Landmark Gene Discovery Cracks Open ‘Black Box’ Of Schizophrenia

Sydney and her mother Lori look into the bedroom mirror where Sydney experienced her first symptoms of schizophrenia. Now 20, Sydney has had no symptoms for almost two years now. (Jesse Costa/WBUR)

Sydney and her mother Lori look into the bedroom mirror where Sydney experienced her first symptoms of schizophrenia. Now 20, Sydney has had no symptoms for almost two years now. (Jesse Costa/WBUR)

One November day in her senior year of high school, Sydney accidentally broke the full-length mirror leaning up against the wall of her bedroom.

She felt a gust of superstitious dread: “Oh my God, I have to put this mirror together or I’m going to have bad luck.” Then, it escalated oddly into religious terror: “The devil’s coming to get me!”

Something inside her seemed to snap, she said. She sensed demons invading through the broken glass.

Not long afterward, President Obama spoke to Sydney inside her head: “OK, this is how the world is now,” he told her. “Everyone is so in love with each other, we can hear each other in our heads.”

The menacing voices of demons started to torment her, especially at night. She became convinced that she was going out with the pop star Justin Bieber, that he was chatting with her on her phone and sending her hidden messages in his Twitter feed. She thought he set up paparazzi in her backyard on Boston’s North Shore, that he was sending planes over her house to let her know he cared.

“Is this really happening?” She would ask the voices in her head. “Is this?” Yes, they told her. Yes.

What was really happening? How does a sunny girl who’d never had psychiatric problems before, who grew up loving dance and Disney princesses, a good student who was rich in family and friends, how does that girl suddenly lose her hold on reality?

Schizophrenia affects about 1 in every 100 people, and one thing is clear: Genetics plays a role. Sydney’s uncle had schizophrenia, and scientists have identified more than 100 genes that can raise the risk for it.

Now, researchers based at the Broad Institute in Cambridge and Harvard Medical School have pinpointed the gene that is the biggest risk factor for schizophrenia discovered so far, and figured out how it does its damage: It makes the brain prune away too many of the connections between neurons.

“[I]t may be like you have an over-energetic gardener who prunes back so much that the bushes die off…”

– Bruce Cuthbert, of the National Institute of Mental Health

That finding, just published in the journal Nature, may also explain why schizophrenia tends to hit at such an odd age, in the late teens and early 20s. That pruning of connections is a normal process that ramps up during adolescence, but this genetic culprit may make it go overboard.

Pruning may sound bad, said Bruce Cuthbert, the acting director of the National Institute of Mental Health, but actually, it’s helpful: “It’s like clearing away the underbrush so your brain can function more efficiently.”

But, he said, “in people with this overactive version of the gene, it may be like you have an over-energetic gardener, who prunes back so much that the bushes die off because they don’t have enough branches.”

Cuthbert called the paper a “genetic breakthrough” and “a crucial turning point in the fight against mental illness.” Eric Lander, director of the Broad Institute, said it means we’re finally starting to understand what causes schizophrenia at the level of brain biology.

“For the first time,” Lander said, “we’re opening up the black box and looking inside and seeing, how does the disease really arise? That makes this, in my opinion, perhaps the most important paper in schizophrenia since the disease itself was ever defined,” over a century ago.

This scientific excitement does not mean, however, that the findings will lead to new treatments for schizophrenia any time soon, Lander and others said. It takes years for such basic science to translate into treatments — if it ever does.

But the new paper does suggest some promising new targets for drug development, some already being worked on for other diseases, said Harvard Medical School’s Steve McCarroll, who led the research team. Continue reading

View From Europe: ‘Appraising The Risks Of Reefer Madness’



I was leafing through my Cerebrum the other day.

That is to say, as a longtime follower of the Dana Foundation — a philanthropy that supports brain research and issues helpful updates on the brain in the news — I was electronically leafing through the foundation’s journal, Cerebrum, when an alarming piece stopped me: Appraising the Risks of Reefer Madness, by Sir Robin Murray, M.D.

