The Rest of the Story

Today's NYT contains an article about a study, originally published in Molecular Psychiatry.   The original study report  is here; the NYT article is here (permanent link).   Sometimes, when I see that something I know about has been reported in the newspaper, I wonder what it was about the topic that drew the attention of the reporter who wrote the news article.  After all, there are hundreds of medical journals, some are published every week.  Thus, there are thousands of journal articles to choose from.  Yet, only a few are deemed newsworthy. 

One would hope that reading the news article would answer the most important question: Why should I care about this?  After all, if I am going to take time away from reading blogs, and actually read a newspaper, I was to have some assurance that what I am reading is important. 

So let's give it a try, and see if this particular news article answers the question.  While we're at it, let's see if the study cited here has any other significance, perhaps something other that what the news reporter picked up on. 

Study Suggests Way to Predict Whom Antidepressants Help
By BENEDICT CAREY
Published: December 17, 2004

Scientists studying depression reported yesterday that they had found evidence that a common genetic variation affecting how people manage stress predicts how much benefit they get from taking antidepressants.

Psychiatrists have long known that about half the people found to be suffering from depression also show signs of elevated anxiety. Researchers have tried to explain the correlation, as well as why the same drugs can relieve both conditions.

In the new study, published in the journal Molecular Psychiatry, doctors from Harvard and the University of California, Los Angeles, treated with drugs a group of 54 Mexican-Americans in Los Angeles who were both depressed and highly anxious. (Limiting the study to one demographic group was a control tool.) They found that 60 percent of the group had a common genetic variant that helps govern the body's response to stress.

 The researchers found that after being treated with antidepressants, patients with the genetic variation were far less anxious and depressed than when they began the study, said the lead author, Dr. Julio Licinio of the Neuropsychiatric Institute of the University of California.

 But anxious, depressed patients who did not have the variation got much less relief from the drugs, Dr. Licinio said, adding, "This is the first time we've linked response to antidepressants to a stress-related genetic variation."

Now let's look at the study:

Association of a corticotropin-releasing hormone receptor 1 haplotype and antidepressant treatment response in Mexican-Americans 
Molecular Psychiatry (2004) 9, 1075-1082. doi:10.1038/sj.mp.4001587
Published online 14 September 2004
J Licinio, F O'Kirwan, K Irizarry, B Merriman, S Thakur, R Jepson, S Lake, K G Tantisira, S T Weiss and M-L Wong

There are well-replicated, independent lines of evidence supporting a role for corticotropin-releasing hormone (CRH) in the pathophysiology of depression. CRH receptor 1 (CRHR1), which we first mapped in the brain in 1994, has been implicated in the treatment of depression and anxiety. We studied the association of CRHR1 genotypes with the phenotype of antidepressant treatment response in 80 depressed Mexican-Americans in Los Angeles who completed a prospective randomized, placebo lead-in, double-blind treatment of fluoxetine or desipramine, with active treatment for 8 weeks. Subjects were included into the study if they had a diagnosis of depression without other confounding medical or psychiatric diagnoses or treatments. All patients were followed weekly and assessed for changes in the Hamilton rating scales for anxiety (HAM-A) and depression (HAM-D). Inclusion criteria in the study included a HAM-D of 18 or higher. Because CRHR1 affects both depression and anxiety. Patients were classified into a high-anxiety (HA) group if their HAM-A score was 18 or higher and in a low-anxiety (LA) group if their HAM-A score was less than 18. Utilizing the haplotype-tag single-nucleotide polymorphisms rs1876828, rs242939 and rs242941, we tested for haplotypic association between CRHR1 and 8-week response to daily antidepressant treatment. In the HA group (n=54), homozygosity for the GAG haplotype was associated with a relative 70% greater reduction in HAM-A scores compared to heterozygous (63.1±4.5 vs 37.1±6.9%, respectively, P=0.002). For HAM-D, GAG haplotype homozygosity was associated with a 31% greater reduction in scores after treatment compared to heterozygous (67.3±4.3 vs 51.2±6.0%, respectively, P=0.03). In those with lower-anxiety levels at screening, there were no associations between CRHR1 genotype and percent change in HAM-A or HAM-D. These findings of increased response to antidepressants in highly anxious patients homozygous for the GAG haplotype of CRHR1 need to be independently validated and replicated. Such work would support the hypotheses that response to antidepressant treatment is heterogeneous and that the CRHR1 gene and possibly other genes in stress-inflammatory pathways are involved in response to antidepressant treatment. These findings also suggest that variations in the CRHR1 gene may affect response to CRHR1 agonists or antagonists. All data are deposited in www.pharmgkb.org.

