My Totally Surreal Experience Lecturing on Problem Meds to Psychiatrists and Other Clinicians

In my two previous blog posts, I described my unequivocally frosty reception involving a grand rounds lecture I delivered on meds compliance two years back to a psychiatric facility in Princeton, NJ. My first section involved The Problem Patient, my last The Problem Clinician. Following is my version of the middle part of my talk, Problem Meds ...

Okay, maybe I went out of my way to piss off my audience. "Here's a question for you," I opened. "What is the one drug taken by 85 percent of those with schizophrenia and two in three with bipolar that they are 100 percent compliant with?"

They came up with nicotine right away.

We know that auditory gating is mediated by the alpha-7 nicotinic receptor. Those with schizophrenia have trouble filtering out background noise, thus have trouble concentrating. I recall Robert Freedman of the University of Colorado explaining this to a symposium of the American Psychiatric Association annual meeting a number of years before.

Dr Freedman and his colleagues noticed that those with schizophrenia seemed to experience a desperation that went way beyond normal cigarette cravings and decided to investigate. What they found was that in the brief time a cloud is in the patients' lungs, a cloud clears from the brain.

Mind you, this is hardly a long-term solution. But think about it. Nicotine works. With nicotine, some patients actually get their brains back - even if just for a precious few seconds. I don't know about you, but I don't take my brain for granted. Every precious second the reception comes in loud and clear is a gift to me.

Mind you, I'm not advocating cigarette use. But it appears that nicotine may be an effective drug for schizophrenia. Its major fault is the delivery system, but thanks to the research of Dr Freedman and others alpha-7 nicotinic agonists are in development.

"So, if you prescribe cigarettes," I joked, "you will get much better compliance than if you prescribe an atypical antipsychotic."

Zero degrees Kelvin frozen silence. It probably didn't help that earlier I had called out my audience for all the "No Smoking" signs on the grounds of the facility. (Mind you, perhaps thanks to the nicotine patch, patients and those who speak for them are putting up little resistance to hospital smoking bans.)

Now it was time to compare and contrast. Up on my PowerPoint went this slide from a 2007 editorial in the American Journal of Psychiatry:

Without adequate dopamine signaling, our patients do not feel ‘well.’ When dopamine systems are dysfunctional, patients seek a change. This may involve stopping a medication, such as antipsychotic drugs that block dopamine.

Rather than clearing the brain, these meds actually take major parts of the brain off-line. The major problem with schizophrenia is cognitive deficit. Up went a quote from leading schizophrenia researcher, John Krystal MD of Yale:

"Our medications are least effective for the most disabling symptoms of schizophrenia," namely, "the cognitive dysfunctions that seem to prevent people from performing in the workplace."

The pioneering diagnostician Emil Kraepelin, who "discovered" schizophrenia back in the early twentieth century, pointed to cognitive dysfunction as a core symptom, and we are also recognizing it looms large in bipolar.

I was just getting warmed up. "So, what's your answer?" I asked. "You give patients a drug that actually worsens the most pronounced feature of schizophrenia - and a significant feature of bipolar. Not only that, you're telling us we're going to have to take it the rest of our lives. Sure, it knocks out the psychosis, but so what?"

I could have gone on about the metabolic catastrophes from meds such as Zyprexa - surely the long-term risk to health was as bad as cigarettes - but I compassionately spared my audience. Instead, I simply drove home this point: 

"Far from lacking insight into their illness, even patients with schizophrenia have a much better understanding than the people charged with treating them. Far from refusing to put up with side effects, they are willing to put up with a drug with one of the worst side effects profiles in the world. Why? Because it works. It works where they want it to work."

"Let's face it," I concluded. "We've all been badly oversold on the new generation antipsychotics - you, me, family members. When all is said and done, these new generation atypicals are basically Thorazine with the tires rotated."

For some crazy reason, to my total amazement, they cracked up at that line. Then they went back to being bumps on a log.

"My question for you," I concluded in this part of my presentation, "is why did it take you so long to figure this out? The same info was in the journals you subscribe to, on the labeling of the meds you prescribe. More important, your patients have been telling you this for years. Why haven't you been paying attention?"

As I mentioned in previous blog pieces, my audience heard me out, then made for the exits the second my lips stopped moving.

Trick Question: Meds Compliance

What is the one drug taken by 85 percent of those with schizophrenia and two in three with bipolar that they are 100 percent compliant with?

Answer: Nicotine.

I posed this question last year to 50 or 60 clinicians at a grand rounds lecture I presented at a psychiatric facility in Princeton. Just prior to asking the question, I cited a 2006 study in which four in five patients on Zyprexa dropped out of the long-term phase of the trial.

This is not an isolated finding. The drop-out rate figure fluctuates between 40-to-100 percent over the long term across a broad range of psychiatric meds and diagnoses.

What's different about nicotine? In my talk, I showed a slide citing the research of Robert Freedman MD of the University of Colorado that connected "auditory gating" disturbance to nicotine craving. Apparently, individuals with schizophrenia have trouble screening out the second of two repetitive sounds, which does hell to their concentration.

This gating response is mediated by - drum roll, please - the alpha-7 nicotinic receptor.

Nicotine works. With nicotine, patients actually get their brains back - even if just for a precious few seconds. Apparently, in the brief time a cloud is in the patients' lungs, a cloud clears from the brain.

The only thing that is wrong is the delivery system, but in the drug development pipeline are nicotinic agonists.

Here's where I won over my audience: "So, if you prescribe cigarettes," I said, "you will get much better compliance than if you prescribe an atypical antipsychotic."

(Clinicians like to show their appreciation by looking like they're holding in their lower intestinal tract versions of auditory gating.)

"Now, compare that with an atypical antipsychotic," I went on to say. "Rather than clearing the brain, these meds actually take major parts of the brain off-line."

For support, my slide quoted a 2007 editorial in the American Journal of Psychiatry:

"Without adequate dopamine signaling, our patients do not feel 'well.' When dopamine systems are dysfunctional, patients seek a change. This may involve stopping taking a medication, such as antipsychotic drugs that block dopamine."

Then I quoted John Krystal MD of Yale from a lecture he gave to the American Psychiatric Association the year before:

"Our medications are least effective for the most disabling symptoms of schizophrenia," namely, "the cognitive dysfunctions ..."

Cognitive dysfunction also looms large in bipolar.

Let's start connecting the dots: We have psychiatrists prescribing patients a class of drugs that work well against psychosis at the expense of worsening the most pronounced feature of schizophrenia and a significant feature of bipolar. No surprise - low compliance rates.

Meanwhile, we have a drug that doctors try to ban that actually helps bring patients' brains back online for a few precious seconds. Surprise, surprise - high compliance.

You tell me: Who are the smart people in this equation?

"Far from lacking insight into their illness, from refusing to put up with side effects," I said, "patients are willing to put up with a drug with one of the worst side effects profiles in the world. Why? Because it works. It works where they want it to work."

I was just getting warmed up:

"Let's face it," I said, "we've all been badly oversold on the new generation antipsychotics - you, me, family members. When all is said and done, these new generation atypicals are basically Thorazine with the tires rotated."

I wasn't through:

"The CATIE studies brought this out loud and clear. My question for you is why did it take you so long to figure this out? The same info was in the journals you subscribe to, on the labeling of the meds you prescribe. More important, your patients have been telling you this for years.

"Why haven't you been paying attention?"

This part of my talk was interrupted by a spontaneous display of stony cold silence. The temperature in the room literally dropped ten degrees.

What were they expecting? A CME lecture sponsored by Eli Lilly with free "Zyprexa" pens and coffee mugs?