Psychology Today Blogs - In Practice

Madonna-Whore: Not Complex

Peter D. Kramer — Fri, 16 May 2008 07:36:22 -0700

If you want to pass on your genes, you might hold out for a quality mate and raise your offspring with care. On the other hand, you might just enjoy promiscuous sex and let the pups fend for themselves.

What determines which strategy you’ll choose? Your mother — or rather, the early life experience she provides. That, and how your genes fold. At least it’s that way for rodents.

At the annual meeting of the American Psychiatric Association, Michael Meany, a psychobiologist at McGill, presented the results of years of work on mothering, genes, and behavior in rats.

If a rat mother is nurturant (she tends to lick and groom her pups, making her “high LG”), her offspring will be less anxious, better at facing stress, and good at parenting their own broods. Low LG mothers produce does who encounter puberty early, show greater sexual receptivity, enjoy an increased pregnancy rate, and neglect their young. Subsequent generations of female offspring will do the same — unless a lucky pup is “cross-nurtured” by a mother who licks and grooms, in which case the cosseted rat will grow up to be be calm and picky.

These responses typify two Darwinian strategies. If the early message is that life is nasty, you pass your genes on any which way. If you begin with a quality environment, you adopt a more patient approach.

The personality variants result from the way the brain handles the usual suspects: stress-responsive hormones, serotonin, and oxytocin. But in Meany’s rat model, at the base of the difference is an extremely simple difference in epigenetics.

Remember epigenetics? It refers to changes in the configuration of chromosomes that maintain the same gene sequences. Here, neglectful rearing results in the methylation of single base, a cytosine, found in a “non-coding” region of DNA that turns out to influence the production of receptors for stress hormones, via a “glucocorticoid receptor promoter.” It's not your genes, it's how they're folded, a geometry that encodes the trouble you've seen.

A “histone deacetylase (HDAC) inhibitor” that helps reverse the methylation and refold the gene will make the low-LG offspring more resilient in face of stress. Absent this chemical re-parenting, once the methylation occurs — as it invariably does in the offspring of low LG mothers — it persists for a lifetime, muting the production of stress modulators even in flush intervals. The pattern will continue for generations, in a sort of rat family “culture of poverty.”

In human terms, if you, as a woman, get knocked up young and neglect your child in favor of more hot hookups, it may be a single methylated cytosine that’s to blame — or to praise, if that strategy works for you and yours. And if, as a man on the prowl, you think that the complaisant babe you’re ogling learned life’s lessons in the school of hard knocks, you’re probably right.

For more detail, you can download the first paper listed in this bibliography of Michael Meany's work. The essay concludes: “The quality of the environment influences the behavior of the parent, which in turn is the critical factor in determining whether development proceeds along an optimistic versus a pessimistic pattern of development. In mammals, . . . parental signals serve as a ‘forecast’ of the level of adversity that lies ahead. . . . various levels of environmental demand require different traits in the offspring. This is a simple, even obvious message, with significant social implications.” It’s also one that may be encoded reasonably simply in the mammalian brain, via DNA that’s responded to the way of the world.

Scarred DNA and How It Might Heal

Peter D. Kramer — Mon, 12 May 2008 09:01:52 -0700

What makes for resilience?

Say you take two seemingly similar mice and humiliate them. One becomes submissive and anxious. The other continues to behave normally. What distinguishes the two?

Researchers have performed this experiment, taking normal small mice and exposing them to large, aggressive mice in a model called “social defeat.” The defeated mice are then housed next to the aggressive mice. Most of the small mice show signs of what looks like anxiety, depression, and low status. For the rest of their lives, they will defer even to companion mice they had engaged with before.

But some of the small mice don’t change, even after days of exposure to the large bullies. And the small mice — the anxious and the unflappable — are not just similar, they are genetically identical.

Of course, genetically identical twins are not indistinguishable. Through the vagaries of very early development — the random movement of molecules, changes related to position in the womb, differences in nutrition — by the time of birth, twins differ slightly. Their DNA segments show varying levels of activity.

Scientists can now measure these differences, using microarray DNA chips that compare thousands of genes, gene sections, or indicators of gene activity. The research shows that mice with the same sequence of DNA on each chromosome are epigenetically distinct.