The newspaper article states that the study "Suggests Way to Predict Whom Antidepressants Help."   The abstract of the article says no such thing.  In fact, the methodology of the study would not permit such a conclusion.  Granted, the newspaper article did not say that the researchers had found something clinically useful; rather, the author stated that the study "suggests" it.  The newspaper article quotes the lead author as having said "This is the first time we've linked response to antidepressants to a stress-related genetic variation."  OK, I guess that is a "suggestion," but it is no more than that. 

Actually, this is not the first time that researchers have found some kind of biological marker that could someday be used to predict antidepressant response.  All the the others have failed to generate anything clinically useful, though.  They all have been interesting, but only to researchers.  None has been particularly newsworthy, with regard to the average citizen. 

Is there any  reason for this study to have been reported in the New York Times?  Perhaps.  But if so, it is not for the reason cited in the newspaper article.  The fact is, the study by Licinio, et. al., is important only in the context of the entire body of scientific literature that demonstrates biological markers for mental illness.  Just as a single fossil doesn't really mean much, a single study in a biological psychiatry journal does not mean much.  It is only when you look at what all the studies add up to, that any meaning emerges.

There have been many studies that demonstrate conclusively that there are detectable, quantifiable abnormalities in the anatomy and physiology of persons with mental illness.   The shear volume of studies pretty much forces the conclusion that there is something wrong with the anatomy and physiology or these patients.  It does not say anything directly about the causes of the the conditions.  So far, it does not say much about the treatment, either.   Of course, if we could  say something about causes or treatments, that would be newsworthy.  People, in general. tend to be curious, even eager, to learn about matters of practical significance.  The Licinio study does not meet that criterion.  It has no practical significance.  Rather, the significance is a philosophical and social one. 

In a social context, a person who chronically functions poorly tends to be judged, even stigmatized.  However, if there is some kind of demonstrable biological marker -- say, a blood test or a brain scan -- that is abnormal, then the tendency is to treat the person with a bit more compassion.  This does not make any sense, of course, but it is true.  Most value judgments serve no useful purpose, but it seems inevitable that humans go around making such judgments of others. 

Thus, the significance of the finding -- of objective biological markers -- is that it might, someday, lead to a reduction in the frequency and severity of these senseless judgments.  That would make the world a better place.

As reported in CCN Money, among other sources, a pharmaceutical company called Sepracor had obtained FDA approval for its new drug, Lunesta (eszopiclone).  Their stock went up by 15% immediately.  Looking through the news reports, most of them focus upon the financial implications of the impending release of this new product.  Patients, however, probably don't care much about that.  They want to know about the drug itself.

It turns out that technical information is hard to come by.  For a short, general discussion of insomnia, see this Medscape CME article (free registration required.)  For the package insert, see this PDF file.  A list of references can be found at the Sepracor site, here.  A Medline search reveals only one article with relevant information. 

Sustained efficacy of eszopiclone over 6 months of nightly treatment: results of a randomized, double-blind, placebo-controlled study in adults with chronic insomnia.

Krystal AD, Walsh JK, Laska E, Caron J, Amato DA, Wessel TC, Roth T.

Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27710, USA. krystal@phy.duke.edu

STUDY OBJECTIVES: To determine the long-term efficacy of eszopiclone in patients with chronic insomnia. DESIGN: Randomized, double-blind, multicenter, placebo-controlled. SETTING: Out-patient, with monthly visits. PATIENTS: Aged 21 to 69 years meeting DSM IV criteria for primary insomnia and reporting less than 6.5 hours of sleep per night, and/or a sleep latency of more than 30 minutes each night for at least 1 month before screening. INTERVENTIONS: Eszopiclone 3 mg (n = 593) or placebo (n = 195), nightly for 6 months MEASUREMENTS AND RESULTS: Efficacy was evaluated weekly using an interactive voice-response system. Endpoints included sleep latency; total sleep time; number of awakenings; wake time after sleep onset; quality of sleep; and next-day ratings of ability to function, daytime alertness, and sense of physical well-being. At the first week and each month for the study duration, eszopiclone produced significant and sustained improvements in sleep latency, wake time after sleep onset, number of awakenings, number of nights awakened per week, total sleep time, and quality of sleep compared with placebo (P < or = 0.003). Monthly ratings of next-day function, alertness, and sense of physical well-being were also significantly better with the use of eszopiclone than with placebo (P < or = 0.002). There was no evidence of tolerance, and the most common adverse events were unpleasant taste and headache. CONCLUSIONS: Throughout 6 months, eszopiclone improved all of the components of insomnia as defined by DSM-IV, including patient ratings of daytime function. This placebo-controlled study of eszopiclone provides compelling evidence that long-term pharmacologic treatment of insomnia is efficacious.

The paucity of hard information is a byproduct of the competitiveness of the pharmaceutical industry, as well as the extent to which the Industry now controls medical research.  Fifteen years ago, I usually knew what drugs were under development, and I knew quite a bit about the pharmacology of the drug before it was put on the market.  Now, everything is a tightly held secret. 

At this point, most of the technical information available is in the package insert.  The PI is a monograph that is written by the drug company, according to FDA specifications.   Every word, literally, has to conform to the specifications; every word has to be approved before the PI can be published. 

The main points are these: eszopiclone is chemically unrelated to most other sleeping pills.  It is similar to zopiclone, which is available in countries other than the USA.  It is absorbed best if taken on an empty stomach.  It reaches a peak blood level in about one hour, and has a half-life of about six hours, on average.  It is not water soluble, but it dissolves easily in ethanol.  As a relatively lipophilic drug, one would expect that it would cross the blood-brain barrier rapidly.  This is desirable for a sleeping pill, since it means it will take effect quickly.  It is broken down in the liver and the metabolites are excreted by the kidneys.  There are two enzymes responsible for breaking it down (catabolism).  This reduces the risk of drug interactions.  It is not highly protein-bound, which also reduces the risk of interactions.  It does not inhibit the action of many of the major drug-metabolizing enzymes in the liver, which further reduces the risk of interactions with other drugs. 

It appears that the primary risk of interaction occurs with drugs that inhibit the cytochrome P450 3A4 enzyme.  That would include itraconazole, nefazodone, clarithromycin, ritonavir, troleandomycin, and nelfinavir.  It would be expected to have additive sedating effects if given with other sedatives. 

According to the PI, eszopiclone binds to GABA receptors, although they do not specif what subtype of receptor, and they do not say what it does once it binds.  Presumably, it either is an agonist, or it acts to potentiate the natural effect of GABA.  GABA is the primary inhibitory neurotransmitter in the human brain, so it basically helps put the brain to sleep. 

