OBJECTIVE: To critically review the antiobsessional properties of serotonin-norepinephrine reuptake inhibitors (SNRIs) (venlafaxine and clomipramine) in the treatment of obsessive-compulsive disorder (OCD) as an alternative to selective serotonin reuptake inhibitors (SSRIs), which are currently considered the first-line treatment of OCD. DATA SOURCES: A MEDLINE search was performed to identify clinical trials with the SNRIs venlafaxine and clomipramine published from 1996 to 2004 (keywords: SNRIs, venlafaxine, duloxetine, and clomipramine, each matched individually with the term OCD), focusing on the best-designed studies for inclusion. DATA SYNTHESIS: Much of the literature about SNRIs in OCD supports the efficacy of these compounds in the treatment of OCD. However, double-blind, placebo-controlled studies with venlafaxine are lacking, and the most relevant studies consist of active comparison trials between SNRIs and SSRIs. In these studies, SNRIs seem to be as effective as SSRIs in OCD; SNRIs might be preferred for patients with certain types of treatment-resistant OCD or those with particular comorbid conditions. A large number of placebo-controlled and active comparison trials with clomipramine document efficacy in OCD, and meta-analytic studies suggest a small superiority over SSRIs. Compared with clomipramine, the SNRI venlafaxine showed fewer side effects and better tolerability. CONCLUSION: The SNRIs may represent a valid alternative to the SSRIs, particularly in specific cases. Double-blind, placebo-controlled studies are, however, needed to confirm the positive findings reported by several studies with venlafaxine.

Pharmacotherapy of obsessive-compulsive disorder
and obsessive-compulsive spectrum disorders.
Denys D.
Psychiatric Clinics of North America, 2006 Jun;29(2):553-84

This article reviews new developments of pharmacotherapy in obsessive-compulsive disorder (OCD) and OC spectrum disorders of the past five years. New developments primarily involved the extension of evidence of efficacy of serotonin reuptake inhibitors (SRIs), the use of atypical antipsychotics in addition to SRIs for treatment refractory patients, the combination of pharmacotherapy with behavior therapy, and studies assessing predictors of response. Today, frontline pharmacological treatment of OCD still consists of drugs with potent serotonin reuptake inhibition proper-ties. In case of non-response, treatment options comprise adding another drug, increasing the dose, switching drugs, or changing the mode of delivery.

Selective serotonin reuptake inhibitor use in the treatment of the pediatric
non-obsessive-compulsive disorder anxiety disorders.
Seidel L, Walkup JT.
Journal of Child and Adolescent Psychopharmacology, 2006 Feb-Apr;16(1-2):171-9.

The non-OCD (obsessive-compulsive disorder) anxiety disorders in the pediatric population--separation anxiety disorder, generalized anxiety disorder, and social phobia and others--are arguably the most common psychiatric disorders in this age group. Anxiety disorders, in addition to being common, also significantly impair the affected child at home, school, and with peers. A small developing evidence base suggests the selective serotonin reuptake inhibitors (SSRIs) are the pharmacological treatment of choice for pediatric non-OCD anxiety disorders. In clinical trials, SSRIs are often very effective in reducing symptoms and improving functioning and generally well tolerated. The U.S. Food and Drug Administration's (FDA) review of the safety of antidepressants in the pediatric population suggest a small, but significant, increased relative risk for suicidality adverse events on antidepressant versus placebo. Despite the apparent increased risk, the larger magnitude of benefit of the SSRIs for pediatric non-OCD anxiety disorders compared to depression suggests the benefit/risk ratio for anxiety disorders is more favorable than that for depression. This paper will review available studies on the treatment of non-OCD childhood anxiety disorders with antidepressants, including the SSRIs, and discuss pertinent safety issues.

A randomized, controlled trial of the effectiveness
of cognitive-behavioral therapy and sertraline
versus a waitlist control group for anxiety disorders in older adults.
Schuurmans J, Comijs H, Emmelkamp PM, Gundy CM, Weijnen I, van den Hout M, van Dyck R.
American Journal of Geriatric Psychiatry. 2006 Mar;14(3):255-63.

