Human Subject: An Investigational Memoir

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7. Further Adventures with the Pharma Team

“S'il fallait donner une comparaison qui exprimât mon sentiment sur la science de la vie, je dirais que c'est un salon superbe tout resplendissant de lumière, dans lequel on ne peut parvenir qu'en passant par une longue et affreuse cuisine.”

I showed up as scheduled for my depression screening at PsychoPharm. Well, not quite as scheduled. They couldn't have asked for a more pathetic psychiatric specimen than the panting, sweating, cringing subject who arrived 15 minutes late. Not only had I taken the wrong bus, but I had forgotten to bring my phone, so I couldn't call to let them know I'd be late. (At times like that it doesn’t help to remember something a chronically late, dysfunctionally laid-back boss once said to me: “My experience begins when I get there.”) As it turned out, and as is so often the case, no one else seemed to care that I wasn't on time.

During the course of my association with PsychoPharm, I had interactions with about fifteen staff members: three doctors, three nurses, three study coordinators, at least three receptionists, a psychologist, and an ECG technician. At each visit I would meet with up to six people (not counting the receptionist), either moving from one to the next like a half-built car on a well-oiled assembly line or sitting in one of those general-purpose offices while they took turns coming in to visit with me. I never knew ahead of time which study coordinator or receptionist I would see, because the former took frequent vacations and the latter just as frequently took other jobs.

At the screening visit, first I saw Dr. C, who told me that only one of the studies they were currently running would allow me to take another drug concurrently. It was a study comparing two doses of a new drug, desvenlafaxine, with an established drug, duloxetine. Both drugs are in the class called serotonin/norepinephrine reuptake inhibitors (SNRIs). The study sponsor was Wyeth Research, the maker of desvenlafaxine.

Desvenlafaxine (besides being unpronounceable) is a metabolite of venlafaxine, a Wyeth drug with the brand name Effexor. Since Effexor was no longer enjoying patent protection, and would therefore have to start competing with lower-priced generic equivalents, it didn’t surprise me that Wyeth was trying to bring a new drug to market. Federal and international laws give U.S. drug companies a 20-year patent on new drugs, i.e., the exclusive right to produce a drug for two decades. That sounds like a long time, but the clock starts running before any clinical trials have been done. I’ve seen varying estimates on how long it takes to go through all the phases of clinical trials and then get a New Drug Application approved by the FDA. The useful life of a patent ends up being anywhere from 8 to 12 years. However, thanks to a 1984 law, the drug maker can apply to the Patent and Trademark Office for “patent term restoration,” which gives the drug up to 5 more years of protection, not to exceed a total patent term of 14 years.

I vaguely recalled that when Effexor had first come on the market, it had been seen as a welcome alternative to Prozac, because it had fewer side effects. When I later tried to confirm this recollection by searching on the Web, I mainly found horror stories involving Effexor side effects and withdrawal symptoms. I also learned that Andrea Yates, who drowned her five children in 2001, had been taking Effexor at the time. “Homicidal ideation” is now listed as one of the drug's rare adverse events. To be considered rare, a side effect must occur in fewer than 1 in 1,000 study subjects. (Brown, 2006)

During our screening interview, Dr. C asked me most of the questions she'd asked three days earlier. Then I was interviewed by a nurse, whose white coat revealed her name, Nurse L, followed by the initials RN, MFT. I wondered at first why a marriage and family therapist worked in a place whose only business was conducting clinical trials for psychoactive drugs. After a few minutes with her, I realized that her utter lack of empathy, or even interest, in the people she interviewed would probably rule out counseling as a career. But then maybe it was just me she didn’t like. Anyway, she asked me many of the same questions I'd already answered twice. Then another physician, Dr. J, came in and asked me those questions plus some new ones.

One question they all had was whether I was in any danger of committing suicide. Although I had devised the method described in chapter 1, i.e., taking several oxycodone tablets and then walking into the cold ocean, I knew that I would never carry it out. When I was 20, I had made a suicide attempt that I immediately realized was a terrible mistake (fortunately I hadn’t swallowed enough pills to do me in, or even to require a stomach pump). Since then, no matter how miserable I am, my aversion to pain and discomfort always trumps my desire to do the world a favor by dying. And even in the depths of despair, I have a morbid curiosity about what the future holds.

