Tuesday, April 28, 2009

Brain shock: The new Gulf War syndrome

Editorial: Concussed, stressed or just sick of war?

ONE look at the effects of a bomb blast suggests that you'd have to be extremely lucky to emerge from one unscathed. If you were not burned by the explosion or blasted by shrapnel, the chances are you'd be hit by the shock wave. Travelling at several hundred metres per second, this causes massive fluctuations in air pressure which can knock you unconscious, rupture air-filled organs such as eardrums, lungs and bowels, and stretch and distort other major organs.

Soldiers serving with coalition forces in Afghanistan and Iraq know only too well how devastating bombs can be. The effect of shrapnel on bodies - amputated limbs, broken bones, lacerated and burned flesh - is plain enough. Less obvious and harder to understand are the long-term effects of the shock wave on the brain.

Weeks, months, or sometimes years after being concussed in an explosion, thousands of soldiers are reporting a mysterious clutch of problems. Dubbed post-concussion syndrome (PCS), symptoms include memory loss, dizziness, headaches, unexplained pains, nausea, disturbance of sleep, inability to concentrate and emotional problems.

The US military and veterans' groups see PCS as a growing problem, and the US government is pouring millions of dollars into investigating it. Some doctors, however, particularly in the UK, believe that for many patients the symptoms ascribed to PCS are not caused by concussion at all, but by the shock and stress of wartime events. It may even be getting mixed up with post-traumatic stress disorder (PTSD), an acknowledged psychological reaction to disturbing events. "Some people are saying it's a hideous mistake and that we're talking up a problem," says Simon Wessely, a psychiatrist and director of the King's Centre for Military Health Research at King's College London.

Simple concussion from a blow to the head is not a new problem, of course. Common causes are falls, car accidents or sports such as rugby and football. It can lead to a brief loss of consciousness, amnesia or confusion. Although longer-lasting symptoms are occasionally reported, sufferers usually recover within days or weeks.

Battlefield explosions are nothing new either. For soldiers serving in Iraq and Afghanistan, one of the biggest threats they face is from roadside bombs, often improvised from cast-off artillery shells or other weapons. While more soldiers than ever are surviving such blasts, thanks to better body and vehicle armour, they are often left with concussion, or mild traumatic brain injury (mTBI) as it is usually termed in this context.

In the 1990s, soldiers returning from the first Gulf war started to report persistent cognitive problems after an mTBI. The Brain Injury Association of America and others have described mTBI as a "signature injury" of the Iraq and Afghanistan conflicts. Veterans organisations have voiced growing concerns and are even using words like "epidemic".

But why should a bomb blast be more likely to trigger PCS than a sports injury? The jury is still out, although various theories are being investigated (see "Blasted"). Despite the uncertainties, the US military, government and patient groups designate mTBI and PCS as battlefield disabilities with a high priority. The Defense and Veterans Brain Injury Center (DVBIC) in Washington DC was set up in 1992 to help military personnel with brain injuries. In 2007, the US Congress agreed to provide $900 million for research into and treatment of battlefield traumatic brain injuries and PTSD. Then in 2008, President George W. Bush reauthorised the Traumatic Brain Injury Act, which compels federal health bodies to improve care and treatment of both civilians and soldiers suffering brain injuries and to fund monitoring and research.

Meanwhile, attempts to identify soldiers with mTBI have been stepped up. Both the British and the American military routinely carry out simple mental tests on soldiers exposed to blasts, investigating symptoms and what they remember of the event. Anyone with concussion should be removed from combat and given light duties until they recover. "The key is to limit the exposures [to concussion] and limit the exposures that come on top of each other," says Jeffrey Barth, a neuropsychologist at the University of Virginia, Charlottesville, and an expert on concussion injuries.

The US army also screens for symptoms of mTBI when soldiers return from a tour of duty, and again three months later. The army is also carrying out neurocognitive tests on recruits before they are sent into combat so that doctors can check for deterioration in later tests. However, even if PCS is diagnosed there is no specific treatment. All doctors can do is target individual symptoms, for example, with antidepressants, analgesics and sleeping pills, as well as psychotherapy and behavioural therapy. And the intense focus on identifying cases of mTBI and PCS belies the fact that the mechanism by which mTBI could lead to PCS is still unclear. PCS is not so much a discrete entity as a constellation of symptoms that overlap widely with other mental and physical illnesses. There is no blood test or brain scan that can diagnose it - doctors can only ask if the patient ever had an mTBI, run through the check-list of symptoms, and rule out other causes.

Those sceptical about PCS do not dispute that a worryingly large number of soldiers are returning from Iraq and Afghanistan with persistent cognitive problems. What they question is whether these symptoms can be attributed to an mTBI. "There was this sudden view that we'd stumbled on something completely new," says Wessely. "But blasts are not a new problem in warfare."

The debate has heated up in the past year with the publication of three studies that have cast doubt on the view that PCS is a direct consequence of concussion. In one, a team at Macquarie University looked at 175 civilians admitted to hospital because of physical injuries (Journal of Neurology, Neurosurgery and Psychiatry, vol 79, p 300). About half of the group had sustained an mTBI, and after a few days 43 per cent of them had symptoms consistent with PCS. But 44 per cent of the other group, whose injury was not brain related, also had these symptoms. While this study looked at patients in the first few days after their trauma rather than months, it shows that PCS symptoms aren't necessarily the result of brain injuries.

The other two papers are perhaps more significant as they involve large epidemiological studies in soldiers, rather than civilians, and looked at symptoms over the long term. Both research teams concluded that persistent cognitive problems after an mTBI were in most cases due to psychological causes such as depression and PTSD.

In the first study, researchers questioned more than 2500 US infantry soldiers three to four months after they returned from a year-long tour of duty in Iraq, asking them about their combat experience, any injuries they had suffered and any persistent symptoms. Around 15 per cent of them had suffered an mTBI, and these soldiers had significantly more mental and physical problems than those with other injuries (The New England Journal of Medicine, vol 358, p 453). Charles Hoge at the Walter Reed Army Institute of Research in Silver Spring, Maryland, who led the study, thinks the primary cause of their ill health was probably not concussion but "exposure to a very intense traumatic event that significantly increases the risk of PTSD".

