 25 years sooner, on average, than Americans overall.” And tobacco is one of the reasons why.

Cigarettes, long familiar in institutional settings as a tool for reinforcing desired behavior, are slowly disappearing from state hospitals. “For state inpatient psychiatric facilities responding to surveys,” says Prochaska, “the best estimate is that about half have adopted smoke-free policies.” Increasingly, acute nicotine withdrawal is a strong part of the mix for the recently admitted smoker with schizophrenia.

An earlier study by Prochaska and colleagues, published in Psychiatric Services, found that while 42 percent of psychiatric patients at a smoke-free San Francisco hospital were smokers, averaging slightly more than a pack per day, none of the smokers received a diagnosis of dependence or withdrawal, and none were offered treatment planning for smoking cessation.

“Smokers who were not given a prescription for nicotine replacement therapy were more than twice as likely to be discharged from the hospital against medical advice as nonsmokers and smokers who were given a prescription for nicotine replacement therapy,” the study concludes. The authors believe that “nicotine withdrawal left unaddressed may compromise psychiatric care…. Given the complicated relationship between mental illness and smoking, integration of cessation efforts into psychiatric care is recommended.”

During the first few hours after patients with schizophrenia enter smoke-free psychiatric emergency settings, more than half become agitated, and 6 percent are physically restrained, according to a recent study by Dr. Michael H. Allen and coworkers at the University of Colorado School of Medicine. Published in the American Journal of Psychiatry, the double-blind study looked at 40 patients admitted to the psychiatric emergency service of the Hospital of the University of Geneva, and found that a relatively safe and simple addition to the emergency stabilization of patients with schizophrenia—a 21 mg nicotine patch—markedly reduced agitation in patients who smoked. The practice of “forced abstinence,” which is the consequence of recent trends toward smoke-free institutions, may not be in the patient’s best interest—especially since formal smoking cessation programs are not always a part of hospital routine.

Allen and colleagues gave out either the nicotine patch or a placebo patch to 40 smokers recently admitted to the hospital with symptoms of schizophrenia. While agitation diminished over time in both the intervention group and the placebo group, “the intervention group had a 33 percent greater reduction in agitation at 4 hours and a 23 percent greater reduction at 24 hours.” The authors say that the differences are similar to those observed in industry trials of common antipsychotics. According to Allen, “forced tobacco abstinence may have the effect of increasing aggressive behavior.” For patients with schizophrenia, smoking works.

The importance of nicotine to patients with schizophrenia should not be underestimated. There are rational biological reasons why schizophrenics smoke. A review of earlier studies published in Psychiatric Services suggests that smokers with schizophrenic symptoms may be self-medicating to improve the processing of auditory stimuli, and to reduce the side-effects caused by common antipsychotic medications. 

“Neurobiological factors provide the strongest explanation for the link between smoking and schizophrenia,” writes Edward R. Lyon, the study’s author, “because a direct neurochemical interaction can be demonstrated.” Flaws in sensory gating, the process by which the brain lowers its response to a repeated sound, are believed to be involved in the auditory hallucinations common to people with schizophrenia. And sensory gating improves for schizophrenics after they load up on nicotine.  Other research has shown a reduction in expression of nicotinic receptors in schizophrenia, suggesting that a susceptibility to smoking and schizophrenia may be related.

Prochaska sees smoking among patients in psychiatric settings as the consequence of several factors, including clinicians' failure to treat nicotine addiction, as well as the role nicotine plays as an antidote to drug side effects. Patients are familiar with the side effects of the drugs they take, “so they smoke and it reduces the blood levels of their medications,” she says. “They’re less sedated, and they can focus more.”

This complicates the picture for psychiatric staff: Antipsychotic drugs are metabolized faster in smokers, leading to the need for higher doses of medication. Prochaska notes that tobacco smoke may inhibit the effect of commonly used drugs like haloperidol, and the inhibition “can be as high as an increase clearance of 40–98 percent for olanzapine, a costly medication.”

In an interview, Prochaska said that the heaviest smokers “may need to stay on cessation medications for an extended period, and that’s certainly better for them than smoking. Combination therapy also is recommended. In our studies, we combine the nicotine patch with gum or lozenge so they’re able to add to the patch to get sufficient coverage of withdrawal symptoms.”

Mental health professionals have traditionally argued that patients with schizophrenia do not want to quit smoking, but Prochaska’s work suggests otherwise. Patients in psychiatric settings are about as likely as the general population to want to quit smoking, her research shows. “There is growing evidence that smokers with mental illness are as ready to quit as other smokers and can do so without any threat to their mental health recovery,” she said.

By some estimates, people with psychiatric disorders make up almost half of the current U.S. market for tobacco products. As Prochaska has written, “nicotine dependence is the most prevalent substance use disorder among adult psychiatric patients, and it needs to be placed on the radar of psychiatric practice.”

It’s up to healthcare providers to get the ball rolling. “Many facilities are still struggling with it,” she says. “It’s not been in their purview traditionally, so changing the culture is a big piece of the solution. It’s very much a matter of trying to get tobacco treatment medicalized, having it be automatic, so that nicotine replacement is right there in the admitting orders. And ideally, working with patients while they are hospitalized to motivate smoking cessation, and supporting them when they leave.”

