It occurs as a reaction to stressful life events. The differential diagnosis of anxiety disorders includes common mental disorders, such as other anxiety disorders, major depression, and somatic symptom disorders, as well as physical illnesses such as coronary heart or lung diseases, hyperthyroidism, and others. Anxiety disorders often co-occur with other anxiety disorders, major depression, somatic symptom disorders, personality disorders, and substance abuse disorders.
Box 1 contains a case vignette of the treatment of a patient with GAD. Alice, a year-old female dentist, presented to a psychiatrist with a 7-month history of anxiety symptoms, which included persistent feelings of restlessness, irritability, difficulty concentrating, sleep disturbance, fatigue, nausea, diarrhea, muscle cramps, and the sensation of having a lump in her throat. She was suffering from constant worry that her husband could become ill or might have an accident while driving to work. Her symptoms resulted in frequent absenteeism, which caused significant problems at work.
Her medical history was unremarkable. The psychiatrist diagnosed her with generalized anxiety disorder, DSM-5 F Four weeks previously, Alice had been prescribed the benzodiazepine diazepam by her general practitioner, and initially took it as prescribed. Although it helped with her anxiety, she felt that it made her feel dull and worried that it would interfere with her work as a dentist. She kept thinking that she would become addicted to the drug and stopped the intake.
The psychiatrist started treatment with the serotonin-norepinephrine reuptake inhibitor venlafaxine. Because the patient was sensitive to side effects, the drug was started with She reported mild nausea and fatigue; however, it was not clear whether this was due to the medication or to the illness.
The patient also received weekly sessions of cognitive behavioral therapy. Symptoms of GAD were resolved almost completely after 7 weeks. The psychiatrist advised Alice to continue on venlafaxine for at least 6 months. Then, after 2 weeks on The patient did not report relevant withdrawal symptoms and did no show reoccurrence of significant anxiety symptoms during a follow-up observation period of almost 1 year.
However, treatment is indicated when a patient shows marked distress or suffers from complications resulting from the disorder eg, secondary depression, suicidal ideation, or alcohol abuse. Anxiety disorders can be treated mostly on an outpatient basis. Indications for hospitalization include suicidality, unresponsiveness to standard treatments, or relevant comorbidity, eg, with major depression, personality disorders, or substance abuse.
The treatment recommendations in this article are based on guidelines for anxiety disorders. Studies were analyzed by using internationally acknowledged quality assessment tools, and the recommendations were reviewed by expert panels. Patients with different anxiety disorders show different degrees of health care utilization. For example, in the United States, There is evidence for substantial undertreatment of anxiety disorders.
In a large European study, only Of those participants who contacted health care services, The treatment plan should include psychotherapy, pharmacotherapy, and other interventions, which should be chosen after careful consideration of individual factors, eg, the patient's preference, the patient's history with previous treatment attempts, illness severity, comorbidities such as personality disorders, suicidally, local availability of treatment methods, wait time for psychotherapy appointments, costs, and other factors.
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Whereas many studies have shown the efficacy of medications for GAD, PDA, and SAD, there are very few studies on drug treatment for specific phobias, for example, there is a small study suggesting the efficacy of paroxetine. However, not all drugs mentioned here are licensed for anxiety indications in all countries, and the reader should refer to local prescribing information.
Table III lists drug side effects. For a detailed list of available randomized controlled studies, the reader should refer to guidelines published by Bandelow et al, 27 , 33 which include a systematic evaluation of available studies. Patients should be informed that the onset of the anxiolytic effect of these antidepressants has a latency of 2 to 4 weeks in some cases up to 6 weeks. During the first 2 weeks, adverse effects may be stronger. Initial jitteriness or an increase in anxiety symptoms may occur, which may reduce the patients' treatment compliance.
Lowering the starting dose of the antidepressants may reduce these adverse effects. However, these are much less frequent and severe than the withdrawal reactions observed after terminating benzodiazepine treatment. These adverse reactions may be more frequent with paroxetine than with sertraline or fluoxetine.