Prior to marketing, the drug was studied in 2,100 patients, which is about average.  What is a bit unusual is that it was studied in many patients for up to six months.  That is a positive step by the company, and the FDA, that helps reassure us (somewhat) about the safety of the product.  The company claims that there was no evidnce for tolerance or dependence, which also is positive.  There was slight rebound insomnia the first night after stopping the drug, but this effect disappeared by the second night.  These findings indicate a low potential for abuse.  However, there have been other drugs that were marketed with claims of low potential for abuse, which turned out to be erroneous.  Stadol and Ultram probably are the best examples of this.  The fact is, some people will abuse anything, or at least will try to abuse it.  Therefore, we need to be cautious about any claims of low abuse potential.  To their credit, Sepracor did not make any claims about an absence of abuse potential in any of the literature I found. 

There were a few overdoses reported in clinical trials, but no fatalities.  The PI states "Individuals have fully recovered from racemic zopiclone overdosages of up to 340mg."  Lunesta is provided as the pure s-enatiomer, so 340mg racemic zopiclone is equivalent to 170mg of eszopiclone,  which is 57 times the maximum recommended dose.  That means that taking an entire one-month supply would not be expected to be fatal, if ingested alone.  Since people commonly overdose on more that one drug simultaneously, though, the real-world safety in overdose is not yet known. 

I'm sure it won't be long before we have more information on this.  As an aside, I would like to state that insurance companies that give patients a discount for getting a 3-month supply of medication should consider revising this policy, for drugs that people are especially likely to be used in suicide attempts. 

In premarketing trials, the adverse effects of eszopiclone were mild, and most occurred at a rate comparable to that with placebo. 

Overall, it appears that Lunesta will be a useful product, although there are so many sleeping pills on the market that there probably is little reason to use it, in the average patient, within the first six months of it coming on the market.  After that, if clinical experience is positive, it probably will be used widely.  Competitors likely will undertake six-month trials of their own products, to try to compete.  Insurance companies will urge doctors to use the less-expensive alternatives, even though some of the alternatives probably will have a higher potential for abuse. 

The current political apparatus has not been very productive lately.  Even though the Republicans control the House, Senate, and White House, they have shown signs of degenerating into a quagmire of infighting, barely able to pass the 9/11 reforms. 

Perhaps they should take on something that ought to be easy to pass, and is just as important.  In the first debate, both major Presidential candidates agreed on the answer to the question: What is the most serious threat to national security?

LEHRER: New question, two minutes, Senator Kerry.

If you are elected president, what will you take to that office thinking is the single most serious threat to the national security to the United States?

KERRY: Nuclear proliferation. Nuclear proliferation. There's some 600-plus tons of unsecured material still in the former Soviet Union and Russia. At the rate that the president is currently securing it, it'll take 13 years to get it. [...]

LEHRER: Ninety seconds, Mr. President.

BUSH: Actually, we've increased funding for dealing with nuclear proliferation about 35 percent since I've been the president. Secondly, we've set up what's called the -- well, first of all, I agree with my opponent that the biggest threat facing this country is weapons of mass destruction in the hands of a terrorist network. And that's why proliferation is one of the centerpieces of a multiprong strategy to make the country safer. [...]

OK.  Great.  They agree on something.  Now let's do something about it. 

To check on their progress so far, I went to Google News and searched for Bush nuclear proliferation.  The results:

1. US tied over nuclear kingpin
By Kaushik Kapisthalam

The United States is selling the theory that the Pakistan-based nuclear proliferation ring has been broken up and its mastermind, Dr Abdul Qadeer Khan, has been "brought to justice". He is under house arrest in Pakistan. Unfortunately, as much as the Bush administration would like to wish away the Khan issue, it continues to dog two of the biggest foreign-policy crises for the US. [...]

2. Charm offensive on Bush's foreign policy fails to hide Nato strains
By James Harding in Washington and Daniel Dombey in Brussels
Published: December 10 2004 02:00 | Last updated: December 10 2004 02:00

[...] Western diplomats have welcomed Mr Bush's outreach to Europe but cautioned that, so far, it remains a change in tone, not direction.

