When Mechanism Matters

August 1st, 2013 by gelenberg No comments »

By the late 1970s, the only antidepressant medications were the MAOIs and the TCAs. Obviously, the perceived unmet need was great.

The late 70s and early 80s brought us 3 new antidepressants: Amoxapine (Asendin and others), maprotiline (Ludiomil and others), and bupropion (Wellbutrin and others). Amoxapine’s manufacturer initially claimed it would work faster; it didn’t. There were seizures among patients in a small study of bupropion in eating-disorder patients, resulting in its withdrawal from the market. It was subsequently re-introduced with warnings about the seizure risk and remains a widely used and versatile antidepressant.

Seeking a marketing edge, maprotiline’s manufacturer focused on its presumed antidepressant mechanism—norepinephrine reuptake blockade. “When mechanism matters,” bannered the large advertisements in prominent medical journals.

How wonderful it would be if we could tell which depressed patient would benefit from which molecule. There probably are different biological anomalies underlying different patients’ depression symptoms, and someday we will be able to dissect nature along its relevant “joints.” But so far, multiple studies since the 1950s that have sought to predict antidepressant response and tailor pharmacologic treatments have come a cropper. For maprotiline, the emperor had no clothes. It had no clinical advantage over other compounds, produced a high rate of seizures, and faded from use.

Vilazodone (Viibryd) was introduced a few years back. The pre-launch hypotheses for a new medicine that would have to be priced higher than inexpensive generic antidepressants were two, based on vilazodone’s pharmacologic mechanisms: (1) it would work faster, and (2) it would have fewer sexual side effects than other serotonergic drugs. Neither hope materialized.

On July 26th, FDA approved levomilnacipran extended-release (Fetzima). It is another serotonin-norepinephrine reuptake inhibitor (SNRI)—like venlafaxine (Effexor and others), duloxetine (Cymbalta), desvenlafaxine (Pristiq), and its racemic “sister,” milnacipran (Savella). For that matter, TCAs also are SNRIs. To gain market share in a competitive field, advertising may focus on the fact that pharmacologically, levomilnacipran is a more potent norepinephrine reuptake blocker than other SNRIs. This time, will mechanism finally matter? The answer will not emerge from ad copy, promotional talks, fancy graphics of neurons, or argument. The answers will come from time-consuming, expensive clinical studies (if the manufacturer is willing to take the risk) to test the hypothesis that the new drug’s pharmacology will translate into some clinical advantage—like greater efficacy in a measureable way. We’ll see.

-Alan J. Gelenberg, M.D.
Editor, Biological Therapies in Psychiatry
Shively/Tan Professor and Chair, Psychiatry, Penn State University
Editor-in-Chief, Journal of Clinical Psychiatry

We’re Melting

April 26th, 2013 by gelenberg No comments »

In its current state of dysfunction, immigration reform is one of several hot-button issues the U.S. Congress debates with rancor and vitriol but seemingly little view to the future and vigor of our society.

Both sets of my grandparents immigrated to the United States – the great melting pot – from Eastern Europe in the early twentieth century. My dad came to America as a 13-year-old. He spoke no English but put himself through school and became a pharmacist. Thanks to his hard work, I was privileged to attend superb universities and have tried to give back to the nation that welcomed my family.

Living on our country’s southern border for 18 years, I saw many first- and second-generation Mexican immigrants contributing in so many ways to our society, people, and cultural richness. When I came to Penn State a few years ago and visited a brilliant neuroscientist at our flagship campus in State College, I observed that almost all of his post-docs were from foreign countries, all full of scientific curiosity and drive.

From its foundation, the U.S. has prided itself on its open arms, embodied in our Statue of Liberty in New York Harbor. One generation after the next for more than two centuries have been leavened and energized by the vigor of immigrants. The success of capitalism requires creation of capital which, in turn, demands energy and new ideas. Often these emerge from the passions and restlessness of new Americans.

Today more than ever we worry about security. No one wants to open ourselves to terrorists or criminals. But if we build boundaries and barriers too high, if we stop the melting, if we no longer welcome the hungry—including those hungry to learn and create—I fear we will lose part of our souls and impoverish our future.

-Alan J. Gelenberg, M.D.
Editor, Biological Therapies in Psychiatry
Shively/Tan Professor and Chair, Psychiatry, Penn State University
Editor-in-Chief, Journal of Clinical Psychiatry

Boston

April 17th, 2013 by gelenberg No comments »

I lived and worked in Boston for almost 20 years. I raised my kids there. It’s a great city with wonderful people. I love Boston.