OBJECTIVE: This study is the first to investigate the relative effectiveness of cognitive-behavioral therapy (CBT) compared with a selective serotonin reuptake inhibitor (SSRI; sertraline) in a randomized, controlled trial on the treatment of anxiety disorders in older adults. METHOD: Eighty-four patients 60 years of age and over with a principal diagnosis of generalized anxiety disorder, panic disorder, agoraphobia, or social phobia were randomly assigned to one of three conditions: 15 sessions of CBT, pharmacologic treatment with an SSRI (sertraline; maximum dosage 150 mg), or a waitlist control group. Participants completed measures of primary outcome (anxiety) and coexistent worry and depressive symptoms at baseline, posttreatment, and at three-month follow up. RESULTS: Attrition rates were high in both treatment groups. Consequently, findings are based on a relatively small sample of completers (N = 52). Although both CBT and sertraline led to significant improvement in anxiety, worry, and depressive symptoms both at posttreatment and at three-month follow up, sertraline showed superior results on worry symptoms. Effect size estimates for CBT were in the small to medium range both at posttreatment (mean d = 0.42) and at three-month follow up (mean d = 0.35), whereas effect sizes for sertraline fell into the large range (posttreatment mean d = 0.94 and three-month follow up mean d = 1.02). The waitlist condition showed virtually no effects (posttreatment mean d = .03). CONCLUSIONS: Our findings strongly suggest that the pharmacologic treatment of late-life anxiety with SSRIs has not been given the proper attention in research to date.

A meta-analysis of the efficacy of psycho- and pharmacotherapy
in panic disorder with and without agoraphobia.
Mitte K.
Journal of Affective Disorders, 2005 Sep;88(1):27-45.

The efficacy of (cognitive) behavioural ((C)BT) and pharmacological therapy was investigated using meta-analytic techniques. After a comprehensive review of the literature, the results of 124 studies were included. (C)BT was more effective than a no-treatment control and a placebo control. No difference of efficacy was found when using cognitive elements compared to not using them for anxiety; for associated depressive symptoms, additional cognitive elements seems superior. Pharmacotherapy was more effective than a placebo control; there was no superiority of any drug class. Sample size was related to effect size in pharmacotherapy and publication bias was found. (C)BT was at least as effective as pharmacotherapy and depending on type of analysis even significantly more effective. There were no significant differences between (C)BT alone and a combination approach but characteristics of studies have to be considered.

Evidence-based pharmacotherapy of panic disorder
Bakker A, van Balkom AJ, Stein DJ.
International Journal of Neuropsychopharmacology, 2005 Sep;8(3):473-82.

This paper reviews the literature on the pharmacotherapy of panic disorder, in order to address the questions (1) what is the first-line pharmacotherapy of choice for panic disorder?, (2) for how long should maintenance pharmacotherapy be continued, and (3) what is the optimal approach to the treatment-refractory patient with panic disorder. A MEDLINE search (1966-2003) was undertaken to collate randomized controlled trials of pharmacotherapy in panic disorder. A review of the evidence indicates that SSRIs are currently the first line agent of choice in panic disorder, and that pharmacotherapy should be continued for at least 1 year. There has been relatively little research on the pharmacotherapy of treatment-refractory panic disorder, and this area requires future attention.

Benzodiazepine use, cognitive impairment, and cognitive-behavioral therapy
for anxiety disorders: issues in the treatment of a patient in need.
Otto MW, Bruce SE, Deckersbach T.
Journal of Clinical Psychiatry, 2005;66 Suppl 2:34-8.

Like Drugs, Talk Therapy Can Change Brain Chemistry

By Richard A. Friedman, M.D.
The New York Times
August 27, 2002

After six years of twice-weekly psychotherapy sessions, Eric had plenty of insight. But his anxiety level had barely changed. He was still bedeviled by a ceaseless urge to wash his hands and shameful and repetitive violent thoughts. Out of desperation and against the wishes of his therapist, he visited my office to discuss the possibility of medication. "I thought I could understand my way out of my obsessive compulsive disorder," he recalled recently. "I wanted to be able to do it on my own, without medication." What he did not remember was his vehement opposition to psychotropic medication on the ground that it was not natural and would change his brain chemistry.

Of course, he was right. Like Eric, many patients and therapists share the view that psychotherapy is preferable to pharmacotherapy because it is more "natural" and because it supposedly gets to the root of the patient's problem. They are convinced that self-understanding will bring relief, whether the problem is anxiety, depression or obsessional thinking. Insight is a prerequisite of happiness, the theory goes, and well-being achieved without the hard work of psychotherapy is artificial and inauthentic.

