Monday, March 16, 2009

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?


cretin said...

As you mention, negative symptoms and cognitive dysfunction are the residual problems the main mood stabilizers don't address. Taking a cue from the literature on schizophrenia, there was a study where methylphenidate was added to a regimen of clozapine with some modest success. I have been taking olanzapine for several years now. By itself, it didn't help with the cognitive dysfunction. After a neurological test implicated working memory as the problem, my doctor had me try adding dextroamphetamine. In essence we are adding in more dopamine to the system while blocking enough D2 receptors with olanzapine to avoid any psychotic symptoms. So far that has worked. It would be interesting to see if this combination would lead to greater compliance with medications.

I have always wondered about the self-medicating aspects of nicotine. I know my father had a recurring mood disorder; I believe he smoked heavily to cope. Unfortunately the smoking led to his heart disease and early death.

John McManamy said...

Hi, Cretin. Bullseye! Smart doctor. You've made it clear that I need to do a blog on this topic. Here's a few quick thoughts for now:

One person I know on an antipsychotic was prescribed Wellbutrin to counteract a certain side effect. Bingo - she felt more clear-headed. Wellbutrin has a modest dopamine-enhancing effect.

Another time, I actually suggested to a friend (also on an antipsychotic) to ask his doctor about Provigil - a dopamine-enhancing agent FDA-approved for narcolepsy. Bingo - dramatic improvement. So much so that he credits the Provigil from keeping him from being fired from the job he had just started.

An editorial last year - I think in the AJP - mentioned that dopamine has been overlooked for depression (serotonin gets all the attention).

Street drugs, of course, are dopamine-enhancers.

Here's a bitter irony: When you get the kind of compliance with street drugs they call it an addition (I've seen too many ruined lives with people on street drugs but you get the point.)

Simplistically viewed, Provigil and ADD meds are basically street drugs with brakes. They're safer to take because they don't deliver the sudden rush to the head that drug abusers crave.

So what if more docs prescribed dopamine-enhancers like your doc did?

One, we have a dopamine-enhancer to counter-act the dopamine-blocking of antipsychotics.

Two, we have a dopamine-enhancer to work on the cognitive dysfunctions of our illness.

No doubt there are considerable safety issues involved, but I think it is fear (of us potentially flipping out) that is keeping docs away from prescribing dopamine-enhancers.

In the long-term, I believe there is a need for drug companies to work on a "smart" dopamine med. The ones we have right now are "dumb" dopamine meds.

I really believe if you had great meds combined with smart docs compliance would not be a major problem.

Once again, many thanks for your input and stay tuned for a future blog ...

Anonymous said...

Thanks for us, for standing up to those guys (clinicians) who get a little lazy at times and keep prescribing the drugs they've been told to prescribe. As an ironic matter of fact I am currently an intern in a big pharma, and pretty disturbed with the way and the reasons some projects/chemicals are put in their pipeline, and some could be but are missing...
I have a dream, the dream of pharma by the people for the people...

John McManamy said...

Many thanks for this, Anonymous. I used to be a financial journalist. My take is pharma is the only industry that doesn't listen to their customers. In this regard they're way stupider than Detroit. They make things without customer (that's us) input, then wine and dine the medical profession to dump them on us. At no point in the process do we get a say.

Case in point: I'm an award-winning mental health journalist/author and a patient. Think any drug company has ever contacted me?

Good topic for a future blog.

Welcome to "Knowledge is Necessity." Please keep coming back and posting.

Anonymous said...

I am on mind numbing drugs and have been wondering why I smoke so much it makes me throw up. Thanks for giving me an answer.

Anonymous said...

I experienced significant improvement of cognitive functioning with Provigil. However, after approximately 2 months of 200mg daily use, the benefits definitely tapered off. Most HMO's view Provigil as a "yuppie drug" with unproven efficacy for bipolar depression, resulting in the exorbitant cost after your psychiatrist - provided samples are exhausted. Bupropion provides some benefits, but gives me only 30 - 50% of the cognitive boost of Provigil. Likely one of the challenges of developing a dopamine enhancer is building a drug with very low "tolerance" features. Many of my methylphenidate using peers report difficulty with increasing tolerance/decreasing efficacy