Epigenetics refers to gene expression that derives from experience. I promised in a previous post to convey some of what I had learned about epigenetics at a session held at the recent annual meeting of the American Psychiatric Association. Much of what was reported on was not new; results of the key experiment were published two years ago in Nature Neuroscience, by Nadia Tsankova, working in Eric Nestler’s laboratory at the University of Texas Southwestern Medical Center in Dallas. At the meetings, Nestler reported on subsequent progress.

What follows is reasonably difficult material — in part because I am compressing complex information; in part because I am not an expert in this field and so lack the ability to simplify. (Readers are welcome to point out any mistakes I have made.) If you skip the sentences you don’t understand, you’ll likely still get the gist. So here goes:

Looking at DNA only, we seem to be simple creatures. Relative to worms, mammals have only one-and-a-half times the DNA. But part of what makes us (and rodents) distinctive is that we have many “junk,” or non-coding, sequences, on the order of a hundred times more than worms do. This excess allows for more folding of DNA and the associated chromatin proteins that compose our chromosomes. We display some genes so that messengers can attach to them. Other genes remain hidden in folds.

In some cases, this expression or repression is regulated by the attachment of small chemicals to the exposed parts of the DNA complex — for the chemists in the group, through deacetylation and methylation of histone tails. These alterations affect whether the genes are active or dormant.

In the mouse model, methylation of the histone tail prevents the cell from producing factors that allow for the making of new cells and the formation of new cell connections. For those are familiar with the brain-derived neurotrophic factor (BDNF) theory of depression (I outline it in Against Depression), the methylation suppresses the production of BDNF and thus acts against resilience.

Scientists knew to look at this process because when they compared gene arrays in the defeated and resilient mice, researchers found differences in the methylation of a part of a gene that regulates the production of BDNF.

In theory, if you can prevent or reverse the methylation of key parts of the DNA complex, you prevent the effects of intimidation or make the timid mouse ordinarily bold again. Conventional antidepressants have this effect — almost. If you treat the intimidated mice with imipramine, one of the oldest antidepressants, you get a return of BDNF production and, with it, normal boldness. (Similar results in other experiments occur with the newer antidepressants, the SSRIs, like Paxil and Prozac.) But imipramine does not fully undo the initial damage; instead, it induces a neurochemical compensation. On an epigenetic level, the antidepressant-treated mice still bear the marks of social defeat.

And epigenetic change may be heritable change within the mouse brain. When the mouse makes new nerve cells, they, too, will have DNA folded in a form that sustains timidity. The social defeat is an environmental change that has a genetic effect — within the given mouse, though, of course, not in its sperm or eggs. The early experience appears to mark the brain forever.

At the meetings, Nestler and others reported on attempts to induce more direct antidepressant (or anti-timidity) effects. Instead of imipramine, researchers looked at “histone deacetylation (HDAC) inhibitors.” Some of these medications are used in cancer treatment. Some psychiatric medications, like valproic acid (Depakote), used in bipolar disorder, are HDAC inhibitors as well. But some of the HDAC inhibitors infused into mouse brains are keyed to the specific injury induced by social defeat. The HDAC inhibitors appear to work as antidepressants and in some cases, more effectively than conventional medications; in particular, combining Prozac and an HDAC inhibitor was more restorative than giving Prozac alone. Direct genetic changes (through genes introduced via viruses) can have similar results, creating resilient mice.

I have written at length about the frustration in psychiatry that for decades we have not seen a truly novel approach to depression treatment, one that goes beyond neurotransmitters. The epigenetic research points in a new direction, looking inside the cell and even beyond the gene, to quite simple gene modulation — the addition or subtraction of a chemical at one or two sites.

It’s a long way from drugs or genes infused into mouse brains to interventions that might work in humans. But the epigenetic studies suggest an original model of social harm, showing how adversity might reach inside the brain and scar the gene within the nerve cell. The research also points toward a medically exciting, if ethically complex, future in which a traumatized people might be restored to the neurobiological state of their resilient twins.

That's it for now. I’m hoping to put up subsequent, shorter posts that will clarify the epigenetic perspective on normal functioning and mental illness.

After Being There: Bullet Points from the American Psychiatric Association's Annual Meeting

Peter D. Kramer — Thu, 08 May 2008 06:54:16 -0700

Bullet points noted down in the airport waiting lounge, en route home from the American Psychiatric Association’s annual meeting.

• In its public face, psychiatry has become humble.