Hoge reasons that PTSD is a more likely cause than mTBI, having many common symptoms. In addition, the psychological symptoms of PTSD persist, while the effects of concussion usually disappear quickly. "When a soldier gets concussed as a result of a blast on the battlefield, that is clearly a close call," says Hoge. "Such traumatic events can set up a cascade of neurochemical events that happen with PTSD, and that can lead to a host of symptoms."
I saw dead people

The second study, by Wessely's team, which looked at nearly 6000 British soldiers who had served in Iraq in 2003, reached similar conclusions (Psychological Medicine, DOI: 10.1017/S0033291708004595). The researchers found no indication that the symptoms ascribed to PCS were caused by an mTBI. While many of those who reported such symptoms had indeed been caught in a blast, some had not. In fact, blast exposure proved no more predictive of PCS symptoms than other stressful combat situations, such as seeing dead bodies or knowingly being exposed to depleted uranium. The findings suggest that the symptoms "are most often an expression of psychological distress", says Wessely.

Michael Jaffee, however, who is national director of the DVBIC, warns against assuming that the symptoms ascribed to PCS are caused exclusively by either an mTBI or by PTSD. Since any kind of combat injury raises the risk of PTSD, and since you are more likely to show PTSD symptoms after a head injury, "there is bound to be overlap", he says.

Jaffee wonders if there might be something about blast-induced brain injury that makes people more vulnerable to psychological disorders, and to PTSD in particular. PTSD is characterised by impaired function in parts of the prefrontal cortex that help regulate how we deal with fear and anxiety and mTBI often involves damage to the prefrontal cortex. Jaffee and others suggest that this sort of damage may disrupt a person's capacity to deal with fear and thus make them more susceptible to PTSD (Journal of Rehabilitation Research and Development, vol 44, p 895).

Wessely questions this kind of association because "when you get concussion you lose your memory, so how can you have flashbacks when you don't remember the incident?". But concussion does not always involve amnesia. Furthermore, Hoge says, traumatic memories can trigger PTSD even when you are not conscious of them.

In any case, does it matter to the patient what the cause of their symptoms is? Many researchers say it matters a great deal. Plenty of studies have shown that what you tell a patient about what is wrong with them has a big influence on how long they take to get better. "If they believe they are going to have lifelong impairment as a result of a brain injury, they are more likely to have persistent symptoms," says Hoge. "On the other hand, individuals who have positive expectations, who are told they are going to get better, actually do better."

Wessely and Hoge even avoid the term mTBI when talking to patients. "The phrase 'traumatic brain injury' makes it sound like you have shrapnel in your skull and will end up in a wheelchair," says Wessely. "Call it concussion and they'll think, I had that playing rugby."

Another reason why understanding the true cause of PCS matters relates to whether it should be screened for. The US military screening programmes have found that up to 18 per cent of its returning personnel have had an mTBI. Figures from the UK military, on the other hand, which does not carry out mass screening, suggest that fewer than 1 per cent of its troops have suffered an mTBI.

Why such a big difference? It is possible, of course, that US troops get blown up more, or perhaps have weaker protective helmets. But another explanation is that US doctors find more head injuries simply because they have systematic screening in place, while British soldiers have to decide they have a problem and take the action of going to see their doctor.

So might the US be overdiagnosing the problem, or the UK underdiagnosing it? Lionel Jarvis, the UK's assistant chief of the UK defence staff (health), thinks the former. Jarvis points out that any soldier returning from a six-month tour of duty in Afghanistan, where they've been away from their family and in an extreme, high-pressure environment, is likely to show symptoms of distress: "How on earth do you unpick the different symptoms and explain whether they are due to a head injury or one of a large number of other potential causes?"

Wessely says his study showed that screening soldiers for PCS when they get home cannot distinguish between those whose problems were caused by concussion and those who have anxiety, depression or PTSD. "It's fraught with danger," he says. "Caution is needed before labelling mTBI as an epidemic because this might become self-fulfilling."
Labelling this as an epidemic is fraught with danger because it might become self-fulfilling

But Barth insists some kind of screening is needed. "At least the military is making an attempt to look at these issues," he says.

When it comes to combat trauma, unpicking the physical from the psychological is bound to be highly complex. As Barth says, perhaps the greatest danger could be in trying to simplify the picture too much. "I recommend that we get comfortable with the complexity," he says, "and treat it as a challenge."

Editorial: Concussed, stressed or just sick of war?
Consequences of combat

PTSD: post-traumatic stress disorder. Once known as shell shock, this is a psychological reaction to shocking events and is characterised by vivid flashbacks, anxiety and insomnia

mTBI: mild traumatic brain injury. A medical name for concussion, the effects are usually limited to days or weeks.

PCS: post-concussion syndrome. The term given to longer-lasting effects after a head injury. How it occurs is hotly debated.

The mainstream view of concussion from an explosion is that the blast wave hits the head, throwing the brain around inside the skull (a). In some cases this could be enough to tear axons, the microscopic fibres that carry messages between neurons.

In the past few years, however, there has been a surge of research into whether other mechanisms could account for the apparently high rate of post-concussion syndrome among US soldiers returning from Iraq and Afghanistan.

Computer modelling by neurologist David Moore, deputy director for research at the Defense and Veterans Brain Injury Center in Washington DC, suggests that the pressure wave enters the head more through the eyes and sinuses than the skull (b). Another theory, championed by neurologist Ibolja Cernak at the Johns Hopkins University Applied Physics Laboratory in Baltimore, Maryland, is that when the blast wave hits the torso, pressure travels up to the brain through major blood vessels (c).

Meanwhile, the US Defense Advanced Research Projects Agency is exposing pigs to explosions to investigate whether a blast's electromagnetic pulse could interfere with the brain's electrical circuitry (d). DARPA is also closely following the health of a group of military explosives experts who are exposed to multiple blasts while training, with results expected in the next few weeks.

Saturday, April 18, 2009

Father's troubles emerge in investigation of family's slaying

(CNN) -- A Maryland man believed to have shot and stabbed his wife and three young children to death before killing himself with a shotgun was having money problems and left a note saying he suffered from "psychological issues," authorities said.

Christopher Wood, 34, may have slashed at least some of his family members in the killings and used a small-caliber handgun on others, Frederick County Sheriff Charles Jenkins said.

He was found dead of an apparently self-inflicted shotgun wound at the foot of the bed where the bodies of his wife and 2-year-old daughter lay, the sheriff said.

