Archive for the ‘Treatments’ category

When Mechanism Matters

August 1st, 2013

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

Knee-jerk Psychiatry

April 7th, 2013

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

What’s MDD?

March 1st, 2013

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

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

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

NCDEU 2012

June 13th, 2012

I just attended the annual NCDEU meeting—this year in Phoenix, AZ. NCDEU stands for New Clinical Drug Evaluation Unit (formerly ECDEU, Early Clinical Drug Evaluation Unit) These are now meaningless acronyms, but it was originally a symposium of clinical psychopharmacology researchers funded by NIMH. NIMH has recently relinquished “ownership” of the meeting to the American Society of Clinical Psychopharmacology, but it, along with its sister institutes NIDA and NIAAA as well as the FDA, retains a partnership stake and roll [?a role] in the program.

No one was certain how this meeting, which many of us are devoted to, would survive the transition from NIMH’s leadership. But this year’s program, with ASCP in the lead, was a sparkling success: in attendance, participation, enthusiasm and—most of all—groundbreaking science.

Meetings evolve. ECDEU/NCDEU began as a methods-focused conclave in the early days of biological psychiatry. Over the decades, it evolved to incorporate understanding of brain function, psychosocial interventions, and combined treatments. NCDEU became a unique assembly of industry, government, and university scientists, regulators, teachers, and clinicians. The papers, posters, and panels contained cutting-edge information, but much of the spark came in the informal conversations, from which flowed new research ideas and collaborations.

This year’s agenda included news on innovative treatments and new data on old techniques and agents. A bold new diagnostic methodology, the NIMH Research Domain Criteria (RDoC) is shifting the focus from DSM categories to dimensions and traits, in the hope of mapping disorders to biological underpinnings and the human genome. Whether—and when—this will bear fruit in furthering understanding of brain disorders and creating new and personalized treatments remains to be seen. It could take years or even decades to unfold.

-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

 

Overall, the information imparted at NCDEU 2012 was invigorating, and the energy in the meeting has never been higher. With the disclosure that I sit on ASCP’s board and have an abiding passion for its mission and NCDEU’s future, I encourage my faculty members and BTP readers to think about ASCP membership and attending NCDEU. BTP (and the Journal of Clinical Psychiatry) are partners with ASCP, which is a dynamic and growing organization. Coming away from this year’s meeting, I am very optimistic about psychiatry’s future.

A Little More Time for Sex

April 3rd, 2012

In the early 1990s, I was intrigued by the nature and degree of sexual side effects engendered by the then-new SSRI antidepressants. These adverse reactions differed from sexual problems associated with tricyclics and MAOIs. Several of us in Arizona created the ASEX scale to track these side effects, and I participated in trials of antidotes and journal reviews of the problem.

Twenty years have passed. A few days ago I chaired a “roundtable” discussion on depression for primary care doctors with my colleagues and friends Michael Thase and Erika Saunders. When we spoke about sexual side effects of serotonergic antidepressants, Michael mentioned the benefits of counseling patients to expect sex to take more time. Here was an obvious and low-tech solution I had never thought of.

I doubt many people book time for sex in their Outlook calendars. Still, couples in stable relationships know roughly how long they need. (For teenagers, the unit of measurement can be seconds.) Few couples will begin a 30-minute encounter if, for example, they’ll need to drive to an appointment or expect the baby to awake in 15 minutes.

So when we start a patient on an SRI antidepressant, suggesting that the patient and partner allow and anticipate more time (and sometimes more stimulation and creativity) can transform what otherwise would be anorgasmia into delayed orgasm.  I recall a middle-aged female patient of mine who observed, “I can get there, but I have to work harder.”

This is good, safe, practical, art-of-medicine advice. Thanks, Michael.

-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

 

Grief and Depression

March 16th, 2012

If you read the popular press, you are aware of the controversy about dropping the bereavement exclusion from the diagnosis of Major Depressive Disorder in DSM-V. The Lancet published an editorial in their February 18th issue decrying what they called the classification of grief as a mental illness. The same issue carried a moving Perspective by Dr. Arthur Kleinman, who described the recent death of his wife, his own bereavement, and his warning against “medicalizing” grief.