The large-scale sessions at this year’s convention involved acknowledgement that our clinical tools have limitations. It’s been years since scientists have introduced a truly novel medication or psychotherapy for the mentally ill. Our treatments are reasonably effective, and we know how to combine them when necessary. But we’ve had that expertise for some time. Meanwhile, psychiatry knows it has an image problem built around the apprehension that the leadership is in bed with Pharma.

In part, that last problem accounts for the low-key presentations. The APA’s new rules require that the slides for all industry-sponsored presentations be vettted in advance by members without drug-company affiliations. Speakers who stray from the script and make unsubstantiated claims can be (and some have been) barred from participation in future meetings. The one Pharma-sponsored lecture I attended was sober, as regards our ability to treat bipolar disorder — although it seemed to me that one overly favorable table, about the benefits of a drug still in development, had slipped through the screen.

• Privately, the field is excited by the promise of neuroscience.

Researchers are moving past old models of mind and brain, the ones that focused on serotonin, norepinephrine, and dopamine. In part, this means considering other neurotransmitters, like glutamate. But it also means looking in more detailed fashion at receptors on neurons and then peeking inside the cell, tracking reactions that lead to cell growth and new cell connections, down to the level of the gene.

• Within neuroscience, the hot topic is gene regulation.

The most striking presentations that I attended involved epigenetics. I’ll explain that term in a future posting. In brief, epigenetics refers to changes that don’t affect the sequence of genes but do determine which genes get expressed and which lie dormant.

• Neuroscience is telling this story: Gene expression is shaped by the environment, including life events, like neglect in childhood.

It works that way for rodents. Raise them in a harsh environment, and for the whole of their lives, they will behave as if resources are scarce. The new science shows what psychological deprivation looks like at the level of the altered gene.

Increasingly, the biological model is a psychological model. Who we are, in our brain cells, is a function of who we have been in our lives.

• Psychotherapy is beginning to speak the new language of neuroscience.

Much of this talk is metaphorical. Psychotherapists want to reshape gene expression, or to help patients circumvent fixed limitations, though new learning that modifies the “fate neurosis” embedded in the altered chromosomes. Combining medication and talk makes special sense, in particular in the treatment of patients whose early lives were difficult. The drugs allow for new connections; the therapeutic relationship shapes them. (I sketch out this model in Against Depression.)

In coming weeks, I’ll weigh in with details about a number of these points. For now, I’m glad to be heading home.

And glad — here’s an afterthought — that while I was away, we Democrats chose our nominee. (Plea to Hillary: Don't become this year's Ralph Nader.) The Drudge Report and Wonkette may or may not be right about Time’s new cover, but it’s fun to see the mock-up.

Being There: The American Psychiatric Association's Annual Meeting

Peter D. Kramer — Sat, 03 May 2008 12:42:17 -0700

What do doctors actually do at the big psychiatric convention? My patients are curious. Increasingly, so is the general public.

It’s that time of year, the annual meeting of the American Psychiatric Association. The going assumption is that these affairs are boondoggles, big bashes sponsored by drug companies, private hospital chains, and other special interest groups. That perspective is not entirely wrong — for years, there’s been an embarrassing commercial cast to the central exhibition hall — but for the most part, it runs counter to the experience.

I’ve attended “APA” faithfully for three decades, beginning in residency, when I had submitted a study about competency to stand trial. That year, in San Francisco, a few fellow trainees and I invited our favorite family therapy teacher to a dinner following the residency reception. The meal became a constant, the Monday night of every meeting. In time, our teacher begged off. By then, the dinner was a hot ticket. It attracted “young Turks” from public health psychiatry and the Federal government. The crowd aged. The numbers shrank. This year, we’ll be back to a small handful.

This sort of tradition makes the meetings intimate. Attendees trade family news and academic gossip. We update each other on science and clinical lore. Overall, doctors divide into interest groups. The writers among us discuss writing: David Hellerstein, Bob Klitzman, Anna Fels, Keith Ablow.

There’s a certain amount of stargazing. I recall the thrill, early in my career, of meeting Otto Kernberg, the great psychoanalytic theorist. I don’t know whom residents watch out for in the pharmacologic era; for most of my career, therapists have been the heroes — Salvador Minuchin, Hyman Muslin, Aaron Beck, Jim Gustafson, the late Michael Basch, and Leston Havens. When the convention was held in New Orleans, I took a memorable walk with my old teacher, Robert Coles; he was visiting some of the girls, now women, he had written about during the school integration struggle. Another year, he introduced me to Ethel Kennedy, and we talked mental health politics.