Wood's sons were 5 and 4 years old, authorities said. His wife, Francie Billotti Wood, was 33.

The boys were found in their beds in a single bedroom, the sheriff said. Authorities did not release the names of the children.

"These are horrific incidents," said Jenkins, who said he couldn't remember another homicide in the past 20 years in Middletown, a one-stoplight town northwest of Baltimore. "No one should ever have to be exposed to this."

Jenkins told CNN that at least five notes apparently handwritten by Wood were found inside the home. While the notes didn't immediately tell investigators what prompted the killings, they did provide some insight into possible problems.

"There is some indication in at least one of the notes that there might have been some psychological issues with Mr. Wood," Jenkins said.

There was "a mention of some medication" in that note, according to the sheriff.

Jenkins said the sheriff's office had no record of domestic violence or other family disputes at the Wood's home.

He said investigators also have learned of money problems for Wood, a salesman for CSX Railroad.

"We are aware there were some, maybe, debt problems -- some financial problems," Jenkins said.

Cpl. Jennifer Bailey said deputies went to the home shortly after 9 a.m. after Mrs. Wood's father called. Her family had not seen the Woods for about a day and her father forced his way into the locked home, finding the bodies, according to Jenkins.

Authorities said a shotgun was found next to Christopher Wood's body and a .25-caliber handgun was found in a "container" in the kitchen. The sheriff said other weapons that could have been used to stab and cut the victims were found, but he did not say what those weapons were. VideoWatch sheriff's department's statement »

Francie Wood's family were longtime residents of the Middletown area. Her brother had recently retired from a career as a sheriff's deputy, Jenkins said.

The family had moved to town from Florida about four months ago.

"We're all in shock," said the Rev. Kevin Farmer, the family's minister at Holy Family Catholic Church. "This was a family, though they hadn't been with us very long, they are an integral part of our community."VideoWatch views from the crime scene »

He said the road the Woods lived on is a shortcut to the church and he would often see the children while riding a scooter he uses when the weather is good.

"They would always stop and wave and get big eyes as the scooter came by," he said. "They were very happy kids."

Jenkins said autopsies will be performed on the bodies over the next few days and that it could be weeks before the results are ready to be released.

Jenkins told CNN that at least five notes apparently handwritten by Wood were found inside the home. While the notes didn't immediately tell investigators what prompted the killings, they did provide some insight into possible problems, the sheriff said.

"There is some indication in at least one of the notes that there might have been some psychological issues with Mr. Wood," Jenkins said.

Cpl. Jennifer Bailey said deputies went to the home shortly after 9 a.m. after Mrs. Wood's father called. The family had not been seen for several days, Bailey said.

Authorities said several weapons, including a shotgun, were found inside the home.

Christopher Wood had been an employee of CSX Railroad, Jenkins said. He said the sheriff's office had no record of domestic violence or other family disputes at the Woods' home.

"In my entire career, just about 20 years, this is probably the worst tragedy I've ever been a part of or ever seen in Frederick County," Jenkins said.

Wednesday, April 15, 2009

With anti-addiction pill, 'no urge, no craving'

By Caleb Hellerman,
CNN Senior Medical Producer

CENTRAL FALLS, Rhode Island (CNN) -- A no-frills bar called Goober's, just north of Providence, Rhode Island, is probably the last place you'd expect to find a debate over cutting-edge addiction therapy. But this is where Walter Kent, a retired mechanic, spends his Fridays. He helps in the kitchen and hangs out in the bar, catching up with old friends.

Most addiction specialists would call this playing with fire, or worse. That's because for more than 30 years, Kent was a hard-core alcoholic. His drinks of choice were Heineken beer and Jacob Ginger brandy, but anything with alcohol would do.

"It's like a little kid wanting a piece of candy. You see it, you want the taste of it." He closes his eyes and sniffs the air, remembering the feeling. "You can be by yourself, and all of a sudden get even a hint of alcohol, just the smell of it, and say, 'Oh, I need a drink.' That sensation is not something you can get rid of."

But today, Kent isn't tempted in the least. He says the credit goes to a prescription medication -- a pill called naltrexone. It's part of a new generation of anti-addiction drugs that may turn the world of rehab on its head.

Dr. Mark Willenbring, who oversees scientific research at the National Institute on Alcoholism and Alcohol Abuse, says alcoholism has reached a point similar to one depression reached 30 years ago -- when the development of Prozac and other antidepressants took mental health care out of the asylum and put it in homes and doctors' offices.

"There will be a 'Prozac moment,' " Willenbring says, "when primary care doctors start handling functional alcoholics." VideoWatch Dr. Sanjay Gupta's quiz: Are you an alcoholic? »

Among the findings that are causing excitement:

• A study led by Dr. Bankole Johnson of the University of Virginia found that topiramate (Topamax) -- already used to treat epilepsy and migraines -- reduced the number of days on which alcoholics drank heavily, by 25 percent more than among alcoholics who got just therapy.

• A federally funded study known as COMBINE compared cognitive-behavioral therapy alone with therapy along with naltrexone. Patients receiving both were more likely to stay abstinent and drank less if they did relapse.

These findings highlight what's become increasingly clear: Addiction is a brain disease, not just a failure of willpower. Naltrexone and topiramate have slightly different mechanisms, but both seem to block the release of brain chemicals that are linked to pleasure and excitement. Unlike earlier drugs used to treat alcoholics, neither is addictive or carries significant side effects. It does appear that each might work better in certain subgroups -- topiramate for repeat relapsers, and naltrexone in people with a strong family history of alcoholism. Interactive: Addiction's lure to the brain »

Johnson is a paid consultant to the company that makes Topamax, but his study appeared in the Journal of the American Medical Association and he says other medications can also work well. "I think everybody who's an alcoholic should be given medication if they're willing to take it," he says. "It's been shown over and over with research studies that effects of medicine are over and above that of therapy. And if you're not getting the medicine, it's a bit like having one hand tied behind your back."