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The drug has sedating properties. Onset of efficacy is earlier with pregabalin than with antidepressants. Pregabalin is not subject to hepatic metabolism and hence does not interact with inhibitors or inducers of cytochrome P enzymes. However, there have been concerns about the abuse of pregabalin in individuals suffering from substance abuse and also withdrawal syndromes after abrupt discontinuation. The traditional tricyclic antidepressants TCAs imipramine and clomipramine are as effective as second-generation antidepressants in the treatment of anxiety disorders.
Thus, these drugs should be tried first before TCAs are used. The dosage should be uptitrated slowly until dosage levels reach those used in the treatment of depression. TCAs should be used with caution in patients considered to be at risk of suicide, due to their potential fatal toxicity after overdose. Buspirone, a 5-hydroxytryptamine receptor 1A 5HT 1A agonist, has been shown in some controlled studies to be effective in the treatment of GAD.
The anxiolytic effects of benzodiazepines begin soon after oral or parenteral application. In contrast to antidepressants, benzodiazepines do not lead to initially increased jitteriness and insomnia. Cognitive functions may be impaired, mainly in elderly patients. After longterm treatment with benzodiazepines eg, over 4 to 8 months , dependency may occur in some patients, 41 - 47 especially in patients predisposed for substance abuse.
Current guidelines do not recommend benzodiazepines as first-line treatments. In exceptional cases eg, severe cardiac disease, contraindications for the standard drugs, suicidality, and other conditions , benzodiazepines can be used for a limited time period. However, patients with a history of benzodiazepine or other substance abuse should be excluded from treatment. In singular cases, acute panic attacks may require immediate drug treatment. In that case, lorazepam melting tablets at a dose of 1. It is usually sufficient to talk calmly with the patient and explain that the attack is not due to a life-threatening medical condition.
Moclobemide is a selective and reversible inhibitor of monoamine oxidase A. It is used in the treatment of SAD. Because not all studies have shown evidence for superiority to placebo, the drug is not recommended as first-line treatment. Some other drugs have shown efficacy in anxiety disorders in randomized controlled studies but are not licensed for the treatment of these disorders in most countries. Medicolegal issues have to be considered whenever drugs that have not been approved for anxiety indications are prescribed off label.
The antidepressant agomelatine—which acts as an agonist for melatonin MT 1 and MT 2 receptors and as an antagonist for serotonin 5-HT 2C receptors—was shown to be effective in four studies in GAD. The atypical antipsychotic quetiapine was shown to be effective in a number of studies in GAD.
However, probably due to adverse effects such as the metabolic syndrome, the drug was not licensed for anxiety disorders in most countries. In general, typical adverse events, such as sedation or weight gain, were less frequent in patients receiving lower doses. The onset of efficacy is earlier than with antidepressants. A new antidepressant, vortioxetine, was investigated in several controlled studies in GAD. However, according to a meta-analysis, significant improvement for vortioxetine could not be demonstrated compared with placebo.
The comparison studies only used low doses of the comparators, eg, 20 mg paroxetine per day 66 or one tablet of lorazepam 0. Studies with Kava-kava Piper methysticum showed inconsistent results, 70 - 72 and the extract was been withdrawn from the market in some countries due to hepatotoxicity in some preparations. Valerian extract was not effective in placebo-controlled studies in anxious patients. Some other phytotherapeutics have been investigated in individuals with anxiety conditions. Due to the low quality of these studies, the evidence for the investigated products is not sufficient for a review, see Sards et al Standardization may be an issue in herbal preparations.
For example, it was shown that different preparations of St. John's wort exhibited large differences in the content of the putatively effective ingredients. In a meta-analysis of all available drug studies in anxiety disorders, 77 the pre -post effect sizes of the different drugs were determined. We simply looked at the absolute difference in anxiety scale scores before and after treatment, without regard to the relative efficacy compared with placebo. This approach makes it possible to include hundreds of studies in comparisons of differential efficacy of all available drugs and not only the few direct head-to-head comparisons.