Since 2004 the FDA has required all SSRIs to carry a “black box” warning, which states that taking the drugs may increase the risk of suicide in children and adolescents. In 2007 they expanded the warning to include adults ages 18 to 24. Black box warnings are reserved for the gravest health hazards, but there's still a lot of controversy about this one. Most of the occasional suicides have occurred within the first few days of starting drug therapy, i.e., while the medication may be giving a person more initiative and energy, but before the start of any antidepressant effects, so the answer could be to monitor patients more closely during those first days (and maybe take away their belts, guns, and razor blades) rather than intimidate both doctors and patients with a dire warning.

There is no consensus as to whether it’s the illness or the cure that causes suicides. As an editorial in the New England Journal of Medicine pointed out, the new black-box warning label also says, “depression and other serious psychiatric disorders are themselves associated with increases in the risk of suicide.” The authors identify a number of problems with the studies that were presented as evidence for requiring the warning. Perhaps most telling is the fact that the suicide risk was substantially lower for people who took the drugs for reasons other than depression. In other words, people who aren’t already seriously depressed don’t suddenly become suicidal just because they’re taking antidepressant medication. (Friedman & Leon, 2007)

With some drugs, there is a slightly higher risk of suicide even for “healthy” people, i.e., subjects in Phase I trials and patients taking the drugs to treat a condition other than depression. I wonder if some of those people could be suffering from undiagnosed depression and therefore be susceptible to the same effect that may impel depressed persons toward suicide: Before the drug has had a chance to change their outlook, it gives them the extra motivation they need to kill themselves.

In February 2007, a CDC study revealed that in 2004, right after the warning labels began to appear on antidepressants, the rate of teen suicide rose 20 percent. Until then the rate had been declining steadily since the early 1990s. At the same time, prescriptions written for patients under 18 dropped 20 percent, leading to a widely held theory that doctors were reluctant to prescribe antidepressants to young people.

Responding to these statistics, psychiatrist David Fassler said, “This is very disturbing news.” (Childs, 2007) Immediately the Alliance for Human Research Protection (2007) issued a press release countering the reports of increased suicide, and describing Dr. Fassler as someone who “has never found fault with prescribing any psychotropic drug or drug combination for children.”

There is no evidence that people 25 to 64 years old are particularly suicide-prone when on antidepressants (in fact, after age 65 the risk goes down), and the drugs that I might be taking were SNRIs, not SSRIs, so I wasn't sure why the exclusion criteria for all participants in the desvenlafaxine study included “significant risk of suicide.” Maybe they just didn’t want to invest the time and drugs in someone who might check out on them.

I assured all three interviewers that I wasn’t at significant risk. That's not to say, I told them, that I don't have moments when I think death would be a welcome relief. They all seemed fine with this distinction, just as Dr. C was quick to categorize my episodes of “panic” as severe anxiety, because panic disorder was another basis for exclusion. She also determined that I never really had anorexia nervosa, another forbidden condition that I had experienced, because I never forced myself to regurgitate food (I had all the other symptoms, but I have a pathological aversion to vomiting). These people were obviously determined to make me eligible for the study.

Still, Dr. J seemed genuinely concerned, more so than Dr. C anyway, about the fact that I would need to stop taking Paxil for two weeks before starting the study medication. He said that most people have muscle aches and other “cold-like” symptoms (surely this medical professional meant flu-like, since muscle aches rarely accompany a cold). He said that if total withdrawal made me sick, I should try taking just 5 mg per day for a while; he also said that I would know after 36 hours whether my symptoms were problematic. He gave me his PsychoPharm business card and said to call him if I had a bad time over the weekend (this was a Thursday). I didn't understand what he thought he could do for my bad withdrawal symptoms, but I was grateful for his concern.