Before he found naltrexone, Kent had tried to quit drinking more times than he can remember. "I was the kind of person who only drank if he was alone or with somebody. Other than that, it was never a problem," he jokes now. He did two stints in residential rehab programs and went to countless AA meetings, but nothing worked. Kent is a giant of a man -- he stands a broad-shouldered 6 feet 5 inches tall, and has two sons who played professional basketball in Israel -- but for most of his life, he couldn't find the strength to put down the bottle. VideoWatch Dr. Gupta: Can a pill help you go cold turkey? »

It got worse in 2000, after an injury from falling off a ladder forced him to stop working. Depressed and in pain, with time on his hands, Kent began boozing from 8 o'clock in the morning, every morning. It went on a few months until his wife, a woman he'd known since grammar school, handed him an ad from a newspaper and an ultimatum: "She said, 'You're killing the marriage, and you're killing yourself,' " Kent said. " ' Get help or I'm gone.' "

The ad was recruiting alcoholics for research at Roger Williams Hospital, part of Brown University. Kent signed up. It was part of the COMBINE study. Kent got 16 weekly visits and also something most addicts never hear about: medication. This time, he stayed sober, even after his doctor took him off naltrexone. That was more than eight years ago. VideoWatch Walter Kent talk about his struggle with alcohol »

Despite studies showing effectiveness, established rehab programs have been slow to adopt the use of medication. At Hazelden in Minneapolis, Minnesota, a small proportion of patients receive anti-addiction drugs, but medical director Dr. Kevin Clark says the traditional model -- based on intensive therapy and the 12 steps popularized by Alcoholics Anonymous -- is still best. "It is a disease of the brain, but it's a multifaceted disease. It has a spiritual component, a behavioral component to it," says Clark. "Our experience tells us that having the network of support and recovery is what really makes the difference."

John Schwarzlose, executive director of the Betty Ford Center, echoes that but takes a more stringent approach. No patients at Betty Ford receive anti-addiction drugs as part of treatment, although a handful of long-time addicts may be referred to a prescribing physician once their stay is over. "Where we battle with [the National Institute on Alcoholism and Alcohol Abuse] is when they say we have trials of a new drug, and then proclaim this is a treatment for alcoholism," says Schwarzlose. "They're smart people, but they're missing how complex this disease is."

Schwarzlose argues that Willenbring and Johnson are using the wrong measure of success. He says abstinence is the only true measuring stick -- that an alcoholic who is drinking less is just at a way station on the road to relapse. "Naltrexone has reduced drinking, but once you're addicted, there is no such thing as 'OK' drinking. This is one of those cases where there's a real schism between the research and actual practice."

This attitude frustrates Willenbring, who estimates that in the United States only one addict in 10 has even heard about medication options. "In most cases, the treatment is entirely nonmedical. Most people are not even told about the medications that are available for treating alcohol dependence, and I think that's a crime."

Still, medication is slowly creeping into mainstream addiction therapy. One big advocate is Percy Menzies, a pharmacist and former sales representative for DuPont, which developed naltrexone. His St. Louis, Missouri-based Recovery Centers for America treats patients in an on-site hospital, then refers them to outside physicians for follow-up treatment. Along with therapy, virtually every patient is given Vivitrol, a long-lasting form of naltrexone that's given monthly by injection.

Kent says naltrexone saved his life. When the COMBINE program was over, Kent's doctor told him to call if he felt the old need for a drink coming back. But it never came. "I have yet to go back and say, 'I have an urge for a drink,' " says Kent, lounging in Goober's. "[My friends] will offer, 'You want a drink?' And I say, 'No, I'm fine. I'll have a soda.' I'm fine with that. Because when there's no urge, no craving, it doesn't bother me. I'm living proof this can happen."

Tuesday, April 14, 2009

Soldiers' Stress: What Doctors Get Wrong about PTSD

A growing number of experts insist that the concept of post-traumatic stress disorder is itself disordered and that soldiers are suffering as a result

By David Dobbs

In 2006, soon after returning from military service in Ramadi, Iraq, during the bloodiest period of the war, Captain Matt Stevens of the Vermont National Guard began to have a problem with PTSD, or post-traumatic stress disorder. Stevens's problem was not that he had PTSD. It was that he began to have doubts about PTSD: the condition was real enough, but as a diagnosis he saw it being wildly, even dangerously, overextended.

Stevens led the medics tending an armored brigade of 800 soldiers, and his team patched together GIs and Iraqi citizens almost every day. He saw horrific things. Once home, he said he had his share of "nights where I'd wake up and it would be clear I wasn't going to sleep again."

He was not surprised: "I would expect people to have nightmares for a while when they came back." But as he kept track of his unit in the U.S., he saw troops greeted by both a larger culture and a medical culture especially in the Veterans Administration (VA) that seemed reflexively to view bad memories, nightmares and any other sign of distress as an indicator of PTSD.

"Clinicians aren't separating the few who really have PTSD from those who are experiencing things like depression or anxiety or social and reintegration problems or who are just taking some time getting over it," Stevens says. He worries that many of these men and women are being pulled into a treatment and disability regime that will mire them in a self-fulfilling vision of a brain rewired, a psyche permanently haunted.

Stevens, now a major and still on reserve duty while he works as a physician's assistant, is far from alone in worrying about the reach of PTSD. Over the past five years or so, a long-simmering academic debate over PTSD's conceptual basis and incidence has begun to boil over. It is now splitting the practice of trauma psychology and roiling military culture. Critiques originally raised by military historians and a few psychologists are now advanced by a broad array of experts indeed, giants of psychology, psychiatry and epidemiology. They include Columbia University's Robert L. Spitzer and Michael B. First, who oversaw the last two editions of the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders, the DSM-III and DSM-IV; Paul McHugh, former chair of Johns Hopkins University's psychiatry department; Michigan State University epidemiologist Naomi Breslau; and Harvard University psychologist Richard J. McNally, a leading authority in the dynamics of memory and trauma and perhaps the most forceful of the critics. The diagnostic criteria for PTSD, they assert, represent a faulty, outdated construct that has been badly overstretched so that it routinely mistakes depression, anxiety or even normal adjustment for a unique and especially stubborn ailment.

This quest to scale back the definition of PTSD and its application stands to affect the expenditure of billions of dollars, the diagnostic framework of psychiatry, the effectiveness of a huge treatment and disability infrastructure, and, most important, the mental health and future lives of hundreds of thousands of U.S. combat veterans and other PTSD patients. Standing in the way of reform is conventional wisdom, deep cultural resistance and foundational concepts of trauma psychology. Nevertheless, it is time, as Spitzer recently argued, to "save PTSD from itself."