From the patients' point of view, the improvement in anxiety symptoms as measured by the change from baseline to end point is more relevant than the difference from a control group. The available medications for anxiety disorders showed considerably large differences in pre-post effect sizes. Quetiapine, however, is not licensed for the treatment of any anxiety disorder in most countries. However, these drugs are not recommended for routine treatment. Patients must be informed about possible adverse effects, interactions, safety warnings, and contraindications, as indicated in the current summary of product characteristics.
If patients are educated about the possibility that some early side effects might later decrease in intensity, compliance may improve. Patients with anxiety disorders are often hesitant to take psychotropic drugs because they are afraid of adverse effects. In particular, patients with PDA may easily discontinue antidepressants because of initial jitteriness and nervousness.
Doses for drug treatments are shown in Table II. In patients with severe hepatic impairment, a dosage adjustment or use of medications that are cleared primarily by the kidney eg, pregabalin may be required. For all drugs recommended in this article, relapse prevention studies in at least one anxiety disorder have been conducted in patients who have responded to previous open treatment with a certain drug and were then randomized to placebo or ongoing blind treatment with the same drug for periods of between 6 and 18 months. All of these studies showed a significant advantage for staying on active medication when compared with switching to placebo.
Based on the findings from these relapse prevention studies and clinical experiences, drug treatment should be continued for 12 months or more after remission has occurred. Given the chronic course of anxiety disorders, it is regrettable that there are almost no controlled studies that investigate treatment periods over 12 months.
To avoid withdrawal syndromes, the dose should be slowly tapered off over a period of 2 weeks at treatment termination. It is a common opinion that patients treated with drugs show immediate relapse after stopping medication, whereas gains of psychological therapies are maintained for months or years after treatment termination.
This would offer psychological therapies considerable advantage over drug treatment. However, in naturalistic studies following up anxiety patients, substantial relapse rates were also found years after CBT treatment. When treating anxiety disorders with medications, drug interactions have to be monitored. Additive CNS depression may occur when drugs with sedating properties are combined, eg, TCAs, benzodiazepines, or pregabalin, resulting in unwanted sedation, drowsiness, or increased reaction time.
Additive effects at the neurotransmitter level can occur when medications are combined that have antagonistic effects on the same receptors, eg, two drugs with anticholinergic effects. Before considering a patient to be treatment unresponsive, it should be ascertained that the diagnosis was correct, adherence to the treatment plan was sufficient, the dose prescribed had covered the full range, and there had been a trial period of adequate duration.
When patients report previous treatment failures, it often turns out that a drug was only prescribed in the lowest dose or was stopped within the first 2 weeks due to side effects that occurred in the initial phase before the patient could experience improvement. Concurrent drugs may interfere with efficacy, eg, metabolic inhibitors or enhancers.
Psychosocial factors may affect response, and comorbid personality or substance abuse disorders are especially likely to complicate anxiety disorders. When initial treatment fails, the physician has to decide when to change the treatment plan. There have been few systematic trials of treatment-refractory patients with anxiety disorders. If after treatment at what is considered an adequate dose for 4 to 6 weeks a patient shows no response, the medication should be changed.
If partial response is seen after this period, there is still a chance that the patient will respond after another 4 to 6 weeks of therapy with increased dosages. For some antidepressants, the studies on a potential dose-response relationship are inconclusive, perhaps due to the lack of statistical power for showing a difference between lower and higher doses. According to clinical experience, however, a trial with a higher dose in patients with insufficient response is warranted. Elderly patients may take longer to show a response.
Table III contains options in case of drug inefficacy or intolerance. In patients who are unresponsive to psychotropic drugs, the addition of CBT is generally recommended. A combination of antidepressants and benzodiazepines is sometimes used in treatment-refractory cases.
When all standard treatments have failed, the off-label use of drugs may be considered, for example, drugs licensed for another anxiety disorder or that are not licensed but have shown efficacy in clinical studies. Such drugs include quetiapine and agomelatine. With the exception of GAD, anxiety disorders are less common in patients over 65 years of age. Therefore, only a few studies for the treatment of GAD have been performed with older patients. Controlled studies have shown the efficacy of duloxetine, venlafaxine, pregabalin, and quetiapine in patients over 65 years old.