But new evidence suggests that the talking cure and psychotropic medication have much more in common than had been thought. In fact, both produce surprisingly similar changes in the brain. Take Eric's obsessive compulsive disorder. It hobbles patients with unwanted thoughts, often violent or sexual, that play in the mind like a broken record. Owing to the sometimes lurid nature of the thoughts, the treatment mainstay had for years been psychoanalytically oriented therapy to unlock the sexual and aggressive conflicts presumed to underlie the symptoms. There was just one problem. That form of psychotherapy rarely, if ever, worked for those patients, a point now widely accepted by most psychoanalysts themselves. But two seemingly different treatments can be highly effective: a form of talk therapy called cognitive-behavior therapy and a class of antidepressants called selective serotonin reuptake inhibitor antidepressants, or S.S.R.I.'s, drugs like Prozac and Zoloft. It is well known that patients with the disorder have altered serotonin function compared with normal controls.

Brain imaging that uses PET scans, or positron emission topography, has shown that the disorder is associated with functional hyperactivity of the caudate nucleus, a structure buried beneath the cerebral cortex. Some researchers hypothesize that the caudate is part of a subcortical circuit that acts as a kind of filter, sifting out extraneous thoughts and impulses. In obsessive compulsive disorder, they theorize, the subcortical filter malfunctions, allowing the unwanted thoughts to reach the cortex and then on to consciousness. In a study by Dr. Lewis Baxter at the U.C.L.A. School of Medicine, patients with the disorder who responded to either a reuptake inhibitor like Prozac or cognitive behavior therapy over 10 weeks showed virtually the same changes in their brains, decreases in the activities of the caudate nuclei and, thus, changes toward normal function. When patients improved, the changes in their brains, as shown in the PET scans, looked the same regardless of whether they had received antidepressants or psychotherapy.

An S.S.R.I. works, in part, by enhancing the neurotransmitter serotonin, whose activity is often abnormal in people with obsessive compulsive disorder and depression. Cognitive behavior therapy focuses on changing distorted patterns of thinking. The intriguing finding from the PET scans is not limited to O.C.D. Two studies of patients with depression, reported last year in The Archives of General Psychiatry, compared the effects of interpersonal psychotherapy with an antidepressant on brain function, as observed in PET scans. In those studies, the depressed patients received interpersonal therapy, a short-term talk treatment that focuses on the effects of social anxiety. In one study, a 12-week trial that compared an S.S.R.I., Paxil, to interpersonal psychotherapy, Dr. Arthur Brody, also at U.C.L.A., found that depressed patients who responded to either treatment had nearly identical changes in their brain function, a decrease in the abnormally high activity seen in the prefrontal cortex before treatment.

In the second study, Dr. Stephen D. Martin at the research unit of Cherry Knowle Hospital in Sunderland, England, reported that six weeks of Effexor, an antidepressant that enhances both serotonin and norepinephrine, and interpersonal therapy produced similar effects in those depressed subjects who responded either to medicine or to psychotherapy. Each had shown an increase in the activity of the basal ganglia, a subcortical brain structure. Although the observed changes with psychotherapy and antidepressant were similar in that study, they were not identical. Subjects with interpersonal therapy but not Effexor also had activation of a brain area called the cingulate gyrus, which responds to serotonin in the brain and has a role in regulating mood. The studies show that pharmacotherapy and psychotherapy can produce remarkably similar effects on functional brain activity. But does that mean that antidepressants and psychotherapy are really equivalent? In a word, no.

Psychotherapy alone has so far been largely ineffective for diseases like schizophrenia, where there is strong evidence of structural, as well as functional, brain abnormalities. So it seems that if the brain is severely disordered, then talk therapy cannot alter it. But it is clear that talk therapy can alter brain function. The reason may come from the elegant work of a Nobel Prize-winning psychiatrist and neurobiologist, Dr. Eric Kandel. Studying the simple and well-mapped nervous system of a sea slug, Aplysia, Dr. Kandel showed that learning leads to the production of new proteins and, in turn, to the remodeling of neurons. Sea slugs exposed to the controlled-learning condition that produced long-term memory ended up with double the number of neuronal connections as the untrained animals. In essence, Dr. Kandel has proved that learning involves the creation of new neuronal connections.