Casting a Wide Net
The overdiagnosis of PTSD, critics say, shows in the numbers, starting with the seminal study of PTSD prevalence, the 1990 National Vietnam Veterans Readjustment Survey (NVVRS). The NVVRS covered more than 1,000 male Vietnam vets in 1988 and reported that 15.4 percent of them had PTSD at the time and that 31 percent had suffered it at some point since the war. That 31 percent has been the standard estimate of PTSD incidence among veterans ever since.

In 2006, however, Columbia epidemiologist Bruce P. Dohrenwend, hoping to resolve nagging questions about the study, reworked the numbers. When he had culled the poorly documented diagnoses, he found that the 1988 rate was 9 percent and the lifetime rate 18 percent.

McNally shares the general admiration for Dohrenwend's careful work. Soon after it was published, however, McNally asserted that Dohrenwend's numbers were still too high because he counted as PTSD cases those veterans with only mild, subdiagnostic symptoms, people rated as "generally functioning pretty well." If you included only those suffering "clinically significant impairment" the level generally required for diagnosis and insurance compensation in most mental illness the rates fell yet further, to 5.4 percent at the time of the survey and 11 percent lifetime. It was not one in three veterans who eventually developed PTSD, but one in nine and only one in 18 had it at any given time. The NVVRS, in other words, appears to have overstated PTSD rates in Vietnam vets by almost 300 percent.

"PTSD is a real thing, without a doubt," McNally says. "But as a diagnosis, PTSD has become so flabby and overstretched, so much a part of the culture, that we are almost certainly mistaking other problems for PTSD and thus mistreating them."

The idea that PTSD is overdiagnosed seems to contradict reports of resistance in the military and the VA to recognizing PTSD denials of PTSD diagnoses and disability benefits, military clinicians discharging soldiers instead of treating them, and a disturbing increase in suicides among veterans of the Middle East wars. Yet the two trends are consistent. The VA's PTSD caseload has more than doubled since 2000, mostly because of newly diagnosed Vietnam veterans. The poor and erratic response to current soldiers and recent vets, with some being pulled quickly into PTSD treatments and others discouraged or denied, may be the panicked stumbling of an overloaded system.

Overhauling both the diagnosis and the VA's care system, critics say, will ensure better care for genuine PTSD patients as well as those being misdiagnosed. But the would-be reformers face fierce opposition. "This argument," McNally notes, "tends to really piss some people off." Veterans send him threatening e-mails. Colleagues accuse him of dishonoring veterans, dismissing suffering, discounting the costs of war. Dean G. Kilpatrick, a University of South Carolina traumatologist and former president of the Inter national Society for Traumatic Stress Studies (ISTSS), once essentially called McNally a liar.

A Problematic Diagnosis
The DSM-IV, the most recent edition (published in 1994), defines PTSD as the presence of three symptom clusters reexperiencing via nightmares or flashbacks; avoidance by numbing or withdrawal; and hyperarousal, evident in irritability, insomnia, aggression or poor concentration that arise in response to a life-threatening event [To see related sidebar please purchase the digital edition].

The construction of this definition is suspect. To start with, the link to a traumatic event, which makes PTSD almost unique among complex psychiatric diagnoses in being defined by an external cause, also makes it uniquely problematic, for the tie is really to the memory of an event. When PTSD was first added to the DSM-III in 1980, traumatic memories were considered reasonably faithful recordings of actual events. But as research since then has repeatedly shown, memory is spectacularly unreliable and malleable. We routinely add or subtract people, details, settings and actions to and from our memories. We conflate, invent and edit.

In one study by Washington University memory researcher Elizabeth F. Loftus, one out of four adults who were told they were lost in a shopping mall as children came to believe it. Some insisted the event happened even after the ruse was exposed. Subsequently, bounteous research has confirmed that such false memories are common [see "Creating False Memories," by Elizabeth F. Loftus; Scientific American, September 1997].

Soldiers enjoy no immunity from this tendency. A 1990s study at the New Haven, Conn., VA hospital asked 59 Gulf War veterans about their experiences a month after their return and again two years later. The researchers asked about 19 specific types of potentially traumatic events, such as witnessing deaths, losing friends and seeing people disfigured. Two years out, 70 percent of the veterans reported at least one traumatic event they had not mentioned a month after returning, and 24 percent reported at least three such events for the first time. And the veterans recounting the most "new memories" also reported the most PTSD symptoms.

To McNally, such results suggest that some veterans experiencing "late-onset" PTSD may be attributing symptoms of depression, anxiety or other subtle disorders to a memory that has been elaborated and given new significance or even unconsciously fabricated.

"This has nothing to do with gaming or working the system or consciously looking for sympathy," McNally says. "We all do this: we cast our lives in terms of narratives that help us understand them. A vet who's having a difficult life may remember a trauma, which may or may not have actually traumatized him, and everything makes sense."

To make the diagnosis of PTSD more rigorous, some have suggested that blood chemistry, brain imaging or other tests might be able to detect physiological signatures of the disorder. Some studies of stress hormones in groups of PTSD patients show differences from normal subjects, but the overlap between the normal and the PTSD groups is huge, making individual profiles useless for diagnostics. Brain imaging has similar limitations, with the abnormal dynamics in PTSD heavily overlapping those of depression and anxiety.

With memory unreliable and biological markers elusive, diagnosis depends on clinical symptoms. But as a study in 2007 starkly showed, the symptom profile for PTSD is as slippery as the would-be biomarkers. J. Alexander Bodkin, a psychiatrist at Harvard's McLean Hospital, screened 90 clinically depressed patients separately for PTSD symptoms and for trauma, then compared the results. First he and a colleague used a standardized screening interview to assess symptoms. Then two other PTSD diagnosticians, ignorant of the symptom reports, used another standard interview to see which patients had ever experienced trauma fitting DSM-IV criteria.

If PTSD arose from trauma, the patients with PTSD symptoms should have histories of trauma, and those with trauma should show more PTSD. It was not so. Although the symptom screens rated 70 of the 90 patients positive for PTSD, the trauma screens found only 54 who had suffered trauma: the diagnosed PTSD "cases" outnumbered those who had experienced traumatic events. Things got worse when Bodkin compared the diagnoses one on one. If PTSD required trauma, then the 54 trauma-exposed patients should account for most of the 70 PTSD-positive patients. But the PTSD-symptomatic patients were equally distributed among the trauma-positive and the trauma-negative groups. The PTSD rate had zero relation to the trauma rate. It was, Bodkin observed, "a scientifically unacceptable situation."