In the elderly, effect sizes for CBT tend to be somewhat smaller than those found in mixed-age populations. There are some randomized, placebo-controlled studies of pharmacotherapy for anxiety disorders in children and adolescents showing efficacy of sertraline, fluoxetine, and duloxetine in young patients with GAD, of venlafaxine and paroxetine in SAD, and of sertraline, fluvoxamine, and fluoxetine in mixed samples, including patients with separation anxiety disorder, GAD, and SAD.
There had been concerns about increased risk for suicidal ideation not suicides in children and adolescents treated for major depression with SSRIs escitalopram, citalopram, paroxetine, and sertraline , mirtazapine, and venlafaxine. For children and youths with separation anxiety disorder, several treatment studies exist. There is also a paucity of treatment studies for children with selective mutism. Small studies have shown that psychotherapeutic approaches were at least better than waitlist controls. For pregnant women, the risk of an untreated anxiety disorder must be weighed against the risk of damage to the unborn child as a result of treatment.
A large study suggested no substantial increase in the risk of cardiac malformations attributable to antidepressant use during the first trimester. In such cases, CBT should be considered as an alternative to medication treatment. All patients with anxiety disorders require supportive talks and attention to the emotional problems that are associated with the anxiety disorder.
Psychoeducation includes information about the physiology of the bodily symptoms of anxiety reactions and the rationale of available treatment possibilities. Many patients may require formal psychological treatment interventions, which are mostly done on an outpatient basis. The treatment of anxiety disorders by CBT is described in more detail in the article by Borza in this issue of Dialogues in Clinical Neuroscience p The efficacy of CBT for all anxiety disorders has been shown in a large number of controlled studies. If avoidance of feared situations is a relevant factor in phobic disorders, exposure techniques should be included in the treatment schedule, in which patients are confronted with their feared situations.
In comparison with CBT the evidence for psychodynamic therapy is weaker. For specific phobias, there are only studies with behavioral therapy, which should be performed as exposure treatment. In the available treatment studies, it was shown that only a few sessions eg, one to five were necessary for effective treatment of specific phobias.
In recent years, many studies have investigated psychological therapies that are performed via the Internet, usually involving minimal or no contact with a therapist. However, at present, evidence is lacking that these treatments are as effective as individual CBT with face-to-face contact. They are also less expensive than face-to-face psychotherapies.
Both psychotherapy and pharmacotherapy have been shown to be more effective than control groups. Therefore, our research group conducted a large meta-analysis of all available controlled short-term studies for anxiety disorders and compared the pre-post effect size differences before and after treatment between medications and psychotherapies.
It was also found that patients included in psychotherapy studies were less severely ill than those recruited for medication trials. Moreover, it was shown that the average pre-post effect sizes for pill placebos were of similar strength to the gains achieved with psychotherapies. This surprising finding cannot be explained by heterogeneity, publication bias, or by allegiance effects. However, this does not mean that psychotherapy is not helpful, as the average effect size obtained with psychotherapies is still strong—it only means that a placebo pill is a very powerful treatment, at least for the first weeks or months of treatment.
Nevertheless, patients should be informed about the relative efficacy of the treatment options they are offered. However, only a few combination studies were available for this comparison, and some of these have not been conducted with the most powerful drugs. Exercise eg, aerobic training, such as jogging 5 km three times a week has been studied in PDA. However, it was found that exercise was less effective than clomipramine and no more effective than a control condition, relaxation.
Hypnosis, autogenic training, and biofeedback or complementary medicine methods such as acupuncture, osteopathy, or homeopathy are often recommended for the treatment of clinical anxiety. However, controlled studies fulfilling at least basic methodological standards are lacking. Although controlled studies on the usefulness of self-help groups are lacking, patients should be encouraged to participate if appropriate. GAD and other anxiety disorders are the most prevalent mental disorders. A large amount of data available from randomized controlled trials permits the formulation of robust evidence-based recommendations for the treatment of GAD, PDA, and SAD.