Tuesday, November 18, 2014

Another Look at Acamprosate

The most popular pharmaceutical treatment for alcoholism, explained.

(First published February 17, 2014)

“Occasionally,” reads the opening sentence of a commentary published online earlier this year in Neuropsychopharmacology, “a paper comes along that fundamentally challenges what we thought we knew about a drug mechanism.” The drug in question is acamprosate, and the mechanism of action under scrutiny is the drug’s ability to promote abstinence in alcoholics. The author of the unusual commentary is Markus Heilig, Chief of the Laboratory of Clinical and Translational Studies at the National Institute on Alcohol Abuse and Alcoholism (NIAAA).

Acamprosate, in use worldwide and currently the most widely prescribed medication for alcohol dependence in the U.S., may work by an entirely different mechanism than scientists have believed on the basis of hundreds of studies over decades. Rainer Spanagel of the Institute of Psychopharmacology at the University of Heidelberg, Germany, led a large research group in revisiting research that he and others had performed on acamprosate ten years earlier. In their article   for Neuropsychopharmacology, Spanagel and coworkers concluded that a sodium salt version of acamprosate was totally ineffective in animal models of alcohol-preferring rats.

“Surprisingly,” they write, “calcium salts produce acamprosate-like effects in three animal models…. We conclude that N-acetylhomotaurinate is a biologically inactive molecule and that the effects of acamprosate described in more than 450 published original investigations and clinical trials and 1.5 million treated patients can possibly be attributed to calcium.”

At present, the Food and Drug Administration (FDA] has approved three drugs for alcoholism— Antabuse, naltrexone, plus acamprosate in 2004. In addition, there is considerable clinical evidence behind the use of four other drugs—topiramate, baclofen, ondansetron, and varenicline. Acamprosate as marketed is the calcium salt of N-acetyl-homotaurinate, a close relative of the amino acid taurine. It has also been found effective in European studies.

What did scientists think acamprosate was doing? Various lines of research had linked acamprosate to glutamate transmission. Changes in glutamate transmission have been directly implicated in active alcoholism. A decade ago, the Spanagel group had decided that acamprosate normalized overactive glutamate systems, and hypothesized that acamprosate was modulating GABA transmission. So it became known as a “functional glutamate antagonist.”  But specific mechanisms have remained elusive ever since.

Now, as Heilig comments, “the reason it has been difficult to pin down the molecular site of acamprosate action may simply be because it does not exist. Instead, the authors propose that the activity attributed to acamprosate has all along reflected actions of the Ca++ it carries.” As the researcher paper explains it: “N-acetylhomotaurinate by itself is not an active psychotropic molecule…. We have to conclude that the proposed glutamate receptor interactions of acamprosate cannot sufficiently explain the anti-relapse action of this drug.” Further work shows that acamprosate doesn’t interact with glutamate binding sites at all.  In other words, calcium appears to be the major active ingredient in acamprosate. Animal studies using calcium chloride or calcium gluconate reduced alcohol intake in animals at rates similar to those seen in acamprosate, the researchers claim.

Subsequently, the researchers revisited the earlier clinical studies, subjected them to secondary analysis, and concluded that “in acamprosate-treated patients positive outcomes are strongly correlated with plasma Ca++ levels. No such correlation exists in placebo-treated patients.” In addition, calcium salts delivered via different carrier drugs replicated the suppression of drinking in the earlier animal findings.

Where there cues pointing toward calcium? The researchers conclude that “calcium sensitivity of the synapse is important for alcohol tolerance development, calcium given intraventricularly significantly enhances alcohol intoxication in a dose-dependent manner,” and “activity of calcium-dependent ion channels modulate alcohol drinking.”

Interestingly, in the late 50s and early 60s, there was a brief period of interest in calcium therapy for the treatment of alcoholism. In 1964, the Journal of Psychology ran an article titled “Intensive Calcium Therapy as an Initial Approach to the Psychotherapeutic Relationship in the Rehabilitation of the Compulsive Drinker.” Now it appears possible that a daily dose of acamprosate is effective for some abstinent alcoholics because it raises calcium plasma levels. Calcium supplements may be in for a round of intensive clinical testing if these findings hold up.

The authors now call for “ambitious randomized controlled clinical trials,” to directly compare “other means of the Ca++ delivery as an approach to treat alcohol addiction. Data in support of a therapeutic role of calcium would open fascinating clinical possibilities.”  Indeed it would.

Spanagel R., Vengeliene V., Jandeleit B., Fischer W.N., Grindstaff K., Zhang X., Gallop M.A., Krstew E.V., Lawrence A.J. & Kiefer F.  (2013). Acamprosate Produces Its Anti-Relapse Effects Via Calcium, Neuropsychopharmacology, 39 (4) 783-791. DOI: 10.1038/npp.2013.264

Wednesday, November 12, 2014

Marijuana Statistics vs. Perception

Who smokes cannabis, and how much?