More practically, as McNally points out, "To give the best treatment, you have to have the right diagnosis."

The most effective treatment for patients whose symptoms arise from trauma is exposure-based cognitive-behavioral therapy (CBT), which concentrates on altering the response to a specific traumatic memory by repeated, controlled exposure to it. "And it works," McNally says. "If someone with genuine PTSD goes to the people who do this really well, they have a good chance of getting better." CBT for depression, in contrast, teaches the patient to recognize dysfunctional loops of thought and emotion and develop new responses to normal, present-day events. "If a depressed person takes on a PTSD interpretation of their troubles and gets exposure-based CBT, you're going to miss the boat," McNally says. "You're going to spend your time chasing this memory down instead of dealing with the way the patient misinterprets present events."

To complicate matters, recent studies showing that traumatic brain injuries from bomb blasts, common among soldiers in Iraq, produce symptoms almost indistinguishable from PTSD. One more overlapping symptom set.

"The overlap issue worries me tremendously," says Gerald M. Rosen, a University of Washington psychiatrist who has worked extensively with PTSD patients. "We have to ask how we got here. We have to ask ourselves, 'What do we gain by having this diagnosis?'"

Disabling Conditions
Rosen is thinking of clinicians when he asks about gain. But what does a veteran gain with a PTSD diagnosis? One would hope, of course, that it grants access to effective treatment and support. This is not happening. In civilian populations, two thirds of PTSD patients respond to treatment. But as psychologist Christopher Frueh, who researched and treated PTSD for the VA from the early 1990s until 2006, notes, "In the two largest VA studies of combat veterans, neither showed a treatment effect. Vets getting PTSD treatment from the VA are no more likely to get better than they would on their own."

The reason, Frueh says, is the collision of the PTSD construct's vagaries with the VA's disability system, in which every benefit seems structured to discourage recovery.

The first benefit is health care. PTSD is by far the easiest mental health diagnosis to have declared "service-connected," a designation that often means the difference between little or no care and broad, lasting health coverage. Service connection also makes a vet eligible for monthly disability payments of up to $3,000. That link may explain why most veterans getting PTSD treatment from the VA report worsening symptoms until they are designated 100 percent disabled at which point their use of VA mental health services drops by 82 percent. It may also help explain why, although the risk of PTSD from a traumatic event drops as time passes, the number of Vietnam veterans applying for PTSD disability almost doubled between 1999 and 2004, driving total PTSD disability payments to more than $4 billion annually.

Perhaps most disastrously, these payments continue only if you are sick. For unlike a vet who has lost a leg, a vet with PTSD loses disability benefits as soon as he recovers or starts working. The entire system seems designed to encourage chronic disability. "In the several years I spent in VA PTSD clinics," Frueh says, "I can't think of a single PTSD patient who left treatment because he got better. But the problem is not the veterans. The problem is that the VA's disability system, which is 60 years old now, ignores all the intervening research we have on resilience, on the power of expectancy, and on the effects of incentives and disincentives. Sometimes I think they should just blow it up and start over." But with what?

Richard A. Bryant, an Australian PTSD researcher and clinician, suggests a disability system more like that in place Down Under. An Australian soldier injured in combat receives a lifelong "noneconomic" disability payment of $300 to $1,200 monthly. If the injury keeps him from working, he also gets an "incapacity" payment, as well as job training and help finding work. Finally a crucial feature he retains all these benefits for two years once he goes back to work. After that, incapacity payments taper to zero over five years. But noneconomic payments a kind of financial Purple Heart continue forever. And like all Australians, the soldier gets free lifetime health care. Australian vets come home to an utterly different support system from ours: theirs is a scaffold they can climb. Ours is a low-hanging "safety net" liable to trap anyone who falls in.

Two Ways to Carry a Rifle
When a soldier comes home, he must try to reconcile his war experience with the person he was beforehand and the society and family he returns to. He must engage in what psychologist Rachel Yehuda, who researches PTSD at the Bronx VA Hospital, calls "recontextualization" the process of integrating trauma into normal experience. It is what we all do, on various scales, when we suffer breakups, job losses or the deaths of loved ones. Initially the event seems an impossible aberration. Then slowly we accept the trauma as part of the complex context that is life.

Major Matt Stevens recognizes that this adjustment can take time. Even after two years at home, the war still occupies his dreams. Sometimes, for instance, he dreams that he is doing something completely normal while carrying his combat rifle: "One night I dreamt I was bird-watching with my wife. When we saw a bird, she would lift her binoculars, and I would lift my rifle and watch the bird through the scope. No thought of shooting it. Just how I looked at the birds."

It would be easy to read Stevens's dream as a symptom of PTSD, expressing fear, hypervigilance and avoidance. Yet it can also be seen as demonstrating his success in recontextualizing his experience: reconciling the man who once used a gun with the man who no longer does.

Saving PTSD from itself, Spitzer, McNally, Frueh and other critics say, will require a similar shift seeing most postcombat distress not as a disorder but as part of normal, if painful, healing. This turnaround will involve, for starters, revising the rubric for diagnosing PTSD currently under review for the new DSM-V due to be published in 2012 so it accounts for the unreliability of memory and better distinguishes depression, anxiety and phobia from true PTSD. Mental health evaluations need similar revisions so they can detect genuine cases without leading patients to impose trauma narratives on other mental health problems. Finally, Congress should replace the VA's disability system with an evidence-based approach that removes disincentives to recovery and even go the extra mile and give all combat veterans, injured or not, lifetime health care.

These changes will be hard to sell in a culture that resists any suggestion that PTSD is not a common, even inevitable, consequence of combat. Mistaking its horror for its prevalence, most people assume PTSD is epidemic, ignoring all evidence to the contrary.

The biggest longitudinal study of soldiers returning from Iraq, led by VA researcher Charles Milliken and published in 2007, seemed to confirm that we should expect a high incidence of PTSD. It surveyed combat troops immediately on return from deployment and again about six months later and found around 20 percent symptomatically "at risk" of PTSD. But of those reporting symptoms in the first survey, half had improved by the second survey, and many who first claimed few or no symptoms later reported serious symptoms. How many of the early "symptoms" were just normal adjustment? How many of the later symptoms were the imposition of a trauma narrative onto other problems?