European officials note that the Bush White House has so far rebuffed European requests to join the effort to negotiate with Tehran on nuclear disarmament, stands opposed to European suggestions of lifting the arms embargo on China and has backed away from European calls to shore up the United Nations in the wake of the oil-for-food scandal. [...]

3. National Energy Commission Report Paints Contrast With One-Sided Congressional, White House Energy Policies

[...] The report findings illustrate just how far off track Congress and the White House have gone with an energy bill that subsidizes the biggest polluting energy companies and does nothing address our dangerous dependence on foreign oil or the problem of global warming. [...]

"Big federal subsidies for constructing new nuclear power plants would be a giant burden on the American taxpayer, especially since nuclear power plants continue to have unresolved issues regarding nuclear proliferation, safety risks and waste disposal," Warren said. [...]

4. Bush manipulated NKorea intelligence like he did in Iraq: US expert
12-10-2004

BEIJING (AFP) - The United States manipulated intelligence on North Korea's nuclear program in a similar fashion to its use of weapons of mass destruction to justify the war on Iraq, a US foreign policy expert said in an article.

"Relying on sketchy data, the Bush administration presented a worst-case scenario as an incontrovertible truth and distorted its intelligence on North Korea (much as it did in Iraq), seriously exaggerating the danger that Pyongyang is secretly making uranium-based nuclear weapons," Selig Harrison said in Foreign Affairs magazine. [...]

5. US daily flays Bush for praising Mush [Pervez Musharraf]
PTI [WEDNESDAY, DECEMBER 08, 2004 06:38:37 AM ]

WASHINGTON: The world’s worst nuclear proliferation emanating from Pakistan was not possible without support from its military, according to a leading US daily, which flayed President Bush for praising Pervez Musharraf during his recent visit here.

"The world's worst case of nuclear proliferation in which sophisticated nuclear technology was supplied to Libya, Iran and other rogue nations never would have been possible without the support of the Pakistani military,” said an opinion piece in The Los Angeles Times.

President Musharraf is the same man who pardoned A Q Khan and refuses to allow foreign investigators to speak with him, the daily said.

"Yet it was Musharraf whom President Bush spent the weekend praising and accommodating." [...]

6. U.S. needs to do more on arms controls
2004-12-10 / Taiwan News, Staff Reporter / By Jonathan Power

[...] All but unreported upon, Bush has been using the power of the U.N. Security Council, a body that he is supposed to detest and distrust, to introduce what Chaim Braun and Christopher Chyba in the current issue of Harvard University's "International Security" have described as "a remarkable new approach to global enforcement of non-proliferation requirements."

In April this year the Security Council imposed an expansion of export controls on all the countries of the world, compelling nations to make proliferation a criminal offense. This short cut the need for a new time consuming treaty and if it had been put in place before would not have allowed Pakistan President Pervez Musharraf to pardon his rogue chief weapons' scientist who turned his country's nuclear program into a personal money making machine.

Yet three months after that U.N. vote the Bush administration paradoxically announced a major shift in policy toward the important negotiations on a Fissile Material Cutoff Treaty. It decided it would oppose the treaty's verification provisions, a move which while protecting America's secrets would protect everyone else's. The treaty has been in discussion since 1993 and its central idea is a simple one: by capping the production of fissile material for nuclear weapons it would prohibit the further manufacture of nuclear weapons. This would make irreversible the reductions already made by the big powers; it would cap the arsenals of China, France and Britain; and effectively rein in the programs of India, Israel and Pakistan, even though these three haven't signed the Nuclear Non-proliferation Treaty. Not least, it might have some appeal to Iran, North Korea, Japan, Syria and Saudi Arabia- although it would render illegal their attempts to produce weapons-usable fissile material they would earn the satisfaction of knowing that they would not be overtaken by what a U.N. report recently warned might be a "cascade" of new nuclear weapons' states.

The Administration's somersault on verification make it difficult to conclude a satisfactory treaty. Likewise its opposition to a Comprehensive Test Ban Treaty and its desire to build new weapons that can penetrate underground bunkers are working against its own non-proliferation urges. [...]

