Tag: Pfizer

06/13/23

Overdiagnosing Depression with the PHQ

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According to PsychCentral, in 2020 there were more than 252 million prescriptions prescribed for mental health conditions. The total cost spent on psychiatric medications was more than $15.6 trillion. Zoloft (sertraline) was the most prescribed psychiatric medication with 38.22 million prescriptions, but only made Pfizer $523 million. This is because Pfizer’s patent on Zoloft expired in June of 2006. In its last full year of patent exclusivity, Pfizer’s sales for Zoloft totaled $3.3 billion. And it seems Zoloft’s popularity as an antidepressant can be credited at least in part to the introduction of the Patient Health Questionnaire (PHQ-9), which was developed by Pfizer shortly after Zoloft came on the market.

Writing for Insider, Hilary Bruek said Pfizer was persuaded to invest in the research necessary to develop what became the PHQ-9 by Howard Kroplick, one of their marketers. Kroplick told STAT: “It wouldn’t have happened if it wasn’t for me.” The PHQ-9 became a quick and easy tool that made many primary care doctors more comfortable prescribing antidepressants. Once Pfizer decided to underwrite the development of the PHQ-9, they contracted with Robert Spitzer and his wife Janet Williams, who were central figures in the revisions of the DSM-III.

In September of 2001, Kurt Kroenke, Robert Spitzer and Janet Williams published “The PHQ-9” in the Journal of General Medicine. The authors thought brief measures like the PHQ-9 were more likely to be used in the busy setting of primary care clinical practice. “Brevity coupled with its construct and criterion validity makes the PHQ-9 an attractive, dual-purpose instrument for making diagnoses and assessing severity of depressive disorders.” Note that the creators of the nine item PHQ-9 thought it could be used to diagnose depression. STAT reported the PHQ-9 has become an omnipresent tool, being cited in more than 11,000 scientific papers and routinely used in primary care and other routine visits.

Prescribing antidepressants in primary care based upon a PHQ-9 score of 10 or greater appears to be a sensible medical decision. There have been multiple studies such as Moriarty et al in General Hospital Psychiatry, that find the cutoff point of 10 on the PHQ-9 to have “acceptable diagnostic properties” for major depression. Studies, such as Negeri et al in the BMJ find the PHQ-9 has a combined sensitivity of 85% at the standard cutoff value of ≥10. A referral to a psychiatrist to confirm a depression diagnosis means a delay in treatment, meaning a delay in prescribing an antidepressant. Why not just recommend to the patient that they try a SSRI if their PHQ-9 score is equal to or greater than 10?

Malpass et al noted their concern that self-administered questionnaires like the PHQ-9 were regularly used in clinical practice to guide prescribing or to measure recovery and response to treatment. They thought when patients were given the PHQ-9, they were not interpreting the question items in the same way. They used a research technique called cognitive interviewing to identify ‘interpretive measurement error’ (IME). They found a wide range of comprehension and answer-mapping difficulties on the PHQ-9 that persisted over time.

Clinicians have expressed uncertainty about the PHQ-9’s validity and utility, and in the management and diagnosis of depression within primary care have a strong preference for clinical judgement over scores on severity measures. In light of the numerous ways the PHQ-9 may be missing the presence and/or intensity of certain symptoms that are meaningful to patients, clinicians should continue to adopt caution when using and interpreting questionnaire scores. The study raises the question that longer assessments may be better in providing opportunities for distinguishing frequency and severity.

Writing for Mad in America, Peter Simons commented on a meta-analysis study by researchers in the Journal of Epidemiology that concluded the PHQ-9 did not accurately estimate the prevalence of depression. The researchers concluded that that the PHQ-9 “substantially overestimates depression prevalence. There is too much heterogeneity to correct statistically in individual studies.” Simons said they found it was twice as likely to diagnose depression as the SCID, a semi-structured interview guide for making diagnoses according to the diagnostic criteria published in the DSM. 24.6% of participants in the study were found to be depressed by the PHQ-9, while only 12.1% met the criteria for depression on the SCID.

In primary care settings doctors will likely consider a positive score of ten or higher (the standard cut-off for depression screening with the PHQ-9) as indicating the presence of depression and consider it good enough to diagnose patients with depression and recommend antidepressant treatment. “This could lead to massive inflation of the estimates of how many people ‘have’ depression in the population.” The PHQ-9 is technically not a diagnostic measure of depression (despite what its creators said), but when it is used that way, the result is overdiagnosis.

Estimates of depression prevalence should be based on validated diagnostic interviews designed for determining case status; users should evaluate published reports of depression prevalence to ensure that they are based on methods intended to classify major depression.

The bottom line is that when screening tools like the PHQ-9 are used alone to assess depression in a person, clinicians are likely to misdiagnose it. And there are additional problems if the misdiagnosed person begins using an antidepressant to “treat” this so-called depression.

The general public widely believes depression is the result of a chemical imbalance, which shapes how people understand their moods. It may also discourage them from discontinuing a prescribed antidepressant medication, potentially leading to lifelong dependence on these drugs. An umbrella study by Moncrieff et al found “there is no convincing evidence that depression is associated with, or caused by, lower serotonin concentrations or activity.” The researchers said most studies did not find evidence of reduced serotonin activity in people with depression when they were compared to people without depression. The chemical imbalance theory of depression is now seen as an urban legend, “never a theory seriously propounded by well-informed psychiatrists,” according to pro-medication psychiatrist Ronald Pies.