There's some controversy over the use of so-called “washout” periods in studies of psychiatric drugs. Some critics argue that forcing patients to go drug-free for a specified period violates a basic principle of the Declaration of Helsinki: that even the subjects in a control group are “assured of the best proven diagnostic and therapeutic method” available. Supporters of washout studies maintain that the washout is critical for determining how effective a drug is; it can also prevent unhealthy interactions between a previous drug and the study drug.

After convincing all three mental health practitioners that I indeed had major depressive disorder, I was liberated of some urine and blood and then given an ECG. Since I'd had to fast for the blood draw, the blood-drawing nurse was also kind enough to give me a granola bar and coffee. Then Dr. C conducted a medical exam that was fairly cursory except that she checked a vital sign I never knew I had: the pulse on the top of my foot. The last person I met was a study coordinator, who gave me a copy of the consent form I'd signed and a check for $25 (she also told me she was about to go on a lengthy vacation). Pretty paltry for 3.5 hours work, but the subsequent visits wouldn't be as long and would be paid at the same rate.

The consent form revealed that a doctor I hadn't even met was the principal investigator. Looking at PsychoPharm's Web site later, I learned that Dr. J was called a “sub investigator"; I pictured him inspecting sandwiches at lunch every day. Dr. C wasn't even listed on the site, but then she had said that she'd only been there about 9 months.

I had asked the ECG technician whether PsychoPharm was a good place to work, and she had said yes. (Ironically, I never saw her there again. All my future ECGs were done by a nurse, so I think the tech must have quit.) It certainly did seem like a congenial, collegial environment. And everyone really seemed to care about me, notwithstanding their willingness to let me to forgo a medication that had kept me panic-free for 10 years, just so I could help them earn a living. They had told me that after the study was over they would prescribe whatever medication seemed most appropriate and that they would “follow” me for 6 months. It was entirely possible that by then, due to medication or a lack thereof, I would at least think that they were following me.

Based on what Dr. J had told me, I expected to start feeling the lack of Paxil by the next day. As it turned out, I felt just fine the next day, and also the next. On Saturday though, just in case, I began keeping a daily journal of my post-Paxil experience. Here are a few excerpts.

Day 3—Went for a long walk to dispel some of my excess nervous energy. Kept telling myself that I didn't need any drugs to stay healthy and happy. I really didn't. Really.

Day 4—Am definitely under stress: Despite the antiviral drug I'm now taking, my herpesvirus has been awakened and is trying to breach my immune system. Sent an email query about a research study that would teach me ten relaxation and stress-reduction techniques. The goal of the study is to minimize one’s chance of getting breast cancer, but I just want to be less stressed.

Day 6—Partly gloomy with occasional paranoid fantasies and periods of insecurity, becoming numerous by midnight.

Day 7—Very little sleep, thanks to 3 a.m. garbage pickup. [I lived in a mixed commercial-residential zone, where people got away with making noise at all hours.] Hopelessness and distorted perceptions prevail, intermixed with bouts of firing off email complaints about sundry phenomena, including 3 a.m. garbage pickup. I'm thinking of wearing a disclaimer when I go out in public that says, “Off my meds.”

Day 10—Feeling dejected, defective, and rejected. But did I really feel any better when I was on Paxil? I can't remember. Signed up for an online discussion group for users of Effexor, even though I don't know for sure whether I'll be taking Son of Effexor.

Day 12—My first day of true depression in years. Tried smiling a lot to convince myself that I was happy, but that just made me feel like an in-denial phony. When you're depressed, you think, “This is the real me. Everything else is just a pathetic attempt to fit in and seem normal.” Is it possible to turn that view around and convince my depressed self that the real me is happy? Sure, and while I’m at it, maybe I’ll convince my cat that the armchair is not a scratching post.

Day 13—The previous day's indignities were forgotten as I found new things to feel rotten about.

It didn't help my worsening mood that I accidentally broadcast my full name to the Effexor discussion group. I wasn't really bothered by disclosing personally identifiable details of my life, but I was afraid that someone from Wyeth or PsychoPharm might be monitoring that discussion group and get me kicked out of the study for trying to discuss it. As far as I could tell, the consent form didn't prevent me from disclosing my own personal health details, and the existence of the study was public information, so I'm not sure on what basis they could have excluded me. But then depressed people have their own sick and twisted variety of optimism: Anything negative is possible.