It cites a growing scientific consensus that in a small minority of users, particularly younger users, cannabis use raises the risk of psychosis, and it suggests that newer, higher-potency strains of pot may pose particular risks. It opens:

Beginning in the mid-1980s, European psychiatrists like me started seeing an increasing number of previously well-functioning teenagers who had developed hallucinations and delusions: the characteristic picture of schizophrenia. These troubled patients puzzled us because most had been bright and sociable and had no ties to the usual risk factors such as a family history of the disorder or developmental insult to the brain. Family and friends would often say, “Maybe it was all the cannabis they have been smoking,” and we would confidently reassure them that they were mistaken and tell them that cannabis was known to be a safe drug.

My view began to shift when a colleague, Peter Allebeck from the Karolinska Institute in Stockholm, launched his own investigation. He had been struck similarly by seeing well-adjusted young people develop schizophrenia for no apparent reason. The wonderful Swedish national records system enabled him to trace the outcome of 45,750 young men who had been asked about their drug use when they were conscripted into the Swedish army. From analysis of these data, Allebeck and his colleagues1 reported in 1987 that conscripts who had used cannabis more than fifty times were six times more likely to develop schizophrenia over the next fifteen years than those who had never used it.

Read the full piece here. Sir Robin (he was knighted in 2011) notes that marijuana remains highly controversial in Europe, with a political pendulum swinging between liberalization and restriction. Do you see value in his views?

Study Ignites Debate Over Non-Drug Treatment For Schizophrenia

Antipsychotic medications (Wikimedia Commons)

Antipsychotic medications (Wikimedia Commons)

By Alexandra Morris
CommonHealth intern

Antipsychotic drugs are typically the first-line treatment for the roughly one percent of people who have schizophrenia — often in conjunction with psychotherapy. But for patients who are not helped by the drugs or cannot tolerate their side effects, what’s left?

Last month, the Lancet published a study looking at the effects of cognitive therapy on patients with schizophrenia who refused to take medication – and prompted a heated debate within the mental health community.

Cognitive therapy involves one-on-one meetings between a patient and a therapist to discuss ways to change thinking and behavior in response to their symptoms.

Patients in the study were randomly assigned to receive either treatment as usual — ranging from no treatment at all to psychosocial support and other methods — or treatment as usual plus cognitive therapy. The researchers found that by the end of the study, the patients who received cognitive therapy had reduced psychiatric symptoms as compared to those who did not receive cognitive therapy.

Sounds reasonable, no? But initial media coverage included headlines claiming that cognitive therapy was an effective alternative to antipsychotic treatment. The Guardian posted “At last, a promising alternative to antipsychotics for schizophrenia,” and Science magazine wrote, “Schizophrenia: Time to flush the meds?” BBC News reportedly posted a headline “Schizophrenia: Talking therapies ‘effective as drugs.’”

Shortly after the study hit the press, bloggers were off and running (from PLOS to The Mental Elf), highlighting the limitations in the study design, such as the small sample size of 74 patients and the fact that nearly a third of these patients dropped out of the study partway through. They urged readers not to generalize the effect of cognitive therapy on schizophrenia based on limited evidence.

In fact, cognitive therapy was never compared to antipsychotics in the study. Some patients were even prescribed antipsychotics during the trial as part of their routine treatment. Several of the media reports also failed to mention an important caveat – that the trial was conducted in a specific patient population: those with mild to moderate psychiatric symptoms, as compared to those with severe illness who require hospitalization. The findings therefore cannot be extrapolated to all patients suffering from schizophrenia.

Lead study author Dr. Tony Morrison of the University of Manchester attested to the high drop-out rate. Continue reading

After First Psychotic Episode: Study Finds ‘Less Is More’ Psych Meds

A 1960s ad for the anti-psychotic drug Thorazine (Wikimedia Commons)

A 1960s ad for the anti-psychotic drug Thorazine (Wikimedia Commons)

It got a bit lost in the 4th-of-July whirl, but an intriguing study came out last week in the journal JAMA Psychiatry, suggesting that for long-term recovery from psychosis, it may be better — much better — to go lighter on the anti-psychotic drugs: Your chances of recovery could double.

As a JAMA Psychiatry editorial puts it, during the remission period that follows a first episode of psychosis, when it comes to antipsychotic drugs, “less is more.”

The study immediately made me think of Robert Whitaker’s 2011 book, “Anatomy of an Epidemic,” which presented evidence that in many cases, psychiatric drugs may do more long-term harm than good. Among other points, it notes some data suggesting that schizophrenics who take anti-psychotics fare worse, long-term, than those who don’t.