In the past 3 years, B. Bandelow has served as a paid consultant to Lundbeck, Mundipharma, and Pfizer. He has received honoraria for lectures at scientific meetings and continuing medical education events from Lundbeck, Pfizer, and Servier and honoraria for scientific articles from Servier. National Center for Biotechnology Information , U. Journal List Dialogues Clin Neurosci v. Dialogues Clin Neurosci. Author information Copyright and License information Disclaimer. All rights reserved. This article has been cited by other articles in PMC.
Keywords: drug treatment , generalized anxiety disorder , panic disorder , psychotherapy , social anxiety disorder , treatment. Introduction Anxiety disorders are the most prevalent psychiatric disorders and are associated with a high burden of illness. Diagnosis A short description of the anxiety disorders is given in Table I.
Adapted from reference World Health Organization. Geneva, Switzerland: World Health Organization; Panic attacks can arise out of the blue; however, many patients start to avoid situations in which they fear that panic attacks might occur. Agoraphobia F Fear of being alone is also common. Generalized anxiety disorder F Social Phobia F They are afraid of appearing clumsy, embarrassing themselves, or being judged negatively. Specific Isolated Phobias F Mixed Anxiety and Depressive Disorder F However, neither component is sufficiently severe to justify a diagnosis of anxiety or depression in itself.
If the diagnostic criteria for anxiety or depression or both are fulfilled, then the corresponding diagnosis should be made, rather than mixed anxiety and depressive disorder. Separation Anxiety Disorder of Childhood F In ICD, the disorder can only be diagnosed in children. Selective Mutism F Open in a separate window. Treatment Box 1 contains a case vignette of the treatment of a patient with GAD.
Box 1. Case vignette: generalized anxiety disorder. Pharmacotherapy Whereas many studies have shown the efficacy of medications for GAD, PDA, and SAD, there are very few studies on drug treatment for specific phobias, for example, there is a small study suggesting the efficacy of paroxetine. Pharmacological treatment recommendations for anxiety disorders in adults. Not all drugs are licensed for these indications in all countries. Stepwise plan for drug treatment if the initial standard drug treatment was ineffective or was poorly tolerated. World Federation of Societies of Biological Psychiatry WFSBP guidelines for the pharmacological treatment of anxiety, obsessive-compulsive and post-traumatic stress disorders - first revision.
World J Biol Psychiatry. GAD - Ziprasidone SAD - Levetiracetam, topiramate, tranylcypromine; in refractory cases, addition of buspirone to an SSRI Switch to a drug or drug combination that has been reported to be effective in case reports PDA - The addition of lithium to clomipramine and the combination of valproate and clonazepam have been reported to be effective in refractory cases GAD, generalized anxiety disorder; PDA, panic disorder with agoraphobia; RCT, randomized controlled trial; SAD, social anxiety disorder also known as social phobia ; SNRI, selective serotonin norepinephrine reuptake inhibitors; SSRI, selective serotonin reuptake inhibitors; TCA, tricyclic antidepressant.
Tricyclic antidepressants The traditional tricyclic antidepressants TCAs imipramine and clomipramine are as effective as second-generation antidepressants in the treatment of anxiety disorders.
Treatment of anxiety disorders
Buspirone Buspirone, a 5-hydroxytryptamine receptor 1A 5HT 1A agonist, has been shown in some controlled studies to be effective in the treatment of GAD. Benzodiazepines The anxiolytic effects of benzodiazepines begin soon after oral or parenteral application. Moclobemide Moclobemide is a selective and reversible inhibitor of monoamine oxidase A.
Other drugs Some other drugs have shown efficacy in anxiety disorders in randomized controlled studies but are not licensed for the treatment of these disorders in most countries. Agomelatine The antidepressant agomelatine—which acts as an agonist for melatonin MT 1 and MT 2 receptors and as an antagonist for serotonin 5-HT 2C receptors—was shown to be effective in four studies in GAD. Quetiapine The atypical antipsychotic quetiapine was shown to be effective in a number of studies in GAD.