Authors come speak. I wrote about Joyce Carol Oates’s presentation, in connection with her short story (later a novel), “Zombie,” built around the shameful history of lobotomy. My essay sparked a correspondence. I first met Judy Blume at APA, and Jamaica Kinkaid. I had crossed paths with William Styron in the ‘sixties, but we renewed our acquaintance at an APA meeting and stayed vaguely in touch. One year, I got to exchange a few words with Jorge Luis Borges. I held on to the posture I arrived with in the ‘seventies, admiring and wide-eyed, lucky to be there.

Over time, I did seek out medication research and picked up some genetics and physiology, mostly when I was researching a book. But the talks I recall were on other topics. A seminar on Hubertus Tellenbach led to an interest in German phenomenological psychology, a perspective that pops up now and then in my books, sometimes in hidden form. I’m a sucker for sessions on European philosophy and its relationship to the theory of psychotherapy or diagnosis. Often I brush up on the history of psychiatry. I’ll attend virtually any session on couple or family approaches. Some years, I squeeze in an hour on wonder drugs I’m too timid to prescribe, human growth hormone and DHEA. Back when I was doing reporting, I wrote about Ethel Person outlining her concept of love and Judd Marmor and Donald Klein debating ethical boundaries in treatment. My own presentations tend to be about writing or practicing, but I’ve spoken about the dilemmas of intimacy, mid-life crisis in film, the nature of advice, and reductionism in psychiatry.

Between lectures and seminars, I’ll walk through the “new research” poster hall to see what’s on the horizon, especially in the work of young colleagues. I browse in the bookstalls. I’ve used the APA’s facilities to tape public service spots on mental health topics. The organization’s working committees convene during the conference; some of my time goes to the routine business of position papers and resolutions.

Regarding elegance, it’s true that the drug company speakers travel by limo. I take the convention busses or go on foot. Except when I served in the government, in the Carter Administration, I have always gone on my own dime. I started out sharing hotel rooms with a residency-mate and later saw no reason to change habits. Some years, I did on-the-spot journalism to help pay my way, staying up into the wee hours to file stories. As for Big Pharma buying its way into doctors’ consciousnesses, I’ve never come home from a meeting with loot in excess of a tote bag and a pen.

So there it is, the squalor and the glamour: cramped quarters, long hours, and, with luck, renewed acquaintance, clinical pearls, research findings, quirky theories, and even literary inspiration.

I don’t expect to post again until my return, toward week’s end.

Mental Illness and Creativity: Does Treatment Hurt or Help?

Peter D. Kramer — Tue, 29 Apr 2008 07:25:45 -0700

Are the mentally ill especially creative? If so (or if not), should afflicted writers and artists undergo treatment?

Readers of Against Depression (and, previously, Listening to Prozac) will know my answer. The quick summary: Suggestive studies link bipolar disorder to accomplishment in the arts — and a number of other fields as well. Major depression on its own seems to have no special links to creativity, or only very weak ones. Actually, the case for epilepsy and even alcoholism may be easier to make. The “modern,” that is, nineteenth century, case for linkage begins with an interest in schizophrenia; there the question is highly confused, because the disease was so poorly diagnosed and is so disabling at an early age. In Against Depression I also pose an ancillary question, whether our aesthetics have been shaped by the ubiquity of mental illness.

Correlations aside, the problem remains, if you are creative and you suffer mental illness, should you undergo treatment and, in particular, treatment with medication? In its science section today, the New York Times reviews two books that bear on the subject, Madness: A Bipolar Life, by Marya Hornbacher, and Poets on Prozac: Mental Illness, Treatment and the Creative Process, edited by Richard M. Berlin. I have read neither, but the Times reports that both reach the same conclusion. If treatment works, the work benefits. Even partial responses to quite difficult drug regimens seem to result in more and better writing.

In my practice (where any prescribing tends to be more moderate), I find that the same rule holds. Like other diseases, the mental illnesses may lend perspective to art. But the disorders are destructive in dozens of ways. Medications have their problems. In particular, virtually any psychoactive substance can, over time, induce apathy. But by and large, if my patients do well on medication, they write, paint, compose, and sculpt better. The same holds for successful psychotherapy, another modality that (see the Peter Schaffer play or movie “Equus”) people used to worry over when thinking about the fine arts.