From the JAMA Psychiatry press release:

Dose reduction/discontinuation (DR) of antipsychotics during the early stages of remitted first-episode psychosis (FEP) shows higher long-term recovery rates compared with the rates achieved with maintenance treatment (MT), according to a study by Lex Wunderink, M.D., Ph.D., of Friesland Mental Health Services, Leeuwarden, the Netherlands, and colleagues.

This study was a follow up study of 128 patients who had participated in a two-year open randomized clinical trial comparing MT and DR from October 2001 to December 2002. Continue reading

A Musical On Mental Illness So Powerful You Can ‘Ask The Doc’ After


A scene from the SpeakEasy Stage Company production of Next to Normal, running March 9 – April 15 at the Boston Center for the Arts. (Saglio Photography Inc.)

Diana seems at first like merely a classic harried mother who happens to be staying up all night. She’s worrying as she waits for her teenaged son to come home; then fretting that her brilliant daughter is up at 4 with a can of Red Bull to finish her schoolwork; then having quickie sex with her husband. She sings about keeping the plates all spinning and holding the house together as she starts to make her family’s bag lunches for the dawning day.

It is only when Diana starts making sandwich after sandwich after sandwich, laying the bread out rapidfire not just on the table but unstoppably along the floor, that we in the audience realize this is not just a garden-variety harried mother. This is a woman in the midst of a full-blown manic episode rapidly spinning — like the plates — out of control.

So begins “Next To Normal,” a pop-rock musical about a family living with mental illness that has won three Tony awards and the Pulitzer for drama — and that premieres in Boston beginning this Friday, put on by the Speakeasy Stage Company. Already, ticket pre-sales are setting records for the Speakeasy — and here’s my theory on why, after watching a rehearsal this weekend:

A music box brings back some painful memories for a mother and son (Kerry A. Dowling and Michael Tacconi) in a scene from Next to Normal (Saglio Photography Inc.)

It’s not just a prize-winning show. It has doubly powerful drawing power beyond sheer quality. First, if you take the tens of millions of Americans who have a diagnosable mental illness and add in their relatives and friends, you get to pretty nearly the country’s entire population potentially interested in a well-done show on the topic.

And second, the portrayal of mental illness and its treatment in “Next to Normal” is so contemporary and in many ways so realistic — yes, even in musical form — that it inevitably creates buzz that spreads far and wide, rippling outward from activist circles.


  • A song with overtones of The Sound of Music’s “My Favorites Things” that goes: “Zoloft and Paxil and Buspar and Xanax…Depakote, Klonapin, Ambien, Prozac…Ativan calms me when I see the bills — these are a few of my favorite pills.”
  • A tango-like song about a common relationship: “My psychopharmacologist and I…Call it a lover’s game. He knows my deepest secrets — I know his…name.”
  • A devastating song about depression: “Do you wake up in the morning and need help to lift your head? Do you read obituaries and feel jealous of the dead? It’s like living on a cliffside not knowing when you’ll dive…Do you know, do you know what it’s like to die alive?”

Continue reading

Must-Watch Parody, And The Painful Reality Of Research Funding Cuts It Reflects
I’m no academic, but this 4-minute YouTube video made me laugh out loud. It depicts an administrator telling a research scientist that she must get a new NIH grant within one month to help pay the $800,000 salary of the new “Dean of Health Prevention.”

This post last week — about Deborah Levy, a distinguished McLean Hospital schizophrenia researcher whose funding has run nearly dry because of federal cuts — brought responses from other highly distinguished researchers facing a similar funding drought. I imagine this pain is extremely widespread here in the Massachusetts medical-academic complex, with its billions in NIH funding flat or dwindling. One of those researchers, a Harvard scientist who preferred to remain anonymous, sent me the video above (thank you!) and wrote in part:

While my lab is still afloat, at least for the moment, I worry about the fate of my very large group of researchers. Many I now train from Korea, Japan, Germany, Singapore, etc. One of the people responding to the story you wrote about Debbie notes that it takes 15 years or more to train the next generation of researchers. This is true. Moreover, the average age of investigators when they are awarded their first R01 grant is 42 (R01=the bread and butter of investigator-initiated research funding from NIH).