Moncrieff and others have also noted there are adverse effects from taking antidepressants. In “Persistent adverse effects of antidepressants, she said we are not clear about the nature of the neurochemical and physiological changes that occur when we take an antidepressant. “We are even less certain about how the body, including the brain, adapts to the long-term presence of these drugs.” We also do not know whether the changes produced by the drugs in the brain return to normal when the drugs are stopped; or if the changes persist.

Moncrieff then pointed to the withdrawal effects with long-term antidepressant use. She said the evidence suggests a picture similar to benzodiazepine withdrawal. There is a range of duration and intensity, where not everyone experiences noticeable or debilitating symptoms, but there are numerous reports of “withdrawal symptoms being severe and protracted.”

Moncrieff also referred to a 2006 article by David Healy and others that associated antidepressants and violence in some individuals. Healy said mechanisms that linked antidepressant treatment (rather than the depression itself) to violent behavior included akathisia, emotional disinhibition, emotional blunting, and manic or psychotic reactions. “There is good evidence that antidepressant treatment can induce problems such as these and a prima facie case that akathisia, emotional blunting, and manic or psychotic reactions might lead to violence.”

A group of researchers from the Nordic Cochrane Center in Denmark, including Peter Gøtzsche, published a meta-analysis in 2016 that confirmed Healy et al’s findings, according to Moncrieff. They found the risk of aggressive behavior doubled with the use of antidepressants. They also said akathisia was under-reported. Although akathisia occurred more often with study participants who used antidepressants, the difference was not significant. While they found no significant differences in mortality or suicidality, “our data confirmed the increased risk of suicide in children and adolescents.”

A 2016 literature review of long-term newer antidepressant use (SSRIs and SNRIs) by Carvalho et al noted over 12 adverse effects from antidepressants, that included weight gain, bleeding, sleep disturbance, diabetes, osteoporosis and others. The findings of this review suggest that long-term treatment with SSRIs and SNRIs “should be avoided if alternative treatments are available.” The authors noted there is a tendency to extend antidepressant treatment for long periods of time, believing that it protects against recurrence. However, that was not true in all cases. “This finding indicates that in patients with chronic recurring MDD, recurrences are difficult to prevent with [antidepressant] use only.”

It seems that the PHQ-9 depression scale has contributed to the overdiagnosis of depression and the overuse of antidepressants. One might even suggest this was exactly what it was developed to do. The PHQ-9 helped Pfizer (and eventually other pharmaceutical drug companies) reach into the untapped market of primary care physicians and gave them a tool they felt comfortable using in order to prescribe antidepressants to their patients. Unfortunately for the PHQ-9, the evidence that antidepressants have limited efficacy and multiple adverse side effects is growing.

08/24/18

Misleading Pharma Ads

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Pfizer had a killer direct-to-consumer ad for its anti-cholesterol drug Lipitor in 2006-2008. Robert Jarvik, identified as the inventor of the artificial heart, turns to the camera and says, “Just because I’m a doctor doesn’t mean I don’t worry about my cholesterol.” After recommending that people use Lipitor, the commercial shows him rowing across a lake. While the ad cost Pfizer $260 million, it played fast and loose with several facts. Robert Jarvik had never been licensed as a medical doctor so he could not legally prescribe anything. He didn’t actually invent the artificial heart; and he didn’t even row the boat in the commercial. “Welcome to the world of direct-to-consumer advertising.”

Television direct-to-consumer (DTC) ads have become the most ubiquitous means of Pharma advertising. It is estimated that a person in the U.S. watching an average of 4.3 hours of broadcast television per day will see nine drugs ads, totaling around 30 hours of direct-to-consumer (DTC) ads each year. In 2017, spending on DTC ads in the U.S. reached $6.1 billion; a 4.6% decrease from 2016 ($6.4 billion).

The FDA has oversight of DTC ads by the pharmaceutical industry through the Food, Drug and Cosmetic Act of 1938. Congress approved the Act in an effort to protect the health and safety of U.S. citizens by regulating the food and medical supply. “The Act regulates the pharmaceutical industry to ensure the safety and efficacy of drug produced and sold in the United States, and it gives the FDA authority to carry out its legislative directives.” Amendments in 1962 by Congress to the Food, Drug and Cosmetic Act transferred the regulatory authority of prescription drug advertising from the Federal Trade Commission to the FDA. “With the addition of the 1962 amendments, the regulation of drugs became the most consuming, and at times the most controversial, aspect of all the FDA’s activities.”

As a result of these actions, drug companies are required to submit all their promotional materials to the FDA’s Office of Prescription Drug Promotion (OPDP). However, limitations on the capacity and resources of the OPDP mean it cannot review every single ad. Nevertheless, there was not a significant amount of DTC advertising even after the FDA made it possible in 1985.

The Food, Drug and Cosmetic Act has been traditionally understood by the FDA to restrict unapproved or “off-label” promotion use. FDA regulations explicitly prohibit DTC ads from even suggesting any off-label use. While print ads must state all of the risks in the drug’s FDA-approved label in a “brief summary,” broadcast DTC ads are only required to include the major risks, as long as those risks are verbally communicated and the ad provides a source for consumers to access the FDA-approved labeling for the drug.

In 1997, the Division of Drug Marketing, Advertising, and Communications (DDMAC), a sub-division of the Center for Drug Evaluation and Research (CDER), which is a division of the FDA, released guidelines which allow prescription drug manufacturers to comfortably satisfy the legal requirements for advertising their products to the general public. As a result, pharmaceutical companies have swelled their direct-to-consumer (DTC) marketing budgets and provided the advertising industry with a profitable new line of products to promote. Since the regulatory change was announced, name-brand prescription drug use in the United States has increased, drug prices have gone up, a debate over the effects, efficacy and wisdom of DTC ads has ensued, and scores of heath care issues that affect patients, doctors, insurers, and the federal government have risen to the surface.Despite the wide enforcement authority generally given to the FDA, the Act expressly prohibits any requirement that pharmaceutical companies submit drug advertising content for FDA pre-market approval (except in extraordinary circumstances). This provision, grounded in First Amendment doctrine, has led to a regulatory regime that can only offer a pre-market approval process and enforce compliance post-violation.