Dr. J called to check on my withdrawal progress a week into the washout. I told him that I wasn’t experiencing any physical symptoms, but that I was pretty darned depressed. He said that Dr. C would probably be calling me later to go over my depression history again. I figured it was all part of the ongoing consent process for us decisionally impaired folks.

Dr. C never called, but when I returned to PsychoPharm on the last day of Paxil washout, she was the second person I saw (after the only psychologist on staff, Dr. K, whom I'd never seen before but who became my favorite PsychoPharmer). As it turned out, the reason she wanted to go over my depression history again was that she had lost the notes she'd taken before, or so she said. She interrogated me once again about when I first got depressed and what drugs I'd taken at what times in the past. While we talked, she scribbled on little Post-It notes; I think this was the same unreliable note-taking method she'd used before.

I wondered if we would have to go through this every week, and then I wondered if perhaps it was meant to test my cognitive functioning, kind of like the oxycodone memory tests. Or was it a ploy to test the consistency of my statements? It could have been that she was still suspicious of my authenticity: If I had used exactly the same words that I had first used to describe how I felt—those words that she thought I must have learned from “working with” depression—perhaps she would have said, “Aha!” and shown me the door. As it turned out, this was the last time I ever saw Dr. C (I don’t think she was fired; her name was still stenciled on the door), and no one else there made me go through my whole history again.

I tried to be completely honest with everyone about my symptoms. It seemed pretty amazing that they would accept someone so obviously anxious and panicky. I even mentioned that I would do away with myself if I could do it painlessly. Suicidal “ideation” was a definite deal-killer for this study, but no one seemed any more bothered by my death wish than they had been at the previous visit.

Both of the doctors went over my lab results with me. It seemed that I had pretty good blood and urine—nothing abnormal, nothing illegal. In fact, Dr. C said that I had “a wonderful lipid profile.” I asked if I could get a copy of the lab report, and she said yes, but I had to ask again two weeks later before getting it.

This was Visit 2, or “baseline.” The vital signs taken that day, before I started on the study medication, were the standard against which all subsequent readings would be measured. In addition to blood pressure and pulse, the measurements taken included three electrocardiograms in a 20-minute period. All of these data were collected by a very overweight nurse, Nurse D.

I had recently noticed that at least half of the nurses I encountered were obese. I wondered if they were getting fatter because they could no longer smoke on the job. Nurse D at PsychoPharm had an additional affliction: dyslexia. The first ECG reading indicated that I'd just had a heart attack. Then she realized that she'd literally gotten some wires crossed, so she repositioned them and took another reading, which came out normal (as did every ECG I had there).

I have to take some of the blame for the mix-up. Besides obesity and dyslexia, Nurse D suffered from an inability to grasp the fundamentals of grammar. When she told me to “lay down” on the table, I gently corrected her and explained why “lay” was incorrect. She still kept getting it wrong, despite the fact that she claimed to be a huge fan of a podcaster and author named Grammar Girl, whose work I was not familiar with. (Yes, it’s OK to end a sentence with a preposition. Just ask Grammar Girl.) By the last time I saw Nurse D, three weeks later, I think she had finally grasped the lay/lie distinction, but I had reason to think by then that she had never forgiven me for correcting her.

In what would be the normal pattern, my last contact was again with a study coordinator. This time she gave me a 7-day supply of medication: a beige pill, an orange pill, and one black capsule, all to be taken together each day. The medication was packaged in a dismayingly large and bulky blister-pack folder, with the pills displayed side by side about an inch apart. I was also given a second folder of the same size but containing only three doses, in case I lost some from the other package or wasn’t able to make it back for a while. The folders were stored together in a white box about the size of a hefty hardcover book.

So now I had my drugs—maybe. By this time I almost hoped that they were fakes. Having successfully kicked Paxil, I wasn't sure I was ready to subject my body and brain to more pharmaceutical manipulation, even for the sake of both emotional stability and science.

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