Wednesday, May 04, 2005

CNS Pipeline Update

We usually keep some carrots around, in case someone wants a quick low-fat snack.  This evening, I found out that my wife has eaten all the carrots.  Thus, with my foraging instinct activated but unfulfilled, I searched the web frantically, looking for information about new psychotropic drugs that might be available in the next few years.  Not as good as a carrot, but no calories, either.

The first one I'll mention is desvenlaxafine.  As the name suggests, the drug is good old venlafaxine (Effexor) with a methyl group removed.  This is the structure:

(image courtesy of www.usp.org

This is in phase III trials, which is the last phase before it can be approved.  FDA approval is never guaranteed, but this one probably will make it to the market.  Like venlafaxine, it inhibits reuptake of serontonin and norepinephrine.   At first glance, it seems like another "me-too" drug.  However, it probably will have some real clinical utility. 

The oldest antidepressant on the market, imipramine, also inhibits reuptake of serotonin and norepinephrine.  It does a lot of other things, too, which accounts for the greater adverse effect burden.  Desipramine is the same molecule as imipramine, but with a methyl group removed.  Relative to imipramine, desipramine has a weaker effect on serotonin, and a stronger effect on norepinephrine.  It is well established that some patients respond to one and not the other, and some tolerate one and not the other.  Therefore, it is reasonable to expect that desvenlafaxine will help some people who either do not respond to, or do not tolerate, existing antidepressants.  Not too exciting, but worth mentioning.

Another phase III drug is agomelatine (Valdoxan).  Unlike desvenlafaxine, agomelatine has a novel mechanism of action: it is a melatoninergic agonist and a 5-HT2c antagonist.  The action on melatonin receptors may be responsible for an unusual property of agomelatine.  That is, it improves sleep continuity without causing any daytime somnolence. 

This study indicates that it has efficacy comparable to paroxetine.  This study indicates that it could be effective for hospitalized depressed patients.  The mechanism of action suggests that it will not cause sexual dysfunction.  If that turns out to be the case, it would be a significant advantage.

It has been about ten years since we have gotten an antidepressant with a truly novel mechanism of action.  The most recent one, mirtazapine, works well but tends to increase appetite and cause weight gain.  Agomelatine probably will not affect weight, although that was not mentioned specifically in any of the studies I could find.  The fact that another novel agent is so close to approval should be encouraging to that 5-10% of depressed patients who are refractory to treatment with existing drugs.

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How Big Religion Sold Out to Big Business, Without Even Trying

Please consider the following items, and see if there is a common theme among them:
  1. Salon publishes an article about the new president of the World Bank, Paul Wolfowitz, asking if his "fealty to the oil industry could derail the World Bank's mission to reduce poverty."
  2. The Union of Concerned Scientists publishes many articles, accusing the US Government of suppressing, distorting, and misusing the results of scientific research, all for political purposes.  Most of the time, the politicians are accused of being so pro-business that the interests of the general public are swept aside. 
  3. PBS runs a documentary about how people are influenced to vote against their own economic interests, to the benefit of big businesses. 
  4. The FDA and NIH are embroiled in controversies about conflicts of interest, again with the concern that large corporations may be influencing their inner workings.
  5. Bloggers point out the link between the anti-filibuster campaign and the religious right.  Others point out the hate speech that occurs in subset of religious fundamentalists.  Others express fear at the prospect of a one-party state.

Now, an anonymous blogger () writes a post alleging that these things are all connected.  Major religious institutions, thinking that they are promoting moral values, are subverted into promoting the agenda of big business. 

On item 1: the World Bank has long been suspected of promoting the interests of international extractive industries over the interests of the people in the countries they are supposed to be helping.  But one of their most recent projects involved helping the African country, Chad, set up an oil industry.  This time, they imposed certain requirements that were supposed to ensure that at least some of the money went to helping the general population.  According to the World Bank:
The centerpiece of the pipeline project is the revenue management program. Since the Government of Chad only recently began to draw on the oil revenues and direct them toward actual poverty reduction investments, this program remains largely untested. But as a condition for its involvement in the project, the Bank worked with the Government of Chad to establish what for the world amounts to an unprecedented system of safeguards governing how these revenues would be used.
In other words, prior to Wolfowitz' election, the WB appeared to be developing a policy of actually helping people, not international corporations.  Whether that works out, and whether it even continues under the reign of a Bush loyalist, remains to be seen. 