This protection of the pharmaceutical company’s right to speak has occasionally resulted in ads giving information that did not satisfy the Act’s requirement that all advertisements give a “fair balance” of the drug’s benefits and risks. Drug companies have also used this provision to challenge certain FDA restrictions on off-label marketing.”Recent federal court cases have permitted companies to promote off-label indications, thereby calling into question the FDA’s authority to regulate off-label marketing, even with respect to DTC advertising.”

“Adherence to FDA Guidelines in DTC Advertising” by Klara et al. noted where previous studies have found many Pharma companies do not follow the advertisement guidelines set forth by the FDA. They assessed the degree to which recently aired DTC ads (between January 2015 and July 2016) for prescription drugs adhered to FDA regulations and whether off-label use was suggested. They looked at both prescription and over-the-counter medications. Among the 67 ads with unique drug-indication combinations, the most commonly advertised conditions are noted in the following table.

Indication/Condition DTC ads by number & (%)
Inflammatory conditions 12 (17.9%)
Diabetes 11 (16.4%)
Psychiatric/neurological 7 (10.4%)
Cardiovascular 7 (10.4%)
Bowel/bladder dysfunction 6 (9.0%)
Infections/allergic reaction 6 (9.0%)
Sexual dysfunction 4 (6.0%)
Lung 6 (9.0%)
Other 8 (12.0%)

More than ¾ of the ads were to treat chronic conditions; 18% were for intermediate conditions; and 6% were for acute conditions. Sixty percent referred to potential savings on or payment for the drug. And forty percent advertised drugs with black box warnings.

The median time spent describing drug risks was 45% of the ads, while the median time for other forms of communication, such as a description of the benefits or drug indication was 55%.  The median number of risks mentioned was 16. Forty-two percent of ads used a different announcer for risk and benefit information. When all of the ads presented their risk information, there were distracting visuals like frequent scene changes or characters dancing or singing. Seventy-nine percent had running text on screen that was unrelated to the risks, like “See our ad in Weight Watchers.”

Our findings demonstrate that the quality of information in DTC television ads is low: none described drug risks quantitatively; only one-quarter described drug benefits quantitatively; and suggestions of off-label promotion were common for diabetes medications. Though proponents argue that DTC advertising is educational and empowering for consumers, our findings suggest that the information provided is unreliable and potentially misleading. The promotion of off-label indications, poor quality of information, distracting risk presentations, and the fact that risks are never quantified could distort the perception of benefit and risk information.Suggestions of off-label use, a practice that has been expressly prohibited in prescription drug DTC advertising, occurred in 13% of ads in our sample. All of these ads marketed drugs indicated for the treatment of type2 diabetes, and suggested potential benefits of use, including weight loss and blood pressure reduction.

Data were rarely provided to support the drug benefit claims, and the risks were never quantified. “Broadcast DTC advertising could lead patients to make healthcare decisions and request certain expensive, brand-name medications based on ads containing low-quality and incomplete information.” The researchers noted a suggestion that the FDA should review television commercials for prescription drugs before their release to ensure these ads are more informative for the public. They also suggested further study of the impact of off-label marketing by DTC ads on patient and prescriber decisions. “By enacting such a program and by enforcing more objective requirements for DTC advertisements, the FDA could better protect consumers.” Commenting on the above study for Mad in America, Shannon Peters said:

Patients deserve quality, comprehensive information about drug benefits and risks in order to provide informed consent and be truly empowered in their healthcare decisions. In their current form, most DTC advertisements are misleading rather than promoting informed consent.

The website Medical Marketing & Media provided data on DTC ad spending by pharmaceutical companies in 2017.  There has been an overall increase of $2.6 billion yearly from 2012 to 2016. Broadcast TV spending for DTC in 2016 was $4.06 billion, with magazine spending ranking second with $1.7 billion. The top ten companies by U.S. DTC spending were: Pfizer ($1.2 billion); Bristol-Myers Squibb ($458.2 million); AbbVie ($433.3 million); Eli Lilly ($414.7 million); Allergen ($352.3 million); Johnson & Johnson ($292 million); Merck ($285.2 million); Novartis ($254.8 million); AstraZeneca ($226 million); and Novo Nordisk ($206.7 million).

Pfizer eventually cancelled its Lipitor ad campaign with Robert Jarvik after there was a Congressional outcry over false impressions in the ad. But the marketing misstep didn’t stop Lipitor or Pfizer. Lipitor became the world’s best-selling drug with more than $125 billion in sales over 14.5 years. Pfizer also didn’t lose faith in DTC, as it was number one in DTC spending in 2015 and 2016. But I bet they’ve been shrewder in how they marketed their drugs. You can watch the Jarvik Lipitor ad here.

07/31/18

Risky Alcoholism Treatment

Pregabalin/Lyrica graffiti in Berlin; licensed under the Creative Commons Attribution-Share Alike 3.0 Unported license.

The patent on Pfizer’s blockbuster drug, Lyrica (pregabalin) is running out; it is due to expire in December of 2018. More than six generics companies have lined up tentative approval to sell copies, according to Fierce Pharma. In an apparent effort to keep its blockbuster sales up despite the coming generics, Pfizer rolled out a longer-acting formula in 2017—Lyrica CR. In 2016 Lyrica generated $3.13 billion in sales in the U.S., a 26% increase over the year before. And despite the recent FDA concern that gabapentinoids like pregabalin having a potential for abuse, Pfizer is pushing ahead with a clinical trial to get pregabalin approved for treating alcohol dependence. The Phase 4 clinical trial by Pfizer, “Pregabalin for Alcohol Dependence,” should be completed just as Lyrica’s patent expires in December of 2018.