Incidentally, the Times also makes note of a study in Neurology that links early depression to later Alzheimer’s disease . . . another reason to consider prompt, vigorous treatment. In more general terms, the link between depression and dementia had been documented in the past.

Postscript: Those who like creative wordplay — or who believe that brain exercise wards off dementia — might glance at my prior post about Frank W. Lewis, the puzzle-master for the Nation.

Homage to Frank W. Lewis

Peter D. Kramer — Mon, 28 Apr 2008 11:21:08 -0700

I don’t know that the change signals the end of Western civilization, but certainly we are suffering a decline in our standard of living now that The Nation has made this unwelcome announcement: Frank W. Lewis’s cryptic crossword will appear only biweekly.

For those late to the show, Lewis, now 95 years old, has been composing his amusing puzzles since 1947. The questions and answers are full of wonderful puns. The basic rules are set out in a note to puzzlers. A sample: “You might have pondered a bit over UPBRAIDED AFTER DINNER, which resolved itself to DESSERT (it was a vertical, you'll remember) 'tressed' going 'up' and meaning BRAIDED, of course. Or a clue might merely read S with the more or less obvious answer being LARGESS.”

In this week’s edition, “Implicit meanings from obvious people?” is “overtones,” from “overt ones.”

Devotees get to know Lewis’s quirks. Clues that include a “gin sling” lead to solutions ending in “-ing.” “Flowers” hints tend to concern not horticulture but rivers and streams. More often than not, “workers” points to “-ants,” as a final syllable. Lewis loves old songs, classic theater pieces, and artists of all stripes.

I wish I had recorded favorites, among clues and responses. I’ve discarded my copies of The Nation, which I read mainly for the Katha Pollitt columns (sadly, they, too, appear less often than they once did) and (yet rarer) anything by Paul Berman. But every few weeks, Lewis entertains solvers with unusual words. For some years, I have kept a list.

Herewith, in his honor, a baker’s dozen of words cadged from Frank W. Lewis. If I’ve set the links right, a brief definition will appear as you pass the cursor over the entry. Clicking will get you to The American Heritage Dictionary at bartleby.com or, when that reference has failed, the Free Online Dictionary.

amerce
assegai
banausic
emmet
finjan (see also zarf)
gabbro
leister
nilgai
orle
rathe
ret
rorqual
tinamou

For those who need a concentrated dose of the cryptic, a fairly current Lewis collection is in print; early books can be found by those willing to search farther afield.

Who is Lewis? A Powell’s Books bio reads in part: “Although trained as a musician (with a Master of Music degree) possessing some talent as a conductor, particularly for choral groups, Mr. Lewis worked for thirty years as a cryptanalyst for the War Department and the National Security Agency. Much of his work is still classified. He and his wife retired to the Caribbean in 1969 but had to relocate to Massachusetts after the Montserrat volcano blew. They have five children.”

In the past I had worried over Lewis’s health. The occasional anagram would be in error; I wrote a colleague at The Nation who set me to fretting further — the puzzles were arriving late. But then, the next week would bring a timely, flawless gem.

Frank, wherever you are, be well, we need you.

Afterthought: As Alan Truscott aged, the New York Times cut the frequency of the bridge column to three days a week, from seven; when Philip Alder took over, the deficit was not restored. Plea to Katrina Vanden Heuvel: I’m in favor of any accommodation for the incomparable Frank Lewis. But if (heaven forfend) he should retire and be replaced, we’ll want our weekly puzzle back.

Bonus afterthought: Here's a cryptic clue from the short story "Weekend," by one of my favorite authors, Shirley Hazzard: “I am between water and stone fruit in India.” Once again, run the cursor over the link for the answer. Clicking takes you to Hazzard's 1963 collection, Cliffs of Fall.

Follow-up: From Vets to Pets

Peter D. Kramer — Wed, 23 Apr 2008 07:25:32 -0700

In response to reports that the Veterans Administration has concealed the rate of suicides by former soldiers, three senators (Tom Harkin, D-Iowa, Patty Murray, D-Washington, and Russ Feingold, D-Wisconsin) have introduced legislation requiring the VA to collect and submit this data for the past decade and then for future years.

Plus ça change department: A quick Google scan suggests that the media continues to ignore research that supports mainstream medical views about antidepressants. There has been little response to the stunning report in Science confirming that Prozac confers new resilience on the mammalian brain. Similarly for the research confirming a quite robust separation between antidepressants and placebo in the treatment of depression in adolescents — almost no press coverage. Awareness of the resurgence of the “chemical imbalance” theory is evident only in a spoof.