The was more, of course, but the point is this: I could not find any evidence that the Administration is actually doing anything new about what they agree is the single greatest threat.  In fact, the non-flip-flopper has done a "somersault" on the issue of nuclear proliferation. 

Bloggers are starting to pick up on this.  Via Letters of Marque, I found this quote from Fafblog:

Giblets's plutocratic economic policies will beggar liberals AND conservatives! His incoherent foreign policy and complete negligence on nuclear proliferation will endanger the lives of EVERY American, regardless of race, color, or creed! His ceaseless pandering to a lunatic fringe of apocalyptic religious radicals will curtail civil rights and education reform for everyone, making ALL Americans stupider AND less free at the same time! All will be as one in the new Gibletsian dystopia!

Jakesavin.com chimes in:

[...] Bush's office and supporters have spent the last four years feeding us disinformation, through a despicably willing mainstream press, using a media machine that's been honed for decades. They've repeatedly lied about tax cuts, the environment, the war, the Patriot Act, handling of Iraqi prisoners, big breaks for big-business, tax cuts for the rich, foreign outsourcing of jobs and record job loss, the worst environmental record in recent memory, non-handling of nuclear proliferation, an abysmal execution of the war in Iraq, a failed economic policy, record budget deficits and more. [...]

The Centrist Coalition quotes Kissinger on this topic, incidentally lambasting the current administration, without naming names:

Kissinger has very harsh words for policies that provide incentives in return for denuclearization, and insists that negotiations be multilateral, not bilateral:

. . . the solution cannot be left to bilateral U.S. talks with the proliferators. The insistence on U.S.-North Korea bilateralism would leave America as the sole enforcer of any agreement at the borders of China. And it would invite Pyongyang to use the new agreement for future blackmail—the pattern it followed after the bilateral agreement of 1994. The same applies in a different context to relations with Iran.

From Anti-[everything] v2.0

Congress Makes the Right Choice
Reference: Congress jettisons nuclear bomb funds - President touted bunker buster as vital to U.S. security

Congress made the correct choice in voting to not fund research into new nuclear weapons like Bush's bunker-buster nukes. Nuclear proliferation is something the US should be fighting, not encouraging. It is very difficult, and hypocritical, to tell other nations to cease nuclear weapon research and production when we won't. The solution to proliferation is not to disarm every country but the US. The goal is the end of all nuclear weapons.

From Prague Spring Blog:

The primary mandate of President George W. Bush is to protect US citizens. In fact, Republicans and Democrats alike agree that nuclear proliferation and terrorism are the greatest threats facing the US. In his second term, President Bush has the opportunity to make Americans safer and more secure by implementing responsible nuclear policies that will prevent the spread of nuclear weapons and prevent terrorists from obtaining and using nuclear weapons against the US.

Found on The War in Context:

U.N. to issue alert over spread of nuclear arms
By Mark Turner, Financial Times, November 30, 2004

The world system to prevent the spread of nuclear weapons is being rapidly eroded, threatening a "cascade of proliferation," a high-level panel on UN reform will say this week. [...]

The panel examined a wide range of threats, including terrorism, disease, poverty and environmental degradation. But the risk of nuclear Armageddon may be the most pressing of all, and has led to growing disagreement over how to tackle nuclear advances in the Middle East, Asia and Latin America.

It argues that nuclear weapons states "must honour their commitments to move towards disarmament", and reaffirm promises not to use nuclear weapons against non-nuclear states. The Security Council pledge for "collective action" could help ease non-nuclear states' concerns.

The only reasonable conclusion is that the USA is not doing a very good job of handling the North Korea nuclear arms situation.  There is a more important point, though.  Specifically, there is evidence that the Administration is acting in such a way as to further corrade the credibility of the USA in the International arena.  Sharp-eyed readers may have noted, in particular, the item #4 in the second blockquote.  It refers to an accusation that the US exaggerated the progress North Korea has made with uranium enrichment.  The report is based upon an article in Foreign Affairs by Selig S. Harrison. 