Gabapentinoids like pregabalin and gabapentin (Neurontin) produce euphoria at high doses. Their effects are similar to alcohol and benzodiazepines. And there is a clear abuse potential. Tolerance develops rapidly with repeated use and withdrawal symptoms have been reported. The U.K. is in the process of reclassifying gabapentin and pregabalin as Class C controlled substances because of evidence they can be abused.

An article on the British website for The Independent newspaper said the British Medical Association has called for pregabalin to be made a controlled substance in the same class as Valium, GHB and steroids. Yasir Abbasi, a consulting psychiatrist said pregbalin dependency was “very widespread, all over the UK.” He added it has an effect similar to Valium. “It sedates you and takes the edge off.” It has become a “massive” problem in prisons, where it is a very tradeable and desirable commodity. “When it goes off patent, and there are cheaper versions available, people will start buying it more and more, particularly over the internet.”

BuzzFeed described how Lyrica (pregabalin) is overprescribed and misused in a Greek refugee camp (Vial) in order to treat rampant depression, anxiety and PTSD. Although psychotherapy is supposed to be done concurrently with the medication, it’s impossible to do so under the circumstances. There are only one psychiatrist and one psychologist working at the camp. The UN refugee agency running the camp denied any knowledge of a Lyrica problem. However, others said the going rate on the camp’s black market for a 300mg Lyrica pill is $5.

A Syrian woman who has lived in Vial for months said: “The people here are desperate, they are suffering, and that [Lyrica] is something that makes them feel comfortable and happy. So they can stay here. They must take this medicine, so they can be patient here.” A former psychology student from Syria who was in the Vial camp was quoted as saying:

“Some people get the pill from the doctor, some from anybody here,” said T., a former psychology student from Syria who arrived in Vial in the spring of 2017. But the wait for an appointment with the doctor can be long. “Life here is hard. Some people take the pill. One, then two, three, four.” T. continued to count on his fingers, all the way up to 10 — “This is bad.” He said the medicine helped them relax and switch off for a bit. “They do not take them as medicine,” he said. “They take it like drugs.”

Along with baclofen, pregabalin and gabapentin (Neurontin) are analogues of the neurotransmitter gamma-aminobutyric acid (GABA). Many GABA analogues are used as anticonvulsants, sedatives and anti-anxiety drugs. According to Carleton Erickson in The Science of Addiction, alcohol affects GABA and a few other receptors to produce its intoxicating and behavioral effects. The GABA association between alcohol and these GABA analogues is simultaneously what attracts researchers to investigate their potential use as treatments for alcohol use disorder and what underlies their adverse effects.

In February of 2018, FDA Commissioner Scott Gottlieb commented on the FDA’s ongoing investigation into the misuse and abuse of gabapentinoids such as gabapentin (Neurontin) and pregabalin (Lyrica). “We’re concerned that the misuse and abuse of these drugs may result in serious adverse events such as respiratory depression and death. We want to understand changes in how patients are using these medicines.” Among the actions taken by the FDA is to review websites where opioid users exchange methods for misusing or abusing gabapentinoids. While this abuse does not yet appear to be widespread, the FDA hopes to stay ahead of any potential problem and is willing to take forceful action, if necessary.

Evidence for pregabalin abuse dates back to at least July of 2010, when a case report by Grosshans et al. was published in The American Journal of Psychiatry, “Pregabalin Abuse, Dependence, and Withdrawal.” At the time of the person’s admission, he was consuming 7,500 mg of pregabalin per day; 600 mg is the maximum recommended dose. He had a history of alcohol and cannabis abuse, but had been abstinent from heroin for seven years. Two years before his admission, he began using high doses of pregabalin and it quickly became habit. He developed tolerance and withdrawal symptoms. They did a gradual taper of pregabalin over 12 days, but he complained of a heavy craving for pregabalin and discontinued treatment. He relapsed immediately upon returning home. “Further attempts to motivate him for detoxification” failed and he continued to take pregabalin.

A case report of pregabalin dependence appeared in the Turkish Journal of Psychiatry. A 34 year-old man reported frequently using 7,800 mg of pregabalin daily. The most he’d used at one time was 15,600 mg. In the three years prior to his admission, his longest period of abstinence was three days. “When he tried to stop using pregabalin he experienced pessimism, aggression, anxiety, suicidal ideation, fatigue, excessive sleep, loss of appetite, palpitations, tremors, and vomiting.” Pregabalin use negatively effected his work and his family relationships.

Despite the promising reports on pregabalin use for treating substance dependence, 198 adverse events related to substance abuse and dependence, of which 16 were associated with pregabalin, occurred between 1980 and 2009 according to the Swedish National Register of Adverse Drug Reactions (SWEDIS).

Another case study report in the Indian Journal of Psychiatry by Ashwini et al. reported on yet another case study of pregabalin dependence and an attempted suicide. He was initially prescribed pregablin for neuropathic jaw pain and experienced euphoria and increased energy after taking his medication. After three years of continuous use, he was using 3,000 mg of pregabalin per day and would experience withdrawal if he missed his doses. He attempted suicide twice.” Our case highlights the abuse potential of pregabalin and risk of self-harm behavior with its continuous use.” The researchers recommended all clinicians remain vigilant and mindful of the potential for abuse or dependence, even if their patients are not showing any drug seeking behavior.