My own story is that I am a schizophrenia researcher and my longstanding R01 grant was not renewed when I submitted it for competitive renewal. This was devastating and I will regroup and submit something new at a later point…

What is happening to Debbie and others has been viewed by some as the natural course of evolution in science where the weak are selected out. Sadly this is not the case at all. Some of the best researchers will have their careers ended and for Debbie it is all the more heart-wrenching because she is right now at the threshold of new discovery. I am not sure what can be done to halt this. I see one of the problems being some of the large center grants across NIH institutions that take money away from individual investigator initiatives. There is also the fact that some institutions have less money, such as the National Institute of Aging, which has a “pay line” of under 4% right now (The National Institute of Mental Health is still somewhere between 18 and 20 percent — at least the last time I looked).

I also recently returned from the International Congress of Schizophrenia Research in Colorado Springs and it was like attending a funeral. There was so much concern about funding that you could see and feel it everywhere. My husband, who is not a researcher, was standing in line to buy some aspirin for my altitude sickness and the woman behind him who was an attendee at the conference remarked to him that “there is not enough aspirin in the world to take care of my headache. I just walked out of a meeting where it is clear there is no money for research.”

I recently returned from the International Congress of Schizophrenia Research in Colorado Springs and it was like attending a funeral. There was so much concern about funding that you could see and feel it everywhere.


My own sense, though I would need to find empirical data to support this, is that when the funding gets this tight, merit goes out the window and it becomes a political game in terms of who will find a seat in the musical chairs game and who will not. I worry that a number of outstanding researchers like Debbie Levy will not find a seat when the music stops. She is a stellar researcher who has always received what she has through merit. Unfortunately, merit may not be the current coin of the realm.

On this note, I will end. It is a most discouraging time for research, though I still tell my own trainees that if this is what they really want to do, they will find a way, and that in the end merit and persistence win out. I only wish I believed that now myself.

Readers? Do you know of other “stellar researchers” who have recently lost funding? What’s happening in the trenches of our labs as a result of these abstract federal cuts?

Marathon Morning: Running For Schizophrenia As Federal Funds Dwindle

Dr. Robert Laitman forgot to wear his special marathon watch this morning. But that, he says, is just another reflection of how this, his thirteenth Boston Marathon, is different: This year, what matters is not his time, but the money he hopes to raise for a schizophrenia genetics lab at McLean Hospital, to help fill gaping gaps in its research budget as federal funds dry up. Rob is running as part of “Team Daniel,” named for his son, Daniel, who has schizophrenia. The broader story: Federal budget cuts imperil critical research, including on schizophrenia, which affects 1% of the population. In case you missed our full post on Friday, please read it here.

Running To Support Schizophrenia Research As Federal Funds Dry Up

Team Daniel: Dr. Robert Laitman, second from left, and his son, Daniel, in glasses, at a recent half-marathon. Flanking them are Daniel's cousin Joey and sister Hannah.

When Dr. Robert Laitman lopes by in Monday’s Boston Marathon, the guy in bib #6149, you could see him as just another runner with a cause, a father hoping to help his schizophrenic son. He’ll be raising money for the schizophrenia genetics work at McLean Hospital’s Psychology Research Lab, in hopes it will help his son, Daniel, and many others.

But you could also see Rob Laitman’s 26.2 miles as reflecting something far broader: the federal funding crunch that is hurting even some of the best-established laboratories across the nation.

Massachusetts, with its august academic institutions, has long received more National Institutes of Health money for biomedical research than any other state. And Harvard’s McLean Hospital is a psychiatric research powerhouse. Its program totals about $40 million a year, three-quarters of it from federal grants. That’s more than any other private psychiatric hospital in the world.

But no one is immune. Consider Rob Laitman’s marathon fundraising letter. It begins:

“I am writing to ask you to help a very dear friend and colleague. Apparently after 20 years of being funded, Deborah Levy’s last grant application for her lab was not accepted. She is presently trying to find funding from other avenues and is also reapplying to the NIH. Deborah does critical work in basic schizophrenia genetics. She has been making continuous headway and in fact just contributed to a seminal article that was published in Nature. As director of the Psychology Research Laboratory at McLean Hospital, (Harvard’s Psychiatric Division), she has been universally loved and respected.”

The Psychology Research Lab has been funded since 1978, largely by federal grants as well as private grants and McLean money. It has gathered a priceless pool of families with multiple members who have schizophrenia or other mental illnesses, and has helped pioneer efforts to find important risk genes.