Freud struggled with the separation of grief and depression. His elegant monograph Mourning and Melancholia bears re-reading today.

The thought of turning natural grief into an illness and treating it with drugs is anathema to me. Grieving truly is a normal, personal, intimate process. It requires friends and loved ones and, as Freud describes, it is a gradual, healing path of saying good-bye and moving forward with the rest of one’s life.

But sometimes loss triggers the pathological mood state of depression. I have seen patients whose normal grief went off track and ground to a halt when the pall of depression descended on them. When they were treated with antidepressants or psychotherapy, they were able to resume the healing process, move forward in grieving, and find their place again in the world.

I am no expert in nosology. But as a clinical psychiatrist, I do hope the framers of the next DSM will find a path between the extremes—neither medicalizing a normal process, nor making it impossible for a grieving person who then develops depression to legitimately receive proper treatment.

-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

 

I and Thou

March 8th, 2012

I often sit in on our psychiatry residents’ visits with patients. During one recently, I was reminded of reading Martin Buber when I was in college. Good doctors—certainly good psychiatrists—must establish what Buber called an I-it relationship with patients: objectively collecting, synthesizing, and hierarchically organizing data, maintaining appropriate boundaries and neutrality, formulating a working diagnosis and treatment plan. But without simultaneously establishing an I-thou relationship—involving an ineffable mélange that includes love, empathy, and spiritual connectedness with a companion soul—the clinical encounter is cold.

At a pragmatic level, cold encounters usually result in patients who don’t return, non-adherence to treatment recommendations, and little clinical benefit. Practitioners who can’t put aside checklists and allow a free flow of emotion and experience often “miss the boat” and may not help a fellow human in need.

A while back a resident was evaluating a patient. Going through his standard questions to rule in or out major depression, he asked the patient about her sleep. She said she hadn’t slept very well since a recent incident with her husband. The resident checked a box about insomnia and went on to questions about suicidal thoughts. When he had finished, I followed up and asked the patient about her marriage. The tears flowed, vital information emerged, and our formulation of the problem and treatment recommendations changed.

DSM-III, IV, and presumably V have brought reliability to psychiatric diagnoses. Someday genomics presumably will add validity to our nosology. We should follow the rules of the DSM to ensure clear communication and fidelity with best-practice treatment guidelines. Measurement-based care and evidence-based medicine are watchwords of modern practice and to be honored every day.

But there is a vital role for I-thou, which in no way conflicts with a scientific and objective approach. It’s the human part of the complex equation of two people sitting with one another. In his daily physician’s prayer, the twelfth-century physician and philosopher Moses Maimonides wrote, “In the sufferer let me see only the human being.” Amen.

-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

 

 

 

 

Therapy Is A Journey

April 15th, 2011

If a patient has taken medicines, I always get as much detail as possible: dose, duration, response. If a patient has been involved in psychotherapy, I try to learn what in the patient’s life has changed and through what means. People who demean and disparage the whole concept of psychotherapy claim it’s simply rent-a-friend. It can be, but ideally it should be much more.

Our goal as parents is to render ourselves obsolete. That’s also what I aim for when I’m a therapist: helping patients achieve the competence and confidence to kick off their “training wheels.” Even supportive psychotherapy should have an “end game.” Patients who seem to require the regular advice and encouragement of a professional can be coached on other sources of support: friends, interest groups, religious organizations. Symptom-based treatments or therapies designed to achieve behavior change should move progressively toward specific goals. Progress should be measurable. Endless therapy should be the exception.

When I take a patient’s history, and the patient has been in therapy, I hope to learn that therapy has provided a vehicle, that the patient and therapist have been on a journey—toward a destination. If therapy has just been a place to go and talk, if there has been no obvious progress, I raise questions.