On item 2: the UCS has been one of the most outspoken critics of the Administration's stance on CO2 emissions and climate change.  Despite the astonishing preponderance of scientific evidence that anthropogenic emissions are causing global warming, the Administration refuses to budge on the issue.  Occasionally they make a token effort, but then withdraw funding.  The only rational plausible explanation is that they misunderstand the issue, and think it would be contrary to business interests for the government to take action on environmental problems.

On item 3: the gap between rich and poor is increasing.  While home ownership is at an all-time high, so is homelessness.  While medical science develops the potential to help ever more people, the ranks of the uninsured are growing even faster.  Bankruptcies and home foreclosures are at record levels.  Rather than do something to improve the imbalance in the economy, or improve equality of health care access, the Administration has made it harder to declare bankruptcy.  In other words, rather than trying to help the people who need help the most, the Administration characterizes those in dire financial circumstances as morally deficient, then turns around and helps the business community.  Many of those who voted for this Administration are those who have been most harmed by its policies. 

On item 4) I've already blogged on this extensively, just follow the links in item 4, and, in the interest of being fair and balanced, look at this more recent article in the Baltimore Sun about the NIH.  Let it suffice for now to say that the FDA and NIH, while not at all morally bankrupt, are showing some signs of susceptibility to industry influence.  While the influence may be small now, the fact that it exists at all, in organizations that are supposed to be above that, is disturbing.  Speaking of organizations that are supposed to be above the earthly concerns of big business, we turn a skeptic's eye to Item Five.

There are many factors that were involved in the outcome of the last presidential election in the United States of America.  One could argue, though, that it was the influence of conservative churches increasing turnout among a subset of voters, that made the difference for Mr. Bush's reelection.  "Moral value" issues, such as gay marriage, caused preachers of various sorts to exhort entire flocks to the polls.  Indeed, it was their right to do so -- in a political sense.  I argue, though, that while it was within their rights on a political level, it was indefensible on an ethical level.

To understand why, it is necessary to examine the fundamental flaw in fundamentalist ethics.  The flaw under examination here is not particular to fundamentalist Christianity, by any means, but I have chosen to examine this particular flaw in the context of Christian fundamentalism in order to illustrate some specific points.  Similar criticisms could be leveled against other groups.

If one reads the Ten Commandments, one may get the impression that the essence of ethics lies in the regulation of one's individual behavior, specifically with respect to the impact that the behavior has upon another person.  The concept of society enters into fundamentalist ethics, but only in one particular manner.  Society is considered as having interests very much like those of a father in a traditional family.  Thus, the most complex model of interaction within the framework of fundamentalist ethics is that of a dyadic relationship: either one person interacting with a peer, or one person interacting with society, wherein  the interests of society at large are indistinguishable from those of a single authority figure. 

This model has the virtue of simplicity.  Dyadic relationships are easy to understand.  Unfortunately, the model is at best a gross oversimplification of the world we live upon.  Society consists of many individuals.  These individuals assort themselves in various configurations, subject to change from time to time.  Most actions performed by an individual in this social context will have no effect on most people, positive effects on others, and negative effects on some.  Some persons in the society will experience both positive and negative effects.  Furthermore, certain actions with have effects that magnify or reduce the effects of the actions of others.  This is true particularly when the actions serve to direct the activity of a faction within society. 

Such instances, when the behavior of an individual drives the behavior of a faction, are quantitatively and qualitatively different than behaviors that can be modeled as a dyadic interaction.  Therefore, different ethical principles apply.  Those in positions of power have a responsibility to consider the myriad ramifications of their actions.  Ordinarily, this calls for a high level of restraint.  Most erroneous behaviors that take place in a dyadic context are behaviors that can be undone, ameliorated, or made right in some way.  But collective actions, more often than not, cannot be undone. 