Case reports are not the only evidence of concerns with gabapentinoids. JAMA published a study by Patorno et al. looking at the increased risk of suicidality (attempts and completions) and violent death with a range of anticonvulsant drugs, including gabapentin and pregabalin. “Gabapentin treatment was significantly associated with higher risk of suicidal events and combined suicidal acts or violent deaths in adults and young adults.” Similar findings were not seen with pregabalin. However, it had only been on the market since 2005 (only patients who began taking an anticonvulsant between July 2001 and December 2006 were included in the study). It wasn’t as widely used at the time of the study as gabapentin and it had one of the shortest reported therapy times. The median time of use for all the anticonvulsants in the study was 60 days. Pregabalin would likely be used for a much longer time period in alcohol misuse treatment.

In “Misuse and Abuse of Pregabalin and Gabapentin: Cause for Concern?” Fabrizio Schifano wrote how gabapentinoids have been increasingly reported as having a potential for misuse and a relation to fatalities and a growing black market reported from “a range of countries.” He advised physicians thinking of prescribing gabapentinoids to carefully evaluate whether a previous history of drug abuse exists. Pregabalin has a higher potency (six times that of gabapentin), quicker absorption rates (within one hour) and greater bioavailability than gabapentin. Schifano suggested that while one could conclude the distinct pharmacokinetic advantages of pregabalin would mean an improved therapeutic effect, “[it] may explain as well why pregabalin is anecdotally perceived as more ‘powerful’ by drug misusers.”

Schifano did note that pregabalin, if used at therapeutic levels, “may present with beneficial effects” for alcohol misuse treatment. Similarly, he pointed to how gabapentin has been indicated in the treatment of drug addictions. Nevertheless, “A better assessment/clarification of gabapentinoid misuse potential levels is indeed of interest.”

The epidemiology of gabapentinoid misuse needs further detailed and urgent assessment, and consideration of gabapentin/pregabalin testing in urine drug screens should be routinely considered. Further empirical studies with gabapentinoids should be encouraged, focusing on a better assessment of their addictive liability levels across a range of dosages and in individuals with a previous substance misuse history.

Gabapentin has already become a drug of abuse in its own right. See “Foolishness with Gabapentin” and “The Evolution of Neurontin Abuse.” It’s often used to potentiate the euphoric effects of opioid drugs—both legal and illegal ones. The authors of “Abuse and Misuse of Pregabalin and Gabapentin” said: “Evidence suggests gabapentinoids possess potential for abuse, particularly in individuals with a history of opioid abuse, and reports of such abuse are increasingly being documented.” Over four years ago I expressed concern with using gabapentin to treat alcohol dependence in “The Dark Side of a Pill to Cure Addiction.” The same concern exists today with pregabalin: “well meaning researchers and clinicians could be putting the very people they seek to help at risk with the solutions they propose.”

09/1/17

Circle the Pfizer Wagons

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The U.S. Preventive Services Task Force (USPSTF) recommended that all adults, including pregnant women and women who have recently given birth, be screened in primary care settings for depression. The screening would be done by: general practitioners, family physicians, nurse practitioners or physician assistants. USPSTF said screening adults for depression in primary care settings was accurate, it was effective in relieving depressive symptoms and the likelihood of harm from screening and treatment was small. The problem is that over 60% of individuals diagnosed with depression in primary care did not meet the DSM criteria for major depressive disorder. This rises to 80% with individuals over 65.

Albert Siu and the USPSTF published “Screening for Depression in Adults” in the January 2016 issue of JAMA. The authors said: “The USPSTF found convincing evidence that treatment of adults and older adults with depression identified through screening in primary care settings with antidepressants, psychotherapy, or both decreases clinical morbidity.” Commonly used screening instruments included the Patient Health Questionnaire (PHQ) in its various forms, as well as several others. But the USPSTF did not believe these instruments were getting as many false positives as noted above. “The accuracy of screening tests in the general adult population was established in the 2002 and 2009 USPSTF reviews and found to be convincing.”

Psychiatrist Vivek Datta pointed out the USPSTF guidelines did recommend that screening occurred when there were “adequate systems in place” for further evaluation and treatment. However, “55% of all US counties do not have a single mental health provider.” He noted that many of the symptoms screened for are nebulous and include “symptoms that are quite common in the general population and do not necessarily indicate a mental disorder requiring treatment.” They could represent the effects of a chronic medical problem. Moods are influenced by a variety of factors, such as our level of physical activity, what we eat, our financial security, alcohol and drug use, to name a few.

Symptoms of depression can occur as a result of lifestyle factors, substance use, medical illness, life events, interpersonal difficulties, and as a consequence of wider social policies. Comprehensive assessment frequently does not occur because of the lack of adequate services for those with mental health problems. The recommendation to screen all adults for depression ignores the social matrix in which depression occurs, will lead to further overdiagnosis and overtreatment of minor morbid mental states, and further overburden mental health services.

“A Glut of Antidepressants” was published on August 12, 2013, in The New York Times. It mentioned an April 2013 study published in the journal Psychotherapy and Psychosomatics that found almost 62% of 5,639 individuals “who had been given a diagnosis of depression within the previous 12 months did not meet the criteria for major depressive episode.” Several other studies have reported that: “diagnostic accuracy is low in general practice offices.” The study’s lead author said: “The vast majority of individuals diagnosed with depression, rightly or wrongly, were given medication.” Doctors must resist the temptation “to take out the prescription pad and write down an antidepressant and hand it to the patient.”