Ah, to be in New England department: All winter, I work out on the stationary bicycle. This morning marked my first outdoor foray on my trusty road bike. What a contrast! Practice all you want, there’s nothing indoors to compare to the demands of a real hill. Luckily, the parks department is repairing a section of bike path, so I found an excuse to head home early. A trope's brewing here, regarding the contrast between efforts in psychotherapy and risk in the world. Patients are hereby warned that my sports metaphors are likely to undergo their seasonal switch from skiing to cycling.

One vote department: I know, I know, she won by almost ten points, but hasn’t Hillary become unspeakable? "Some people counted me out and said to drop out." Hill — that’s because politically you’re the corpse that walks. (Yes, if somehow she’s nominated, I’ll vote for her, but that’s what yaller dog Democrat means.) Where’s Samantha Power when we need her?

Subprime department: My daughter and son-in-law have a adopted a cat, who has promptly taken over a kitty condo abandoned by former residents. This squib is a follow-up only insofar as it enacts my pledge to keep the blog random — but I wanted an excuse to throw the photo up on the Web.

Veterans and Suicide: Did the Government Lie?

Peter D. Kramer — Tue, 22 Apr 2008 07:00:19 -0700

Two veterans’ groups and a number of news sources are claiming that the Federal government has systematically and intentionally underreported the suicide rate among former soldiers.

CBS News has conducted the most aggressive investigation. When the network asked the Department of Veterans Affairs for data on suicide attempts among veterans in 2007, the VA provided the number 790. Internal emails released by CBS and the groups Veterans for Common Sense and Veterans United for Truth suggest that the VA’s own estimates for the period were much higher. The New York Times reports on an e-mail message from Dr. Ira Katz, the head of mental health services for Veterans Affairs, that “starts with ‘Shh!’ and refers to the 12,000 veterans per year who attempt suicide while under department treatment. [Katz wrote] ‘Is this something we should (carefully) address ourselves in some sort of release before someone stumbles on it?’” According to CBS, that email was titled, "Not for the CBS News Interview Request."

Even the higher figure, 12,000 attempts, is almost certainly low — extremely low. CBS was able to aggregate data from 45 of the 50 states. This partial survey revealed 6,256 completed suicides — deaths — among veterans in 2005. The rate appears to be about double that expected for American males of comparable ages. A more systematic study found similar figures. This, in a population that has already been screened, at enlistment, to exclude young men and women with mental illness.

The NIMH estimates that in general, there are about 25 non-fatal attempted suicides for each attempt that results in death. Other sources put the ratio at 18 to one, with men much more likely than women to enact a lethal attempt. Even if the ratio were even ten to one, based on the deaths from suicide we would expect over 60,000 attempts. If this figure is anything close to the reality, most suicidal veterans are not receiving VA treatment, Also, the VA’s internal estimates of attempts in patients under care may still be low.

The veterans groups are suing the VA in hopes of attaining more resources for treatment. But if the charges are right, there is also a political scandal here: in wartime, the government corrupted medical statistics, obscuring the true costs of military service.

Seeing Clearly: How Prozac Restores Function to the Brain

Peter D. Kramer — Mon, 21 Apr 2008 06:40:51 -0700

There’s major news on the antidepressant front, but it comes in an odd form: research on treating “lazy eyes” in rats. A study suggests that, yes, Prozac and similar medicines really do make the brain more flexible.

The report, titled “The Antidepressant Fluoxetine Restores Plasticity in the Adult Visual Cortex,” appears in the current issue of Science. It tests the hypothesis, current for some time now, that drugs like Prozac work through stimulating factors in the brain that allow nerve cells there to grow and make new connections. If that theory holds, then perhaps the medications might allow the adult mammalian brain to take on some of the “plasticity,” or capacity for adaptive change, normally present only early in development.

The researchers, José Fernando Maya Vetencourt of the Scuola Normale Superiore in Pisa, Italy, and colleagues elsewhere in Europe, began by depriving rats of the use of one eye by sewing it shut. Over time, the visually-deprived rats came to rely solely on the working eye and lost the capacity for binocular vision even when both eyes were again open.