Did North Korea Cheat?
By Selig S. Harrison

From Foreign Affairs, January/February 2005

[...] Much has been written about the North Korean nuclear danger, but one crucial issue has been ignored: just how much credible evidence is there to back up Washington's uranium accusation? Although it is now widely recognized that the Bush administration misrepresented and distorted the intelligence data it used to justify the invasion of Iraq, most observers have accepted at face value the assessments the administration has used to reverse the previously established U.S. policy toward North Korea.

But what if those assessments were exaggerated and blurred the important distinction between weapons-grade uranium enrichment (which would clearly violate the 1994 Agreed Framework) and lower levels of enrichment (which were technically forbidden by the 1994 accord but are permitted by the nuclear Nonproliferation Treaty [NPT] and do not produce uranium suitable for nuclear weapons)?

A review of the available evidence suggests that this is just what happened. Relying on sketchy data, the Bush administration presented a worst-case scenario as an incontrovertible truth and distorted its intelligence on North Korea (much as it did on Iraq), seriously exaggerating the danger that Pyongyang is secretly making uranium-based nuclear weapons. This failure to distinguish between civilian and military uranium-enrichment capabilities has greatly complicated what would, in any case, have been difficult negotiations to end all existing North Korean nuclear weapons programs and to prevent any future efforts through rigorous inspection. [...]

The complete article is long and highly technical --just right for weekend reading.  Dr. Harrison alleges that the United States was worried about the potential consequences of the warming relations between North and South Korea, and between Japan and North Korea.  He implies this was the reason the US acted when it did to confront North Korea about the alleged uranium enrichment program.  If true, that seriously would damage our credibility.  More damaging, however, is the accusation that the US based its claim on exaggerated intelligence findings. 

Note that the US has publicly denounced Dr. Harrison's findings:

US refutes claims by US expert on North Korea nuclear program
WASHINGTON (AFP) Dec 10, 2004

[...] "I think that those claims are wrong. And we think there is a wealth of clear and compelling evidence about North Korea's uranium enrichment program," deputy State Department spokesman Adam Ereli told reporters.

"We have known since the late 1990s that North Korea was interested in enrichment technology. We obtained clear evidence over 2.5 years ago that it was pursuing a covert program to enrich uranium and assessed that North Korea was pursuing uranium enrichment as an alternate route to nuclear weapons," he added.

"This program was in clear violation of international commitments that North Korea voluntarily undertook, including its obligations under the Nuclear Non-Proliferation Treaty and its commitments under the 1994 agreed framework and the North-South denuclearization declaration," Ereli said. [...]

The State Department spokesman, Adam Ereli, apparently did not read Dr. Harrison's article carefully; or if he did, he spoke on the assumption that the reports to whom he was speaking had not.  Dr. Harrison acknowledges that there is evidence for North Korea pursuing an uranium enrichment program, but he points out that the available evidence most strongly supports the conclusion that the enrichment program was limited.  He was not able to find any evidence that they have developed the capacity to produce highly enriched uranium.  He points out that the production of low-enriched uranium is permitted under the terms of the Nuclear Nonproliferation Treaty.  Thus,, Ereli's assertion that "This program was in clear violation of international commitments that North Korea voluntarily undertook, including its obligations under the Nuclear Non-Proliferation Treaty" appears to be invalid. 

Of course, Dr. Harrison might not have access to all the the intelligence information.  He acknowledges this, and lays out his case carefully, allowing for the limitations in the data available to him.  In fact, he (or the Foreign Affairs editors) seem to have overstated the case in the preface to the article, in which it is alleged that the US "distorted" the data.  What he demonstrates is that the US either distorted the data, or they are withholding data that contradicts what data are openly available. 