The NYT article did indicate that not only are doctors prescribing more medication, their patients are demanding it more. I think this is a likely an outcome of the decision to permit direct-to-the-consumer advertising for pharmaceuticals in 1997. See “Pharma and Advertising” or “Not Everything is As It Appears” for more on this topic. If anything at all was done to “confirm” the patient’s or doctor’s impression that there was a depressed mood state, using a quick screening instrument seems likely given the short time period most patients spend with medical staff in a primary care setting.

James Davies, the co-founder of the Council for Evidence-Based Psychiatry, wrote “The Sedated Society,” where he commented on how a BBC radio program had failed to mention the problem with the PHQ-9 (mentioned above) and the GAD-7, which he said are two of the most powerful questionnaires in the NHS (National Health Service). He said they have been used throughout the primary care system in the UK to assess whether or not a person has depression or anxiety. He said: “They set a very low bar for what constitutes having a form of depression or anxiety for which a drug should be prescribed.” He said the tens of millions of people who filled out these screening questionnaires don’t know that Pfizer Pharmaceuticals paid for their development and continues to hold the copyright for them. Their distribution throughout the NHS was paid for by Pfizer, which incidentally makes two of the most prescribed antidepressant and anti-anxiety drugs in the UK.

Although the BBC didn’t get Davies’s message out about the PHQ-9 and GAD-7, several news outlets did. At Vice, Hannah Ewens said “a few of us in the office” took the test, with everyone except one person got at least a score of mild depression. She personally scored within the “moderately severe depression” range, but doesn’t have depression at the moment. “If I have trouble sleeping ‘on several days’ or ‘nearly every day’ that bumps up my score significantly. And herein lies the problem: all of the indicators are symptoms of a modern lifestyle as well as signals of depression.” Ewens added that James Davies believes reliance on these questionnaires is becoming too commonplace because GPs don’t have the time to do proper interviews.

The Telegraph, another UK media outlet, echoed the Davies concern that the threshold for identifying possible depression was too low. Henry Bodkin noted that a PHQ chart was likely present in almost every GP consulting room over the last 20 years. He also said critics like Davies have said the GAD-7, also developed by Pfizer to screen for anxiety, sets the diagnosis bar too low. “These forms have a very low criteria for anxiety and depression. . . . Millions of people have filled them in and got medication, but did they know they were developed by Pfizer?”

Pfizer enlisted two “rock stars” in the field of psychiatric diagnosis to develop the PHQ-9 and GAD-7: Robert Spitzer and Janet Williams. Spitzer was the chairperson for the seminal changes incorporated into the DSM-III. Originally Williams was his text editor; later she became his wife and collaborator. Listen to an All Things Considered broadcast on Spitzer and the DSM, “The Man Behind Psychiatry’s Diagnostic Manual.”

In the September of 2001 issue of the Journal of General Internal Medicine, Kurt Kroenke, Robert Spitzer and Janet Williams published “The PHQ-9.” Their article examined “the validity of a brief, new measure of depression severity” called the PHQ-9. They concluded that data from their two studies provided “strong evidence for the validity of the PHQ-9 as a brief measure of depression severity.” Kroneke et al. also said brief measures were more likely to be used in the busy setting the typical medical practice. The brevity of the PHQ-9 was thought to make it “an attractive, dual-purpose instrument for making diagnoses and assessing severity of depressive disorders.” The Acknowledgements section said the development of the PHQ-9 was underwritten by an educational grant from Pfizer US Pharmaceuticals. Scrolling down further you’ll see:

From the Primary Care Evaluation of Mental Disorders Patient Health Questionnaire (PRIME-MD PHQ). The PHQ was developed by Drs. Robert L. Spitzer, Janet BW Williams, Kurt Kroenke, and colleagues. . . . PRIME-MD is a trademark of Pfizer Inc. Copyright 1999 Pfizer Inc.

Then in the May 2006 issue of JAMA Internal Medicine, the same three authors introduced the GAD-7, a brief self-report scale to identify generalized anxiety disorder (GAD). Not surprisingly, they concluded: “The GAD-7 is a valid and effective tool for screening for GAD and assessing its severity in clinical practice and research.” They expected the GAD-7 to have “considerable utility in busy mental health settings and clinical research.” Once again is an acknowledgement that the development of the GAD-7 was underwritten by an unrestricted educational grant from Pfizer Inc.

If you want to see or use copies of these scales, Pfizer’s lawyers have been clearly involved in dialing back the company’s responsibilities if the scales don’t live up to their creator’s optimistic expectations. On the Pfizer website, on the “Terms of Use” page for the two scales, is the following. Pfizer said since the questionnaires relied on patient self-report, all responses should be verified by the clinician. A definitive diagnosis should be made on clinical grounds, “taking into account how well the patient understood the questionnaire, as well as other relevant information from the patient.” Diagnoses should rule out normal bereavement, Bipolar Disorder, and other potential causes of depressive symptoms. Then there is the following disclaimer. The “all caps” formatting is in the original.

PFIZER MAKES NO WARRANTIES OR REPRESENTATIONS OF ANY KIND AS TO THE ACCURACY, CURRENCY, OR COMPLETENESS OF THE INFORMATION ACCESSED AND USED THROUGH THIS WEB SITE.
YOU AGREE THAT ACCESS TO AND USE OF THE PHQ AND GAD-7 SCREENERS IS AT YOUR OWN RISK. PFIZER DISCLAIMS ALL WARRANTIES, EXPRESS OR IMPLIED, INCLUDING WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE. NEITHER PFIZER NOR ANY PARTY INVOLVED IN CREATING, PRODUCING, OR DELIVERING THE PHQ/GAD-7 SHALL BE LIABLE FOR ANY DAMAGES, INCLUDING WITHOUT LIMITATION, DIRECT, INCIDENTAL, CONSEQUENTIAL, INDIRECT, OR PUNITIVE DAMAGES, ARISING OUT OF ACCESS TO, USE OF OR INABILITY TO USE THE PHQ/GAD-7, OR ANY ERRORS OR OMISSIONS IN THE CONTENT THEREOF.