I have been a runner for 39 years. I love the sport: getting out on terrain familiar and exotic, feeling the breeze, my pulse race, watching walkers, other runners, dogs with their owners. I love early-morning runs—before big cities awake, along country roads and forest trails as birds are seeking their breakfast, along wharves with fishermen stringing their nets. I can’t count the number of races and fun runs I’ve participated in. I’m not very competitive—never have been. I just like the crowds and the energy, the camaraderie, the loud music, and the t-shirts.

I never ran the iconic Boston Marathon. I ran one though: the Marine Corps. And I stood and watched the Boston Marathon runners with my family when they passed near my home in Newton on Patriot’s Day.

Like people around the world, I was stunned and appalled at the carnage in Boston on Monday. What a tragedy. How sad—and senseless.

Runners are inherently can-do, optimistic, and resilient folks. It seared my heart to see them killed, maimed, and emotionally traumatized. The horror of the bombings and the reactions in the aftermath revealed some of the best in people— in runners, spectators, and the local population: heroism, compassion, generosity. There is so much that is good, so much to be proud of in the human race. But then, there is evil.

-Alan J. Gelenberg, M.D.
Editor, Biological Therapies in Psychiatry
Shively/Tan Professor and Chair, Psychiatry, Penn State University
Editor-in-Chief, Journal of Clinical Psychiatry

Knee-jerk Psychiatry

April 7th, 2013 by gelenberg No comments »

She was a young woman who’d grown up in an abusive family. Like so many others, she re-created her familiar home environment with a series of abusive partners—bearing children from a number of them. She easily grew frustrated and irritable. Feeling desperate one day, she made a life-threatening suicide attempt and was hospitalized.

 He was a middle-aged man who had built and run a successful business for decades. The business came on hard times, he went into bankruptcy, and his wife left him. He too felt desperate, made a very serious attempt on his life, and also was hospitalized.

In both cases, the serious suicide attempts resulted in a general-hospital stay, followed by transfer to a psychiatric facility. Each patient was diagnosed with a mood disorder, then treated with psychiatric medications—lots of medications. Each was discharged on multiple antipsychotics and antidepressants, a couple of benzodiazepines, gabapentin, and an antihistamine (presumably for additional sedation and anxiety relief).

Within weeks of hospital discharge, each patient showed the adverse effects of these medications: akathisia, parkinsonian signs, substantial weight gain, decreased libido, lipid and glucose abnormalities, and more. The mood-disorder diagnoses seemed questionable to me. More, the cognitive and affective side effects of these complex pharmaceutical regimens made it hard to disentangle preexisting symptoms. The out-patient doctors were challenged in their attempts to establish a therapeutic rapport and help these troubled human beings find new coping strategies in difficult circumstances.

So often what I see around the country is superficial, knee-jerk psychiatry. Harried doctors assume a serious suicide attempt must mean a mood disorder—which is often, but not always true. And a mood-disorder diagnosis (even Depression NOS) and psychiatric admission “demand” medications—often many.

How did we get to this state? Everyone loves to hate insurance companies—except their shareholders and senior executives. Most of us complain about DSM-3 and -4 (and in about a month -5). And medical educators know that Psychiatry often fails to attract the best and brightest medical-school graduates: we don’t get enough respect, our patients are stigmatized, managed care forces us to do short visits, our compensation is low among specialties, etc.

It’s all true. But somehow people in crisis deserve a little time with a knowledgeable, thoughtful professional, who can blend neuroscience with social and psychological dynamics, who brings compassion and wisdom to the clinical encounter. Psychiatry in 2013 has powerful tools. Let’s find a way to employ them with care.

-Alan J. Gelenberg, M.D.
Editor, Biological Therapies in Psychiatry
Shively/Tan Professor and Chair, Psychiatry, Penn State University
Editor-in-Chief, Journal of Clinical Psychiatry

Toward the New World Order

March 11th, 2013 by gelenberg No comments »

If the federal health reform initiative proceeds apace, before long almost all Americans will have health insurance. But there are nowhere near enough physicians to care for all of us—especially as the population ages.

Many approaches make sense to enhance the quality and efficiency of our care system—including algorithms, more effective use of extenders, electronic decision support, and patient education. Another feature to come is more selective use of specialists—including psychiatrists.

When care is paid for by a third party, we cannot afford to have many patients cared for primarily by a specialist. The model to come will have specialists create algorithms and protocols for primary care providers (PCPs). Specialists will be available for brief electronic or phone consultations and, less commonly, for one-on-one direct consultation with patients. A psychiatrist will see a patient and refer the patient back to a PCP, with backup as needed. Sometimes we may see the patient for a few visits to ensure stability.

