09/1/17

Circle the Pfizer Wagons

© Darin Burks | 123rf.com

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 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 “who 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.”