Students of the history of medicine will be reminded of the experiments that won David H. Hubel and Torsten Wiesel the Nobel Prize 1981. Using cats, Hubel and Wiesel showed that the brain development necessary for vision in a given eye results from the use of that eye during a critical period of development in infancy and childhood. Amblyopia, or partial blindness in one eye, is a disorder not of the eye but of the brain. Rats have a similar critical period. By the fifty-fifth day of life, they lose the ability to change the way the brain handles vision.

Maya Vetencourt did two sets of experiments, one with rats subjected to temporary visual deprivation and one with rats made amblyopic over the long term. In both cases, the rats remained blind in one eye — except that in rats treated chronically with Prozac, normal vision returned. The recovery had nothing to do with drug effects on the eye. The medication had stimulated BDNF, or brain-derived neurotrophic factor, and the relevant part of the brain had become active again, elaborating new cells and new cell pathways. The stimulation of BDNF probably took place via serotonin, the neurotransmitter that Prozac effects most directly. Another transmitter, GABA, may also have been involved.

Interestingly, “environmental enrichment,” providing the rats with more stimulation and opportunity to explore, also improved vision, possibly through stimulating serotonin and thus BDNF. In the rat literature, environmental enrichment has overtones of psychotherapy, exercise, and good social support — factors that in humans can mitigate depression.

The researchers point to evidence that antidepressants restore adaptability in the human brain. They conclude: “a similar increase in plasticity, which is here described in the rodent visual cortex, may also take place in the human visual system, during chronic SSRI treatment” That is, Prozac may help in the treatment of “lazy eye” in adult humans. The authors add: “Our results open the possibility that chronic treatment with antidepressants may also have similar effects in other brain areas, such as those involved in mood regulation in depressed patients . . .” SSRIs may also help to treat other neurological systems where recovery depends on a renewed capacity for making nerve call connections in the brain.

These experiments serve as further — and quite dramatic — evidence in favor of the current theories of depression and of antidepressant action, the ones I consider in detail in Against Depression. By this account, recovery from mood disorder turns on the brain’s ability to make new nerve cells and then elaborate working connections between these cells. Many studies have pointed in the direction of the first part of this model: antidepressants do seem to protect and restore the brain’s ability to make neurons. This new work with “lazy eye” speaks to the second part: those new neurons can function and restore lost capacities to the injured animal.

I have written often of the worries every doctor must have about long-term use of antidepressants. There may be hidden negative effects. A growing body of research points in a different direction: the medications may confer unexplored benefits as well.

Prozac for the Long Term?

Peter D. Kramer — Tue, 15 Apr 2008 07:18:24 -0700

The New York Times science section today features an essay on the long-term use of antidepressants. The lead refers to the sort of question I introduced in Listening to Prozac: how do these medications shape identity? But most of the piece concerns the biological effects of taking the drugs for years.

The author, Richard A. Friedman, quite properly says that we do not know about the effects of extended use and calls for better post-marketing studies. This point cannot be emphasized enough. Since we have vast numbers of people on antidepressants chronically, it is irresponsible for us as a society not to examine the medications through multi-year studies. This kind of research is hard to motivate; few young scientists in need of publications choose to undertake work whose results will emerge far down the road. The Food and Drug Administration, which has taken baby steps in this direction, should be mandating the relevant investigations; the National Institute of Mental Health should be supervising them.

Because his patient, now 31, was an adolescent when she first took Prozac, Friedman mentions research about suicidality, pro and con — but presumably he knows whether his patient is at risk. She was suicidal before taking medication but not since. Likewise, he refers to the studies I have discussed here and elsewhere repeatedly that show a bias in the publication of short-term drug trials; positive, but not negative or equivocal, outcomes tend to find their way into print. Again, this concern has little to do with Friedman’s patient. Whatever the odds for the average person, Friedman’s actual patient responded to medication. For her, the widely publicized concerns about new-onset suicidality and overall efficacy are red herrings.

Friedman’s case presents the most usual scenario. On medication, a patient gets better. She experiences few side effects, or only ones that are tolerable in the short run. Then, the disease recurs, and the patient requires longer intervals of treatment. Side effects like loss of sex drive become troublesome. Now, issues of the unknown enter in: What does it mean, psychologically and physiologically, to be on a medication for years?

If I were allocating resources for research on the medications we have to hand, I would put a fair proportion here, into investigating what it means for any patient, adolescent or adult, to take antidepressants for much of a lifetime.

Note added 4/22: For thoughts concerning possible beneficial effects of long-term antidepressant use, see my more recent posting on medication and resilience in the brain.