Stevens, for one, is certain these screens are mistaking many going through normal adjustment as dangerously at risk of PTSD. Even he, though functioning fine at work and home and in society, scored positive in both surveys; he is, in other words, one of the 20 percent at risk. Finally, and weirdly, both screens missed about 75 percent of those who actually sought counseling a finding that raises further doubts about the evaluations' accuracy. Yet this study received prominent media coverage emphasizing that PTSD rates were probably being badly undercounted.

A few months later another study the first to track large numbers of soldiers through the wars in Iraq and Afghanistan provided a clearer and more consistent picture. Led by U.S. Navy researcher Tyler Smith and published in the British Medical Journal, the study monitored mental health and combat exposure in 50,000 U.S. soldiers from 2001 to 2006. The researchers took particular care to tie symptoms to types of combat exposure. Among some 12,000 troops who went to Iraq or Afghanistan, 4.3 percent developed diagnosis-level symptoms of PTSD. The rate ran about 8 percent in those with combat exposure and 2 percent in those not exposed.

These numbers are about a quarter of the rates Milliken found. But they are a close match to PTSD rates seen in British Iraq War vets and to rates McNally calculated for Vietnam veterans. The contrast to the Milliken study, along with the consistency with British rates and with McNally's NVVRS calculation, should have made the Smith study big news. Yet the media, the VA and the trauma psychology community almost completely ignored the study. "The silence," McNally wryly noted, "was deafening."

This silence may be merely a matter of good news going unremarked. Yet it supports McNally's contention that we have a cultural obsession with trauma. The selective attention also supports the assertion by military historian and PTSD critic Ben Shephard that American society itself gained something from the creation of the PTSD diagnosis in the late 1970s: a vision of war's costs that, by transforming warriors into victims, lets us declare our recognition of war's horror and absolves us for sending them for we were victimized, too, fooled into supporting a war we later regretted. We should recognize war's horror. We should feel the soldier's pain. But to impose on a distressed soldier the notion that his memories are inescapable, that he lacks the strength to incorporate his past into his future, is to highlight our moral sensitivity at the soldier's expense.

PTSD exists. Where it exists we must treat it. But our cultural obsession with PTSD has magnified and finally perhaps become the thing itself a prolonged failure to contextualize and accept our own collective aggression. It may be our own postwar neurosis.

Monday, April 13, 2009

Atypical antipsychotics: too hard a sell?

Use of drugs such as Abilify, Seroquel and Zyprexa for treatment-resistant depression is gaining ground. Some see an 'unmet need' for medication. Others worry about side effects.

By Melissa Healy

April 13, 2009

About a year ago, patients began trooping into the office of UCLA psychiatrist Andrew Leuchter, asking whether an antipsychotic drug called Abilify "might be right for them." Few appeared to be delusional, plagued by hallucinations or suffering fearsome mood swings. Mostly, they were depressed or anxious, and frustrated by the pace of their recovery.

Leuchter wondered what was up: Depressed patients didn't usually seek out drugs used to quell psychiatry's most disturbing symptoms.

What was up, he soon discovered, was spending on a new advertising campaign touting Abilify as an "add-on" treatment for depression. For the first time since the arrival of a new generation of antipsychotic medications -- six drugs called the "atypicals" because they work differently from the earlier generation of antipsychotic drugs -- the makers of one, Abilify, had been granted the legal right to market to a vast new population of patients beyond those with schizophrenia or bipolar disorder.

This week, a Food and Drug Administration advisory panel recommended that the agency should grant the makers of a second atypical antipsychotic drug -- Seroquel XR -- similar latitude. The drug giant AstraZeneca wants permission to market the drug as a treatment for depression or anxiety that has not yielded to antidepressants alone.

But this time, it wasn't quite so easy a sell. The panel did say the drug was safe and effective for such purposes when used with other drugs, recommending approval for its use as an "add-on" treatment. But the panel recommended against the drug as a stand-alone treatment. And this time, the panel -- echoing an issue expressed by the FDA in convening the meeting -- cited safety concerns about the drugs' use in a greatly expanded population of patients.

Mounting research has made clear that the atypical antipsychotics are not only less safe than originally thought; they are not, on balance, any safer or more effective than older drugs for schizophrenia. And for the population of depressed or anxious patients that some are now proposed to treat, studies suggest the benefits are extremely modest.

The accumulated findings on the larger group of drugs had prompted the FDA to ask its advisory panel whether expanding the population of patients taking Seroquel XR would be wise. Like other members of this class of drugs, Seroquel has been linked to weight gain extreme enough to cause diabetes and to an often irreversible disorder characterized by involuntary tics and jerking movements.

As for Abilify, Sonia Choi, a Bristol-Myers Squibb spokeswoman, said the company "is continually monitoring the safety of Abilify, including the metabolic data, as part of our regular practice and is committed to disclosing clinical trials results" on the medication as they become available.

The concerns expressed by the FDA and its advisory panel, many public health experts say, come too late. In less than a decade, physicians have embraced the broad use of the atypical antipsychotics to treat mental disorders far less severe than schizophrenia and bipolar disorder -- afflictions such as anxiety, sleep difficulties, depression, attention deficit disorder and autism. First prescribed almost exclusively to adults, the drugs are now often used in the treatment of adolescents and kids as young as 2.

The sales of atypical antipsychotics have skyrocketed in recent years, propelling overall sales of antipsychotic drugs past all other classes, to $14.6 billion in 2008, according to IMS Health, a private firm that tracks drug trends. In 2008, 50 million prescriptions for antipsychotics, mostly the new ones, were filled in the U.S. -- a 5% hike in one year alone.

In the process, the spreading use of these costly drugs is raising -- for the nation as well as individual patients -- the rates and the risks of weight gain, diabetes, strokes, fatal heart attacks, an array of movement disorders and potentially, suicide, according to a wide range of critics.

"This is very worrisome; frankly I have serious concerns about these drugs," says Dr. Steven Nissen, who is chairman of the Cleveland Clinic's cardiovascular medicine department and serves as an ad hoc advisor for FDA panels. Studies point to a "very questionable balance between efficacy and safety" for the class, he said. But that message, he said, has been lost in an apparent "marketing bonanza" for the companies that make the medications. A recent report by the consulting firm Decision Resources found the makers of the atypicals spent $993 million in 2006 to promote the drugs to doctors and patients.

That's not to say the drugs haven't helped people.