Since Harrison was writing in a reputable publication, he did not make any claims of conspiracy theories.  Since this is a blog, however, I am not laboring under such constraints.  Therefore, I will add an idle, unsupported speculation based upon Harrison's work.  Read this:

Recent revelations that Abdul Qadeer Khan, the ousted director of Islamabad's nuclear program, ran a black-market supply ring for nuclear materials have strengthened suspicions of a Pakistan-North Korea connection. Here again, however, the facts remain murky. Khan has not discussed the specifics of his misdeeds publicly, and conflicting statements about North Korea have been attributed to him. A June 2002 CIA assessment that was leaked after the Kelly visit said that Pakistan had provided North Korea with centrifuge prototypes and blueprints, but that it was uncertain how many, if any, centrifuges North Korea had made from them. The possibility that such prototypes were supplied to Pyongyang is supported by the fact that the aluminum tubes intercepted by France in 2003 matched the type used by Pakistan. But there is no basis for assuming that Pakistani help went beyond the supply of an uncertain number of demonstration centrifuges and associated replacement parts. When the Khan nuclear smuggling network was exposed, it turned out that a factory in Malaysia had supplied Libya with centrifuges. But the detailed Malaysian police report on the factory's exports makes no reference to North Korea, and U.S. officials acknowledge that there is no evidence that it supplied anything to North Korea. Moreover, the detailed review of British intelligence on nuclear and missile proliferation conducted by the Butler Committee linked Khan solely to Libya and made no mention of any help by his network to North Korea.

Really, AQ Khan is the key to this whole thing.  If he were to speak up and reveal that he had supplied critical material to North Korea, it would strengthen the Bush Administration's claim against North Korea.  But Kahn has not spoken up.  The US settled for him getting a slap on the wrist, and house arrest.  He never has been called upon to reveal the details of what he knows.  Why not?  Why did the US agree to this?  After all, we got worked up into a lather about Clinton lying about consensual sex.  We even impeached him.  Now we know of a guy who has vast knowledge of nuclear proliferation, and we let him get off with a token punishment.  Since it is safe to assume that nuclear weapons are a greater threat to world security than oral sex, it leaves us wondering why the disparity exists. 

Could it be the the US does not want AQ Kahn to speak up?  If not, why not?  Perhaps the truth would discredit the Bush Administration's claims...

There is another point, a serious one, that I would like to bring up.  One point of this post is to demonstrate that Mr. Bush has not taken any, or much, effective action on the issue of nuclear proliferation.  Even after agreeing that it is the single greatest threat to our security, he has done little.  Harrison's article makes this clear.  The Administration's refutation of his conclusions avoids this entirely.  Perhaps they avoid it because they cannot refute it.  Harrison points out:

By scuttling the 1994 agreement on the basis of uncertain data that it presented with absolute certitude, and by insisting that North Korea "confess" to the existence of a uranium program before new negotiations on denuclearization can begin, the Bush administration has blocked action on the one present threat that North Korea is known to pose: the threat represented by its reprocessed plutonium, which could be used for nuclear weapons or transferred to third parties. [...]

The danger posed by North Korea's extant plutonium program has grown since the United States announced it was no longer bound by the Agreed Framework, and it is much greater than the hypothetical threat posed by a suspected uranium-enrichment program about which little is known.

In other words, by kicking up a fuss about the uranium program that may not even exist, Bush enabled North Korea to go ahead with its plutonium enrichment.  Not too bright, that.

If I may return to idle speculation (try to stop me) I would point out that Bush may an even greater misstep.  North Korea is a rogue state.  It is tough to negotiate with them.  We cannot take them on, militarily, for various reasons.  It would be nice if they would just go away...or be absorbed into South Korea.  The two Koreas were making progress toward reunification, until we got involved.  My hypothesis is that the best way to deal with the threat posed by North Korea is to promote reunification, not impede it.