But in this funding climate, there are no guarantees. I asked Dr. Thomas Lehner, director of the Office of Genomics Research Coordination at the National Institute of Mental Health, about the lab’s plight. He could not comment directly on any specific grant, but said, “That’s not the only outstanding lab that finds itself in that position, and it’s unfortunate.”

I asked what he was hearing from labs around the country. “I hear a lot of pain,” he said, “and a lot of concern that good science is just not being funded. I hear that labs are closing. I hear that budgets are insufficient. That has always been a concern, but it’s more pronounced now. And I share the pain of the investigators.”

The news could be even worse, of course. Some in Congress had proposed slashing the National Institutes of Health’s budget by $1.6 billion this year, but the latest budget deal cuts it by only about $300 million. Still, those cuts come on the heels of years of flat or declining budgets. Thomas Insel, chief of the National Institute of Mental Health, wrote on his blog last month that to scientists, these tight times “may feel like a funding desert.”

Please indulge me in a brief rant. Continue reading

Special Report: Do Psych Drugs Do More Long-Term Harm Than Good?

It was an explosive question: Might it be that the overuse of psychiatric medications is making many people sicker than they would have been, and preventing their recovery? Are the medications causing an epidemic of long-term psychiatric disability?

And it was about to be debated at a pinnacle of psychopharmacology, the top-rated psychiatry department in the country.

The match had drawn a full house to the fabled “Ether Dome” at Massachusetts General Hospital, the historic medical amphitheater where ether was first demonstrated as an anesthetic in 1846.

Against a vintage backdrop of glass cases holding a mummy and a well-used skeleton, the two adversaries were about to engage in a “grand rounds” debate — academic medicine’s intellectual equivalent of hand-to-hand combat.

“Thank you,” Massachusetts General Hospital psychiatrist Andrew Nierenberg said wryly, “for coming to the belly of the beast.”

The question is, author Robert Whitaker responded just as wryly, “Will I survive?”

End of humor. The stakes were too high for jokes. In his new book, “Anatomy of an Epidemic,” Whitaker doesn’t just ask whether long-term medication might often do harm. He presents study after mainstream study that inform his thesis, and he calls for the psychiatry establishment to discuss it openly.

‘The ‘Silent Spring’ of Psychiatry?

A science journalism maven at Harvard told me recently, “Mark my words, this book is going to be the ‘SIlent Spring’ of psychiatry” — a reference to the classic Rachel Carson book that opened the country’s eyes to the harmful effects of DDT.

“Anatomy of an Epidemic” only came out in April; it remains to be seen how widely its ripples will spread. But one thing is already clear: It has set Bob Whitaker, an award-winning local journalist and author of four books, on a personal journey into unexplored territory, to the Ether Dome and beyond.

It is taking him to a national conference on his hypothesis led by psychiatrists and providers of mental health services in Oregon next month. And to a line-crossing move for any journalist: the founding of a non-profit,“The Foundation for Excellence in Mental Health Care,” that will aim to present the science on various psychiatric treatments in a clear and unbiased way.

Most recently, that journey led him last week to stand in the Ether Dome beneath the curved rows of stadium-style seats, speaking upward to the full audience. Most of his listeners looked like students, except for a cluster of older men in the front whose bow-ties or suits gave them the look of staff.

Looking up at the Ether Dome

As the psychiatry establishment goes, this truly was “the belly of the beast”: Massachusetts General’s psychiatry is consistently ranked as the top department in the country by U.S. News and World Report. Sitting at the very front in a dark navy sweater was Jerrold Rosenbaum, the department chair.

Whitaker began with the plot-line about psychiatric drugs that tends to dominate in American society: The introduction of Thorazine in 1955 kicked off a “psychopharmacological revolution” that has included a march of new antipsychotics and antidepressants that are “sort of antidotes to these disorders.” They make it possible to empty institutions, and prevent people from becoming chronically ill. All in all, a positive picture of progress.

Troubling questions

Except that there’s a troubling puzzle: Why, then, did the number of Americans on the disability rolls for mental health reasons triple between 1987 and 2007?

And more troubling questions: Yes, the drugs often help people short-term, and sometimes, longer term. But why do some data suggest that schizophrenics who take anti-psychotics fare worse, long-term, than those who don’t? Why do so many people with depression who take anti-depressants seem to flip into bipolar disorder? And why is the disability caused by bipolar disorder rising so sharply, anyway? Continue reading