There will always be a small cadre of chronically ill patients who require ongoing care from specialists—brittle diabetics, unstable cardiac patients, and in psychiatry, people who suffer from schizophrenia or bipolar disorder, for example. People who pay out of pocket can call their own tune. But for most Americans, care will have to be more rationalized. I regularly point out to medical students and residents that this will soon change the way we practice and the lives we lead.

-Alan J. Gelenberg, M.D.
Editor, Biological Therapies in Psychiatry
Shively/Tan Professor and Chair, Psychiatry, Penn State University
Editor-in-Chief, Journal of Clinical Psychiatry

What’s MDD?

March 1st, 2013 by gelenberg No comments »

I chaired the APA workgroup that authored the third edition of the treatment guideline for major depressive disorder (MDD), published at the end of 2010. MDD is a typical DSM-3 (and beyond) diagnostic category—a behavioral syndrome, which doubtlessly encompasses many biologically distinct diseases. (Hence the varied responses of patients to our ministrations.) But even while we eagerly await the dawning of the era of personalized, genomically informed medicine in psychiatry, we can still assess each depressed patient with a careful differential diagnosis—considering substance abuse, medical and neurologic diseases, and personality disorders, among other possibilities.

This came to mind when a resident presented a case to me. The chief complaints were lack of energy and interest—certainly key components of MDD, but easily reflecting a host of other diagnoses. When I saw the middle-aged man, he had mask-like facies, bradykinetic features, and a resting tremor. On examination he displayed muscular rigidity. We referred the patient to a neurologist, who confirmed a diagnosis of Parkinson disease. The patient’s psychiatric complaints responded favorable to the antiparkinson regimen, as did his motor signs. We will soon taper his SSRI. It didn’t take long, and it sure helped this man.

-Alan J. Gelenberg, M.D.
Editor, Biological Therapies in Psychiatry
Shively/Tan Professor and Chair, Psychiatry, Penn State University
Editor-in-Chief, Journal of Clinical Psychiatry

“Inheriting” A Patient

February 27th, 2013 by gelenberg No comments »

Cases presented to me recently at another medical school and within my own department highlight a common clinical problem: picking up (“inheriting”) a patient previously under another doctor’s care. In resident clinics, it is commonplace, as residents advance through their training.

I shudder at how often I see complex pharmacologic “cocktails,” with at least one agent from every psychiatric drug category—sometimes two or three in a category. Truly there are some patients who benefit from polypharmaceutical regimens—as they do in hypertension treatment and other medical specialties. But more often, no one can say why the patient is taking these medicines at these doses: not the chart, the patient, the family, or other caregivers. Commonly, providers inheriting such patients go into “autopilot”—continuing the regimen without understanding it. It’s quicker and has less hassle. A resident recently told me how she worked to understand, then disentangle a complicated multi-drug regimen, then explain it to the patient, family, and other staff. By the end of the session, she was exhausted!

When a physician assumes care of a new patient on a complex treatment regimen, I recommend slow and cautious but methodical diligence. Ask everyone for input on the regimen, review the clinical record, and try to contact previous clinicians. At an initial visit, put confidence building and establishing trust first, but mention that the regimen is complex and might conceivably be less than optimal. Suggest future conversations toward simplifying the regimen, and document the discussion. And over time, consider cautious tapers—one drug at a time—with careful observation for adverse outcomes.

It is time consuming. And emotionally draining. And when a patient or family is adamant against change, I take their wishes seriously. But if I assume medical responsibility for care, I am responsible—not the doctor or doctors who created the regimen in days past.

-Alan J. Gelenberg, M.D.
Editor, Biological Therapies in Psychiatry
Shively/Tan Professor and Chair, Psychiatry, Penn State University
Editor-in-Chief, Journal of Clinical Psychiatry

Personalize This

January 17th, 2013 by gelenberg No comments »

The future of psychiatry, and indeed all of medicine, will emerge as we unravel the double helix of the genetic code, the proteins DNA commands, and the epigenetic factors that allow our environment to influence genetic expression. Today, I caught a brief glimpse of that future.

I just attended the ceremonial opening of the Penn State Hershey Institute for Personalized Medicine, one of a handful of high technology centers that will pave the way to a new era in health care. This multimillion dollar facility was enabled by federal, state, and private funds, and the inaugural event was attended by a U.S. senator and many United States, Pennsylvania, and university dignitaries. The Institute consists of laboratories that can quickly and relatively inexpensively map individual genomes, a tissue repository for samples from thousands of patients, and an information technology hub.