Leuchter, who has prescribed Abilify for some with treatment-resistant depression, says that for certain patients and in certain circumstances, it works. "These are very effective medications, and like all medications, they have side effects," he says. But he adds: "I wouldn't want people to think this is the first thing they should reach for when a patient doesn't respond well to first-line antidepressants."

Newer drugs 'safer'

Introduced through the 1990s and early 2000s, the atypical antipsychotics -- drugs marketed as Abilify, Seroquel, Zyprexa, Geodon, Clozaril and Risperdal -- were widely hailed as superior to older schizophrenia drugs such as Thorazine and Haldol, which began to be used in the 1950s and 1960s, respectively. The first-generation antipsychotics could be highly effective at taming hallucinations and delusions. But some studies indicated that as many as 1 in 5 who took them developed involuntary tics and muscle movements called tardive dyskinesia, a condition that frequently cannot be reversed.

The newer drugs were supposed to be safer and more effective. That claim has now been roundly challenged.

A landmark 2005 study concluded that the drugs have brought marginal improvements at much greater expense than traditional antipsychotics in their primary use of treating schizophrenia. The CATIE study (for Clinical Antipsychotic Trials of Intervention Effectiveness) compared four of the atypicals -- Zyprexa, Geodon, Seroquel and Risperdal -- with the first-generation antipsychotic perphenazine (Trilafon), a drug costing on average a tenth the price of the newer drugs. It found the risk of tremors and tardive dyskinesia to be the same for all. And while all the antipsychotics are associated with weight gain, it was more frequent and more likely to be extreme among patients taking atypicals -- leading many to develop diabetes.

Last December, the British journal Lancet published a comprehensive analysis that further punctured the new drugs' claims to superiority. A separate study found Seroquel by many measures to be no more effective in treatment of schizophrenia symptoms than Haldol. And a 2008 study on Abilify found it was little better at banishing depressive symptoms than a placebo.

"The results are extremely unimpressive," said Dr. Daniel Carlat, a Massachusetts psychiatrist who publishes a respected monthly report on psychiatric research. "They just squeak by."

Many forces -- chief among them medical need and commercial imperatives -- have converged to make the atypical antipsychotics the prescription drug of the moment.

Psychiatrists and patients, disappointed in the effectiveness of antidepressants, have been hungry for treatments capable of curing depression, not just easing its hold on patients. Atypical antipsychotics influence different brain chemicals than do most current-generation antidepressants; their mode of action is thought to complement the ways in which standard antidepressant drugs affect the brain, and boost their effects on mood.

"There certainly is an unmet need out there," says UCLA's Leuchter, who has conducted extensive research on antidepressants' effectiveness. "Only about half the patients [on antidepressant drugs] will improve, and fewer than a third will get well with the first antidepressant they try."

That "unmet need" represents a potentially huge business opportunity for drug firms. Each year, as many as 10 million to 12 million depressed Americans could still be seeking relief after trying an antidepressant -- many more than the number who suffer from schizophrenia (2.4 million adults) and bipolar disorder (5.6 million adults). About 6.8 million adults suffer from generalized anxiety disorder.

"The story's pretty clear, and pretty embarrassing for the profession of psychiatry, which has allowed itself to be led by marketing," says Robert Rosenheck, a psychiatrist at Yale University who has studied the effectiveness and expanded use of the atypical antipsychotics. "We know now what these companies' strategies are: The number of people with schizophrenia is limited, so the road to profitability goes through soccer moms. They need to market these drugs to ordinary people who have dissatisfactions in life."

Side effects

In the run-up of use across the nation, weight gain and metabolic changes quickly emerged as a worrisome side effect. And in August 2008, the FDA, responding to a flurry of new research, required all antipsychotics to carry the agency's most urgent warning: The drugs' use in geriatric patients with dementia (by then very common) would raise their risk of dying from any cause.

Recent research has darkened the drugs' safety profile even further.

* Early this year, a Lancet Neurology study concluded that Alzheimer's disease patients given the drug to control aggression were nearly twice as likely to die of any cause than those not given the drug.

* Another study published in August 2008 -- this one in the British Medical Journal -- concluded that taking any antipsychotic medication raises a patient's likelihood of suffering a stroke, and added that "the risk of stroke might be higher in patients receiving atypical antipsychotics."

* Then, in January, the New England Journal of Medicine delivered a further blow to the new class of drugs. A federally funded study compared the rate of fatal heart attacks in patients taking the newer class of antipsychotic drugs, those on the older class, and patients taking neither. Patients on any antipsychotic drug -- new or old -- were twice as likely to die of a heart attack as those not on such medications.

Although drug makers are forbidden to promote, market or advertise drugs for any indication other than those approved by the FDA, that hasn't stopped physicians from legally writing "off-label" prescriptions. Rosenheck estimates roughly 60% of prescriptions for atypical antipsychotics have been written off-label.

In January, Eli Lilly & Co., which makes the atypical antipsychotic Zyprexa, was ordered by the Justice Department to pay more than $1.4 billion in penalties in connection with alleged illegal off-label marketing efforts. The company admitted no wrongdoing. The attorneys general of several states have sued the makers of Seroquel and Risperdal, alleging they've unlawfully marketed their medications to state Medicare and Medicaid agencies. The suits, still pending, allege that widespread prescribing of the drugs, encouraged by pharmaceutical companies that downplayed risks, caused harm to patients and unjustified cost to taxpayers.

One spokesperson for AstraZeneca, which makes Seroquel, says the company "fully supports the work of the FDA" in assessing the drug's benefits and risks in the treatment of depression and anxiety.

Responding to allegations made in several states' suits, another spokesman, Tony Jewell, said Seroquel's detailed package insert "has always provided adequate and appropriate information and warnings based on available data."

Currently, of all the atypical antipsychotics, only Abilify -- the drug that Leuchter's patients began asking about -- may legally be promoted as a treatment for psychiatric conditions other than schizophrenia and bipolar disorder. In November 2007, the FDA granted permission to its maker, Bristol-Myers Squibb, to promote the drug as a treatment for depression that has failed to respond to one or more antidepressants.

The FDA's decision on Abilify came without calling a hearing of its advisory panel on psychopharmacological drugs. In considering AstraZeneca's petition for Seroquel's new use, however, the FDA proceeded with greater caution, asking the committee to sift through the evidence and offer its recommendation.