The rhetoric about the GAD-7 and PHQ-9 and its variations related by their creators, Spitzer, Williamson and Kroneke seems to have been negated by Pfizer. Instead of the PHQ-9 being “an attractive, dual-purpose instrument for making diagnoses and assessing severity of depressive disorders” and the GAD-7 being “a valid and efficient tool for screening for GAD and assessing its severity in clinical practice and research,” Pfizer disclaimed all warranties expressed or implied for a particular purpose. Pfizer nor any party involved in creating the PHQ/GAD-7 will be liable for any damages from access or use of these questionnaires. Any users access and use the PHQ and GAD-7 does so “at your own risk.”

It seems that Pfizer circled their wagons to avoid any corporate liability coming from the use of these questionnaires despite the fact they paid for their development and continue to market them aggressively to general practitioners in the US and the UK. But the potential for the over diagnosis and over treatment of depression through the PHQ-9 has now reached a new height. Psychiatry Advisor reported in August of 2017 that Google announced whenever someone searches for ‘clinical depression,’ they have an option to take the PHQ-9. Google partnered with NAMI, the National Alliance on Mental Illness, to make depression screening with the PHQ-9 part of searching for ‘depression’ on the site. NAMI said: “We hope that by making this information available on Google, more people will become aware of depression and seek treatment to recover and improve their quality of life.”

So where did all that effort with the PHQ-9 and GAD-7 get Pfizer? Pfizer currently hold the rights to the brand rights for Xanax (alprazolam), an anti-anxiety drug, and Zoloft (sertraline), an antidepressant. Both have been available as generics for a number of years. And although The Telegraph article didn’t name Pfizer’s top selling antidepressant and anti-anxiety drugs in the UK, they must be the same two. Up-to-date yearly sales data for psychiatric drugs is hard to come by, unless you pay an organization like IMS for access to their sales data. But there is data available from 2013.

IMS Health listed the top 25 dispensed prescriptions in the US in 2013. Xanax and its generic, alprazolam, was the 13th most prescribed medication. Zoloft and its generic, sertraline, was the 18th most prescribed medication. Among the psychotropic medications listed they were number one and number three respectively. PsychCentral reported similar findings, with the added information that Xanax was the number one prescribed psychiatric drug in 2005, 2009, 2011 and 2013. Zoloft sank as low as the 4th most prescribed psychiatric drug in 2009 and the 3rd most in 2011.

09/30/16

Chantix Tug-of-War

© AndreyPopov | stockfresh.com
© AndreyPopov | stockfresh.com

On May 18, 2008, George MacDonald was at Fort Benning Georgia. George and his identical twin brother James had successfully completed Infantry Training and the Airborne Course at Fort Benning. They had also been selected for the U.S. Military Academy Preparatory School. George was a one-time Eagle Scout. He got up from his bunk to do some laundry and slipped a knife into his pocket. He approached the bunk where Rick Bulmer, who he did not know, was sleeping. Then he stabbed and slashed Rick more than 50 times. A month before, MacDonald had been prescribed Chantix by an Army doctor to help him stop smoking.

Nine hours after the killing, Macdonald wrote: “I snapped and didn’t like it … I was stretched and it made me crazy.” The military judge refused to allow an involuntary intoxication defense and quashed a subpoena issued to Pfizer by MacDonald’s lawyer. Within a month of the judge’s decision, the FDA imposed a black box warning on Chantix. “Within weeks of the military trial judge’s decision in 2009 to quash the subpoena, Pfizer began getting hit with civil lawsuits claiming Chantix had caused suicides, suicide attempts or other neuropsychiatric problems.” MacDonald was convicted of premeditated murder in 2009 and sentenced to life without parole.

The U.S. Court of appeals for the Armed Forces overturned MacDonald’s conviction saying the trial judge had erred in not allowing the involuntary intoxication defense. MacDonald agreed to plead guilty to the unpremeditated murder of Rick Bulmer and his sentence was reduced to 45 years. Bulmer’s family was outraged, according to Tom Jackman writing for The Washington Post. “’It’s a mindblower, and we don’t understand it,’ said Bulmer’s mother, Wendy Smith. ‘He cold-bloodedly killed my son. He knew what he was doing and … he should take his punishment.’”

In a 2010 clemency request for his brother, James wrote that he remarked to his brother that life had started to feel like a video game, where he was disconnected from his body. James had also been prescribed Chantix. George agreed he felt the same way. James said, “I remember the two of us waking up at night having really weird dreams, scary dreams.” In 2013, James killed himself by jumping off of a 19-story building. His sister said he never got over his grief over his brother’s ordeal. You can read more about the MacDonald case here, here  and here on McClatchyDC.

George MacDonald is not alone is claiming that his use of Chantix led to violent acts. In the beginning of August 2016, a Maryland man was found not criminally responsible for shooting his wife in the neck because he was “involuntarily intoxicated” from Chantix. A woman who was taking medication for other reasons used Chantix briefly in 2007. She got her daughter off to school and the next thing she remembered was standing in her kitchen in a puddle of blood. Six hours has passed during which she had used a kitchen knife to cut her left arm. Federal prosecutors dropped charges against a man who “was extremely psychotic and disorganized” aboard a United Airlines flight because of a “Chantix-induced psychotic disorder.”