For example, consider the gay marriage issue.  Two persons with the same gender phenotype decide to share their lives together.  That decision will have a profound effect on the two persons involved, and relatively little effect upon anyone else.  If it turns out to have been a bad idea, they split up.  But have an agitated faction draft, promote, and pass legislation banning gay marriage, and you see complex and unpredictable effects ripple throughout society.  Sure, the legislation can be repealed; but by the time that be done, tens of thousands of persons have been affected. 

The gay marriage example serves to illustrate the concept, that actions undertaken by leaders must adhere to a higher standard.  However, it illustrates mainly the quantitative effects of leadership.  There are qualitative effects as well.  How does this occur?  It occurs in the context of large, heterogeneous populations, in which collective decisions can be expected to have some effects that are good, and some that are bad.  In such situations, a simplistic ethical framework fails to provide adequate guidance. 

Consider, for example, the context of a presidential election.  A faction may be opposed to gay marriage on the grounds that it somehow debases the entire institution of marriage.  In the interest of preserving marriage, they vote in a candidate who opposes gay marriage.  But suppose it turns out that the economic policies of that candidate destabilize the economy, increasing the rates of joblessness and homelessness.  That would have the predictable effect of increasing the incidence rates of domestic violence and divorce. Even a small increase in unemployment could contribute to the breakup of thousands of marriages.  Likewise, imagine voting in a candidate who is pro-life.  Imagine that candidate also is in the habit of starting wars, and likes to let industry spew toxins into the environment.  Imagine that the candidate also weakens consumer protection laws, increases the number of person without health insurance, and allows industry to influence the organizations that oversee the safety of food and drug products. 

Imagine that candidate funding the development of a new generation of nuclear weapons.  Imagine that candidate weakening the institutions that promote international cooperation.  Imagine that candidate sitting idly by, while genocide occurs on the other side of the world.  Imagine that candidate weakening the protections provided by checks and balances and the separation of powers. 

Imagine a one-party state emerging, thereby amplifying the effects of all of the problems mentioned so far.  OK, so maybe a few hundred thousand abortions are prevented each year.  But it would not be far-fetched to think that this would occur at a horrifying cost, millions of lives lost each year.  Yes, some corporations would profit enormously, but that is hardly exculpatory.

There is no rational ethical system in which such an outcome would be permissible.  Yet that is exactly what is happening.  Our political system has tied together policies that promote the profits of large corporations, with those that affect individual choices with limited social impact.  Thus, people have to choose between the minimization of a few controversial practices with limited effect, and the limitation of corporate activity that has widespread, potentially catastrophic consequences.  Following a simplistic moral framework, some persons see only the controversial individual practices, because that is all that their model reveals.  Their model does not have the sophistication to portray the consequences of actions that occur in a complex society.  Those issues are not seen on the radar, because the radar simply lacks the capacity to detect them.

I would not allege that churches have engaged in a vast conspiracy with corporate America, nor would I allege that corporate America has mounted a campaign to turn churches into pawns on the chessboard of American politics.  Rather, I would say that the particular characteristics of fundamentalist ethics provide fertile ground for the advocacy of policies that are essentially amoral or immoral, but which do not involve simple dyadic interactions.  Some -- by no means all -- leaders in these churches have taken it upon themselves to campaign for the limitation of certain controversial practices, either not realizing, or not caring, about the broader ramifications.

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Sunday, May 01, 2005

Moral Relativism in Action

Link skipping this morning, I happened across of tangle of posts about the topic of moral relativism.  TO give credit where it is due, I first encountered a link on Majikthise, then Left2Right, then Yglesias.  All very erudite, but with something missing.  What is missing from those posts is a good, concrete example, to help people know moral relativism when they see it.

Naturally, comedians had a field day with this, but most people recognize that Mr. Bush was being culturally sensitive when he kissed and held hands with the Crown Prince.  Nothing wrong with that: it would be considered proper in the Prince's own culture.  If Bush had done it with Dick Cheney, that would have been indecent.  That's moral relativism.

In fact, I don't care what Bush and Cheney do to each other, either in public, or behind closed doors.  The point is that some people would judge such behavior between two men as decent in one context, but indecent in another context.   I encourage those who would be inclined to make such differential judgments to recognize that as an instance of moral relativism. 

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