(First published 12/27/2013)

Most statistical surveys of marijuana focus on a single quantitative measurement: How many people are using? But there’s a problem: More marijuana use does not necessarily translate into more marijuana users. And that’s because a clear majority of the consumption, and black market dollars, come from the heaviest smokers.

Drug policy researchers at the RAND corporation decided that frequency of use and amount of consumption were valuable parameters gone missing in most policy discussions. So they put the focus not just on use, but also on “use-days,” and pulled a number of buried tidbits from a very big data pile. If you zero in on consumption, and not just consumers, they insist, you will find a wholly different set of inferences.

For example: “Although daily/near-daily users represented less than one-quarter of past-month cannabis users in 2002 and roughly one-third of past-month users in 2011, they account for the vast majority of use-days and are thus presumably responsible for the majority of consumption,” write Rachel M. Burns and her RAND colleagues in Frontiers of Psychiatry. As with alcohol, the majority of cannabis consumption can be accounted for by a minority of users. The heaviest users, the upper 20 percent, consume 88 percent of the U.S. marijuana supply, say the RAND researchers. “Furthermore, if over time there were no change in the number of cannabis users, but the ratio of light vs. heavy users switched from 80/20 to 20/80, then consumption would increase by 250% even though there was no change whatsoever in the number of users.”

The RAND group used two data sets on cannabis consumption—the National Survey on Drug Use and Health (NSDUH) in the U.S., and the EU Drugs Markets II (EUMII) in Europe. Data included figures for past-year and past-month use, past-month use days, and past-month purchases.

Other intriguing figures come to light when you study cannabis use, as opposed to cannabis users. The researchers declared that “only 14% of past-year cannabis users [primarily males] meet the criteria for cannabis abuse or dependence, but they account for 26% of past-month days of use and 37% of past-month purchases.”

Happen to smoke blunts? That turns out to be very telling, according to the RAND study. “Perhaps the most striking contrast concerns blunts. Only 27% of past-year cannabis users report using a blunt within the last month, but those individuals account for 73% of cannabis purchases.” Casual users, it seems, don’t do blunts.

Clearly, it takes a lot of casual users to smoke as much marijuana as one heavy user. But exactly how many? The RAND researchers ran the numbers and concluded that, in terms of grams consumed per month, it would take more than 40 casual smokers to equal the intake of a single heavy user. The share of the market represented by daily/near-daily users is clearly the motive force in their analysis.

The study in Frontiers in Psychiatry also found patterns of interest on the buy side. General use took an upswing beginning in 2007. While the probability of arrest per marijuana smoking episode hovers somewhere in the neighborhood of 1 in 3,000, everything changes if you are purchasing cannabis. RAND reported that young people collectively make more purchases per day of reported use than do older users. Therefore, “statistics indicating that the burden of arrest falls disproportionately on youth relative to their share of all users may not be prima facie evidence of discrimination if making more purchases per day of use increases the risk of arrests per year of use.” Once again, those aging Baby Boomer potheads get the best deal. They have more money with which to buy bigger amounts less often, thereby greatly lessening their chances of arrest and prosecution.

This also applies to minority arrests for marijuana offenses. “Non-Hispanic blacks represent 13% of past-year cannabis users vs. 23% of drug arrests reported by those users, but they report making 24% of the buys. Thus, some of their higher arrest rate may be a consequence of purchase patterns… African-Americans may not only make more buys but also make riskier buys (e.g., more likely to buy outdoors).”

The researchers were able to draw some conclusions about the growth in marijuana usage from 2002 through 2011, based on the NSDUH data. Their main conclusion, after exploring the demographics of this 10-year record of use, is that “consumption grew primarily because of an increase in the average frequency of use, not just because of an increase in the overall number of users.”  The driver of consumption turns out to be… greater consumption. And that increased consumption is coming from… older adults. Those older adults, it turns out, are smoking more weed.

The shift is dramatic: “In 2002, there were more than three times as many youth as older adults using cannabis on a daily/near-daily basis; in 2011 there were 2.5 times more older adults than youth using on a daily/near-daily basis.” The record of alcohol and cigarette use over the same period showed no such inversion of use patterns.  And the tweeners? “In 2002, 12-17-year-olds represented 13% of daily/near-daily users; in 2011, that had dwindled to 7%.” These trends are not just the obvious result of an increase in the proportion of older adults in the population at large. Increases in the proportion of older heavy cannabis users were much greater than the general population drift.

Among the questions raised by the RAND analysis:

— Are older marijuana smokers primarily recreational, or medicinal?

—Do increased use days among older, college-educated marijuana smokers indicate greater social acceptance, or something else?

—Are younger people replacing traditional cannabis use with other substances?

—Why did Hispanic use increase more over the study period than other ethnic groups?

Burns R.M., Caulkins J.P., Everingham S.S. & Kilmer B. (2013). Statistics on Cannabis Users Skew Perceptions of Cannabis Use, Frontiers in Psychiatry, 4   DOI: 10.3389/fpsyt.2013.00138