When I was a medical student in the 1960s, virtually all children with leukemia died. Today, almost all survive. The difference has been discoveries about the mysteries of individual cancers and how to target treatments to their unique signatures. Not only has survival increased, but when cancer treatments can be personalized, doctors can apply less toxic medicines than the systemic poisons we have used for decades.

I am committing significant discretionary funds from my department to leverage our new center’s technology to achieve breakthroughs in psychiatry. Instead of blasting every cell in the body with increased levels of serotonin, someday we should be able to target interventions to distinct pathophysiology underlying diseases of impulse, mood, and thought. As in other medical specialties, we will bank tissue samples from psychiatric patients, establish diagnoses, track symptoms systematically over time, record responses to treatments, and use computer programs to link biology to pathology and ultimately to cure. It is an exciting time.

-Alan J. Gelenberg, M.D.
Editor, Biological Therapies in Psychiatry
Shively/Tan Professor and Chair, Psychiatry, Penn State University
Editor-in-Chief, Journal of Clinical Psychiatry

Run For Cover

December 18th, 2012 by gelenberg No comments »

Lawmakers and other politicians have been ducking and running for cover from the NRA and gun lobby for more than a decade. Perhaps after the slaughter of first graders in Connecticut—many little feet trying vainly to run for cover from an assault rifle—that may change.

In the shooting’s aftermath, I heard pundits and politicians call for better “mental health screening.” Say what? We have no valid instruments to predict which mentally ill people are likely to erupt in random violence. Unquestionably, we can improve our system of care for people with mental illness. Outpatient commitment laws can use judicial powers to assure a higher rate of adherence to treatment for many at-risk individuals. And state systems are sorely in need of more funds and better leadership, with accountable management and best practice standards.

But we really need better gun laws. Semi-automatic assault-style weapons, with high-capacity ammunition clips, make no sense for sport or self-defense. Background checks and other restrictions will help. An angry or psychotic person can wreak havoc with a baseball bat or knife, but rapid-fire firearms can kill and maim large numbers of defenseless innocents in seconds.

Monday is my clinic day. This week it followed the Newtown killings by three days. A mother of young children, whom one of my residents treats for an anxiety disorder, feared sending her kids to their elementary school and was considering home schooling as safer. A woman in her 70s re-experienced dormant grief. A mother of a disturbed youngster felt anticipatory guilt, as she identified with the shooter’s mother. Patients with PTSD felt re-traumatized, with resulting recurrent symptoms.

The residents and I did our best. We consoled, offered advice and perspective, suggested limiting exposure to continuous television scenes of carnage. We counseled on ways to explain the events to children.

We helped our patients grieve. And along with our own families, friends, and colleagues, we grieved. Many tears have been shed since last Friday’s senseless loss of life. How many more children must die before our state and federal governments take reasonable steps to enhance public safety?

-Alan J. Gelenberg, M.D.
Editor, Biological Therapies in Psychiatry
Shively/Tan Professor and Chair, Psychiatry, Penn State University
Editor-in-Chief, Journal of Clinical Psychiatry

 

When Passion Trumps Practicality

November 19th, 2012 by gelenberg No comments »

My department at Penn State reaches out regularly to medical students who may be interested in careers in psychiatry: movie nights, mentorship, electives, and much more. A few days ago we held an open question-and-answer lunch, in which three faculty members and a senior resident fielded questions from a couple of dozen students from all four years. We munched on take-out Chinese food and chatted.

One student asked about careers in psychiatry, unmet needs, and subspecialties. He was reasonably trying to sort out his options. I knew that if I told him what had been the facts over my 40 years in practice, and what the world looks like today, he would make his calculations and decision for his practice over the coming 40 years. But the world of U.S. healthcare is anything but static. The changes coming over the next few years will be huge.

I am certain that psychiatry—and our subspecialties even more—will remain short of manpower. But who can say what tomorrow’s psychiatrists will do, what their hours will be, how long they will spend with patients, or what they might earn? I would say the same for the choice of specialty, whether surgery, medicine, pediatrics, or any other. Science and technology will bring major new developments, and the healthcare delivery infrastructure is undergoing a sea change.

What I am sure of is that there will be patients. People will be scared, in pain, confused, and uncertain. They will require ministrations, explanations, treatments, and comfort. The safest course for young doctors looking forward is to follow their passion, to chart their paths by what they most want to do—independent of practical, economic, and lifestyle factors. The joy in medical practice will remain forever—if they can follow their own hearts.

-Alan J. Gelenberg, M.D.
Editor, Biological Therapies in Psychiatry
Shively/Tan Professor and Chair, Psychiatry, Penn State University
Editor-in-Chief, Journal of Clinical Psychiatry