The clear implication for humans is that learning literally changes the structure and function of the brain. Now it may seem a big leap from a snail to a human. But if psychotherapy is thought of as a form of learning, then when therapists talk to patients, they cause them to learn, perhaps changing their brain function and, perhaps, for the long run. In the end, Eric chose cognitive behavior therapy and improved drastically. Through exposure to those situations that he feared like messy dirty places, he became desensitized to them and lost his compulsion to wash. Had he chosen an antidepressant, chances are that he would also have improved. If psychotherapy produces nearly the same brain changes as pharmacotherapy, then the boundary between mind and brain is purely artificial - even unnatural.

The author is a psychiatrist who directs the Psychopharmacology Clinic at the New York Weill Cornell Medical Center.

ASDI note:
The placebo response rate in most studies of non-OCD anxiety disorders is >30%.

On the windowsill of his Columbia University office, psychiatrist B. Timothy Walsh has a little golden bottle labeled "placebo." The container is filled with sugar pills -- breath mints, to be exact -- and purports to treat everything from "bad hair" to "can't take a joke" to "no rhythm" to "the blahs." About 50 conditions are listed with a box next to each. The label directs patients: "Select symptom. Check box. Take 2 mints. Bingo. . . all better!" Walsh's "cure" is reminiscent of the snake oil, tonics and magical elixirs that used to be popular in this country -- the kind of carnival quackery that no one falls for anymore. Right? Well, not quite.

According to a recent report by Seattle psychiatrist Arif Khan, who conducted analyses of the placebo effect in 96 clinical trials submitted to the FDA between 1979 and 1996, sugar pills were often as effective as antidepressants. And judging by the media's reaction to the publication of Khan's findings, you might think that people are getting ready to throw away their little green-and-white Prozac pills. It all leaves our collective faith in modern medicine a little shaken. But it shouldn't. Studies like Khan's, which was first reported in The Post, are confusing, and and some people have assumed that his findings mean that sugar pills work just as well as Prozac, Paxil and Zoloft. But in fact, as the original article pointed out, these studies don't mean that antidepressants don't work, or that sugar pills work just as well or even that antidepressants don't work as well as we previously thought.

Quite the opposite. We're seeing these results because antidepressants do work -- and because of our increased faith in the power of modern medicine. What has happened is that our confidence in antidepressants has grown -- partly because of modern pharmaceutical marketing techniques. Our belief in their power causes placebos to work better. When people volunteer to take part in clinical trials, they expect the medication they are given to work -- and it does work, even if it is just sugar. Confusion abounds about the "placebo effect" -- the term that doctors use to describe the phenomenon where patients get better because they expect the treatment to work, even though they're actually ingesting a pharmacologically inert substance. And that confusion has been compounded by a variety of recent studies that seem to contradict each other.

Last year, an article in the New England Journal of Medicine declared the placebo effect to be a statistical chimera, arguing that sick people tend to get better over time, regardless of whether they take sugar pills, and that belief plays no part in that process. Khan's study seemed to refute that: Prozac had five clinical trials, and in only two of them did it work significantly better than sugar pills. For Zoloft and Paxil, it took even more trials to obtain a positive result. There is an answer to these apparent contradictions -- and it's not to stop taking antidepressants.

The first step is to ask why the placebo effect is so strong relative to the actual effect of the drug. A major reason for the placebo's efficacy stems from the care and concern shown to patients during clinical trials, which has a big impact on their well-being -- especially in the case of depression. "Care, concern, and general attention are crucial factors in our patients' recoveries from illness -- not only from depression, but from all medical illnesses," says Andrew Leuchter, a professor of psychiatry at UCLA. Another factor is the time scale. Clinical trials are fairly short (usually eight weeks) and often that's not enough time to observe the long-term effects of a depression treatment. A placebo group might show equal improvement to a medication group at first. But if a placebo study were done over a period of several years, the placebo group would almost certainly fall behind. But the main factor that explains why antidepressants often fare no better than sugar pills is more mysterious, and it was suggested by a separate study: The placebo effect is growing more powerful.

