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by Cynthia Robbins-Roth, Ph.D.


BioWorld Today Love, Gambling And Biotech: Side Effects Of CNS Drugs

By Cynthia Robbins-Roth
BioWorld Today Columnist

The most disconcerting news in the biopharma world this month was not the speculation over why the Avastin clinical trial had to be halted, nor concerns over the latest addition of “serious warnings” to Bristol-Myers Squibb's antibiotic.

It was the conjunction of two Wall Street Journal articles around Valentine's Day: Scott Hensley's report on the increasing evidence that Parkinson's treatments can stimulate compulsive gambling and other impulsive behavior while cranking up dopamine levels, and Tara Parker-Pope's story on the potential for antidepressant medicines to turn down patients' capacity for romance and long-term attachment to others while modulating serotonin and dopamine actions.

Love As An Obsessive-Compulsive Disorder

One new class of antidepressant drugs, selective serotonin reuptake inhibitors (SSRIs), was specifically designed to avoid the nasty side effects of earlier medications by acting on only one class of neurotransmitter - serotonin. They were widely heralded as safer than the old drugs, which acted broadly by blocking the breakdown or the reuptake of neurotransmitters in the synapse and which acted on other receptors in and outside the brain.

Last April's issue of Neuron described new evidence that SSRI's also highjack the dopamine reuptake receptors, sneaking serotonin into dopamine nerve terminals and releasing the serotonin along with dopamine. Researchers are trying to figure out how this might affect the action of antidepressant drugs and the implications for treating depression.

One of the unexpected side effects of the SSRI drugs is emotional blunting - significant reduction of a wide range of emotions. Clearly, you want to reduce some emotions in depression - sadness, crying, obsessive thinking, irritation and anger. But these drugs also mess with positive emotions - empathy, sexual desire and creativity.

It turns out that release of dopamine in the brain is “facilitative to copulation” (in the classic science geek speak found in Behavioral Brain Research, Nov. 1, 1999, pgs. 105-106), but serotonin generally inhibits sexual feelings and physical reactions.

Okay, so you're not depressed, but you've potentially lost the ability to fall in love! That's depressing.

And On The Flip Side

On the flip side of the dopamine/serotonin modulation, we find a group of drugs developed to treat the tremors of Parkinson's disease. Parkinson's patients are losing their dopamine-producing brain cells, leading to decreased muscle control and other symptoms.

Mirapex, a dopamine agonist from Boehringer Ingelheim, seemed like a pretty straight-forward treatment. Clinical studies showed a range of minor side effects, all of which seemed reasonable for a drug that modulates important neurotransmitter activity.

And then, out of the blue, recent analyses for FDA show that Mirapex and related Parkinson's drugs are associated with compulsive gambling. Granted, we are talking about eight patients, a 1.5 percent rate in 529 patients, all of whom lived in Phoenix (apparently lots of local gambling opportunities), vs. a general population rate of 0.3 - 1.3 percent. However, all affected patients claim to have started gambling only once on the drug, and some lost huge sums of cash. A study by Mayo Clinic doctors described 11 patients who developed gambling addictions. Changing the medication seemed to get rid of the problem.

It turns out that dopamine also affects brain processes that control emotional responses, the experience of pleasure and pain and potentially addictive behavior. Boehringer Ingelheim and its U.S. partner Pfizer Inc. are the targets of at least two lawsuits alleging Mirapex caused compulsive gambling, shopping, sexual behavior and eating.

So you can treat your depression and avoid compulsive behavior but lose out on romantic and sexual feelings. Or you can lose the Parkinsonian tremors but find yourself spending way too much time at Atlantic City.

So why is this disconcerting news?

Because it is a great illustration of a huge challenge faced by the biopharma industry. Science and the latest research tools are allowing researchers to take aim at the molecular underpinnings of complex diseases that need new treatments. These diseases, especially psychiatric and neurological diseases, have been poorly served for a very long time. The ability to pinpoint specific protein receptors - and the single subtype of receptor - on the specific brain cells involved in these serious illnesses has given hope to the industry's ability to create treatments that can make a real difference for patients (in spite of Tom Cruise's silly rantings).

But as the human body likes to keep reminding us, none of this is simple or straightforward. Drugs expected to zero in on a specific target are turning out to cause unexpected side effects in unrelated systems. I am pretty sure that Boehringer never expected to stimulate gambling behavior in its patients (though perhaps we should check its holdings in Monte Carlo).

As we have seen with Biogen Idec's Tysabri for multiple sclerosis and the various Cox-2 blockers for pain, exquisite targeting often is not quite as targeted as you hope. As a new drug makes its way into larger patient populations, unknown pathways can suddenly show up in other body parts that use that same target molecule. A drug for hypertension bizarrely turns out to stimulate hair growth. An angina drug turns out to be a money-making treatment for erectile dysfunction.

Who knew?

And that's the point. Even as the science continues to shine light on molecular and cellular processes underpinning health and disease, Mother Nature has more tricks up her sleeve to thwart the easy conversion of discovery into cash.

-- February 27, 2006

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by Cynthia Robbins-Roth, Ph.D.


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