Al Jazeera reported that Chantix has been linked to 544 suicides and 1,869 attempted suicides.  As a result of a report issued by the Institute for Safe Medication Practices that said the organization had “immediate safety concerns” about individuals operating aircraft, trains buses and other vehicles who were using Chantix, the FAA and Defense Department banned Chantix use among pilots and air traffic controllers.

Eventually some 2,700 former Chantix users sued Pfizer in 2011. Pfizer began to settle with the lawyers representing the mass of civil lawsuits at a cost of $299 million through the first quarter of 2013. Pfizer said the settlement would allow the company to focus on the benefits of the drug. This strategy has been the typical way pharmaceutical companies try to settle lawsuits they aren’t sure they can win. It keeps subpoenaed records out of the hands of the public and other individuals who may want to sue them as well. And it prevents the articulation of a coherent argument about the association between a specific drug and an adverse event from being made in the public square. It enables the pharmaceutical continue to assert as Pfizer did in a statement to McClatchy: “There is no reliable scientific evidence that Chantix causes serious neuropsychiatric events.”

Chantix is approved for use in more than 100 countries and has been prescribed to over 20 million patients worldwide, including more than 10 million in the United States.

Then in April of 2016 the results of a study on more than 8,100 people were published in Lancet. The study had been ordered by the FDA because of the ongoing reports of neuropsychiatric adverse events with Pfizer’s Chantix and GlaxoSmithKline’s Zyban. “The study did not show a significant increase in neuropsychiatric adverse events attributable to varenicline or bupropion relative to nicotine patch or placebo.” However, the funding for the study was from Pfizer and GlaxoSmithKline.

Writing for STAT News, Ed Silverman quoted the study authors as saying: “The findings show that it is highly unlikely that (the medicines) contribute to neuropsychiatric adverse events.” The results of the EAGLES study, which the Lancet article was reporting, were processed by Clinical Trials.gov on September 1, 2016, and are available here: Clinical Trials.gov Identifier: NCT01456936.

The results may be a boon for Pfizer, which has struggled for a decade to transform Chantix into a blockbuster product, but instead has encountered negative publicity, expensive litigation, and stalled sales.

Pfizer plans to ask the FDA to remove the black box warning from Chantix. A company spokesperson said: “Available scientific evidence concerning neuropsychiatric events in patients attempting to quit smoking does not support a boxed warning in the Chantix label.” The FDA will review the findings along with additional scientific evidence as they continue to evaluate the issue.

Thomas Moore, a senior scientist with the Institute for Safe Medical Practices, said it would be a mistake to claim the study proves that severe psychiatric side effects don’t occur with Chantix. Because it was a manufacturer-sponsored study done in 140 different centers in 16 countries, Moore suggested it be independently reviewed. Early onset cases of psychosis, aggression and suicidal behaviors have been observed with Chantix by regulators in many countries, “far outnumbering those reported for other smoking treatments.”

With eight different treatment arms, the number of patients in each may not be enough to capture the severe psychiatric side effects for which the drug is known.  The study’s severity assessments were subjective judgments, and the combined endpoint included many psychiatric side effects that Chantix is not suspected of causing.

The criticism by Moore has some legitimacy. Here is a study that found Chantix (varenicline) was no better than NRT (nicotine patch) and C-NRT (nicotine patch and lozenge) with regard to abstinence. “However it is notable that there were significant adverse events of varenicline compared to NRT (e.g. nausea, insomnia, sleepiness) and C-NRT compared to NRT (indigestion, nausea, mouth problems and hiccups).” The website RxISK described several examples of “Chantix and Violence” that were originally reported in the FDA database for adverse drug events.

MacDonald’s case was one of the ones reported on RxISK. There it was reported that George and his twin brother (James) enlisted in the Army were selected for an appointment to the United States Military Academy Preparatory School.  The reported adverse effects experienced by MacDonald included: nightmares, psychosis, homicidal ideation, senseless act, and homicide. The Case report said:

Appellant had been experiencing “new and strange thoughts” including a “person [was] telling me . . . dangerous things that arent [sic] me.” These included violent thoughts of killing someone. On May 18, 2008, one month after the Army doctor prescribed Chantix, Appellant fatally attacked Private (PVT) Bulmer while he was sleeping, stabbing him to death. Prior to this attack, Appellant did not know nor had he ever interacted with PVT Bulmer.

The other cases reported suicidal and homicidal ideation, a suicide attempt, uncontrolled aggression/anger, and senseless violence. What follows are two more of the case reports on RxISK. Thomas Moore sent this information to RxISK.

By the third day of taking Chantix I was completely out of control. I woke my boyfriend up in the middle of the night and started physically beating him. I contemplated suicide about 5 times a day and contemplated homicide about 3 times a day. On Saturday while at home she got into a verbal argument with her mom over a minor issue and reports now that she was ‘totally out of hand’ and she was unable to control her impulses and was yelling and screaming and crying. She acutely became suicidal and also became homicidal threatening her mother with a shotgun. Her mother fled the house and called police. She locked herself in the bathroom and eventually calmed down.

In October of 2014, five nonprofit consumer organizations (Consumer Reports, Institute for Safe Medication Practices, National Center for Health Research, National Physicians Alliance, and Public Citizen) petitioned the FDA to require that the Chantix have boxed warnings clearly describing adverse psychiatric adverse events: suicidal behaviors, aggression/violence, psychosis, and depression. Additional risks with Chantix the petition noted were: sudden blackouts, seizures and impaired vision. I hope and expect they will again protest when Pfizer formally requests that the FDA drop its black box warning for Chantix.

For a previous article about the tug-of-war over problems with Chantix, see “Smoke and Mirrors.”