In a survey of antidepressant trials from 1981 to 2000, Walsh found that the placebo effect grew more pronounced over the years. (As Walsh jokes, "They're making placebos better and better.") But why? The answer to that question is cultural, not medical. After all, those trials were conducted in basically the same way 20 years ago as they are today. The thing that's changed is us. It's well established that confidence in a treatment can have a mind-over-body effect on how well the treatment works. And our culture's faith in technology generally, and in medicine in particular, has grown in that time period. In 1981, the first year examined in Walsh's study, AIDS was just appearing on our radar screens.Doctors were diagnosing a mysterious and frightening new disease and no one knew how to fight it. Now, people expect to live long and productive lives with HIV. That's just one of the examples of the ways the medical and technological breakthroughs of the past 20 years have changed our expectations of medicine and science. We are mapping the genome, can explore the brain using magnetic resonance imaging, transplant organs and build artificial hearts.

Today, we also have a better understanding of mental illness. We know that many people experience depression, we view depression as an illness, and the stigma about seeking treatment for it is fading. A study published in January in the Journal of the American Medical Association found that the number of Americans being treated for depression had tripled between 1987 and 1997, and the number taking antidepressants had doubled. In fact, according to an ABC News poll, one in every eight Americans has been treated with antidepressants at some stage in their lives.

Pharmaceutical marketing also has bolstered our feelings of faith in drugs. With a million antidepressant prescriptions a week in this country, drug giants can afford to spend billions on advertising to convince us their products work. Commercials feature animations of sad neurons weeping, presumably because they don't have enough serotonin to go around. Once they get Zoloft, they become smiling, flying, animated neurons. That marketing has an effect on our psyche. We have become more willing to believe that depression can be caused by a chemical imbalance in the brain -- and that it can be treated chemically. "It has to do with the profoundly cognitive nature of depression," says Jack Glaser, a social psychologist and professor of public policy at the University of California at Berkeley. Since depression can be treated without medication, using cognitive therapy, taking a pill you think will make you better can break the cycle and help you cope.

"The most likely reason placebo effects are getting bigger is the increasingly prevailing belief that pills work for treating depression -- thus the placebo has more credibility." Walsh's study found that, for the most part, the effectiveness of a drug increased along with the effectiveness of the placebo. But he found that the placebo effect is not only stronger today, but more variable. This variability accounts for why placebos sometimes score better than real drugs. "The drugs are more effective, but there's so much noise in the system, and people are getting better for so many different reasons, that it can be hard to show every time that the drug is better than placebo," says Walsh. "But it is." Doctors have long known that the power of suggestion can have real medical effects. And expectation of harm -- the so-called nocebo effect -- can be as powerful as the placebo effect. In one nocebo study, patients were given sugar water and told it was an emetic. Eighty percent vomited. In another, asthmatic patients inhaled saline spray thinking it was an irritant. Many had breathing problems and asthma attacks. Many recovered when researchers gave them the same spray again, this time telling them it was a bronchiodilator.

Other studies have demonstrated that placebos improve blood pressure, cholesterol levels, heart rate and allergies, and can make warts vanish. For some reason, red sugar pills kill pain better than green, blue, or yellow ones; blue sugar pills work better as sedatives than pink ones. Patients don't just think they get better on placebos: They really do get better, and the changes are reflected in brain scans and blood tests. Because people are suggestible, doctors know that the hype (often, true hype) surrounding a medication can make it more effective. One old doctors' cynical joke goes, "Use new drugs quickly, while they still work."

What does all of this research imply for pharmaceutical companies and for the public? The first conclusion is that if the kind of care and attention patients received in the clinical trials can have such a strong impact on an individual's recovery, health insurance companies should realize that encouraging longer doctor's visits will save money in the long run, and we should make sure that depressed people receive therapy or counseling. The ABC News poll that found one in eight Americans had taken antidepressants also showed that 59 percent had not received therapy in conjunction with the medication.

The Journal of the American Medical Association, which reported that antidepressant use has gone up, also reported that face-to-face therapy has gone down: From 1987 to 1997, the percentage of patients in counseling dropped from 71 percent to 60 percent. The key to understanding the placebo effect is to disentangle the effect of the drug from the effect of the care. But in the real world, we don't have to worry about which is helping more.

The message we should take from Khan's new research is not that antidepressants don't work, but that they work best in conjunction with increased care and concern -- in the form of therapy. That's the combination of treatment that the medical profession should aim to provide.

Jay Dixit is a writer living in New York City.

Anxiety and Stress Disorders Institute of Maryland:
Treating anxiety disorders and stress-related disorders in Towson, Maryland, since 1978.