Vortioxetine A new antidepressant, vortioxetine, was investigated in several controlled studies in GAD. Relative efficacy of drugs In a meta-analysis of all available drug studies in anxiety disorders, 77 the pre -post effect sizes of the different drugs were determined. General treatment principles Patients must be informed about possible adverse effects, interactions, safety warnings, and contraindications, as indicated in the current summary of product characteristics.
Drug-drug interactions When treating anxiety disorders with medications, drug interactions have to be monitored. Unresponsiveness to standard treatments Before considering a patient to be treatment unresponsive, it should be ascertained that the diagnosis was correct, adherence to the treatment plan was sufficient, the dose prescribed had covered the full range, and there had been a trial period of adequate duration. Pregnancy and breastfeeding For pregnant women, the risk of an untreated anxiety disorder must be weighed against the risk of damage to the unborn child as a result of treatment.
Psychotherapy All patients with anxiety disorders require supportive talks and attention to the emotional problems that are associated with the anxiety disorder. Combining psychotherapy and medication Both psychotherapy and pharmacotherapy have been shown to be more effective than control groups. Other treatment options Exercise eg, aerobic training, such as jogging 5 km three times a week has been studied in PDA.
Conclusions GAD and other anxiety disorders are the most prevalent mental disorders. Acknowledgments In the past 3 years, B. Kessler RC. Twelve-month and lifetime prevalence and lifetime morbid risk of anxiety and mood disorders in the United States.
Int J Methods Psychiatr Res. Wittchen HU. Eur Neuropsychopharmacol. Chisholm D. Lancet Psychiatry. Jacobi F. Results from the National Comorbidity Survey. Arch Gen Psychiatry. N Engl J Med. Bandelow B. Epidemiology of anxiety disorders in the 21st century. Angst J. The generalized anxiety spectrum: prevalence, onset, course and outcome.
Eur Arch Psychiatry Clin Neurosci. Epidemiology of depression and anxiety.
- Clinical Trials.
- Clinical Trials | Anxiety and Depression Association of America, ADAA.
- Experimental Medication For the Treatment of Generalized Anxiety Disorder.
- Depression | Anxiety and Depression Association of America, ADAA.
Handbook on Depression and Anxiety. A handful of journalists and bloggers who had followed the trial soon waded in, some more carefully than others.
These comments included numerous remarks from about 10 to 12 people identifying themselves as patients in the trial. Somewhere from seven to nine commenters said the treatment had worked for them or their spouses; several called it lifesaving. Others drew on mischaracterized or mistaken reads of the sparse data to paint the trial as a massive failure.
Speculation filled the data void. Mayberg, reading such coverage and comments and hearing of rumors flying around among colleagues, was appalled. Jude stayed mum. Before long, colleagues at conferences were offering Mayberg condolences. Others said similar things. Mayberg began to worry her entire research program was endangered. The patients got better. As expected, it failed to help many.
In the first year, 10 of the 90 patients left the study and four had their devices removed , for reasons ranging from worsening depression to a suicide attempt. Also as expected for a surgical intervention in so depressed a population, some experienced side effects and complications of the sort mentioned by commenters on the Neurocritic post.
Overall, at least nine people reported increased depression, six got infections, and several more suffered side effects such as headaches or postoperative discomfort or pain, either at one of the surgery sites or from a condition called bowstringing, in which the battery leads running under the skin between chest and skull bond with tissue and create pulling sensations.
Three patients grew more anxious. One considered suicide. One tried it and lived. Two tried it and died. Perhaps the best known of those with complaints was Steve Ogburn, an architect who was implanted at Stanford in late November and soon experienced complications. None of these, he says, were relieved when Stanford removed the implants, wiring, and battery in December Lisa Wick, an elementary-school teacher from Minnesota, also suffered complications, but hers developed seven years after what had otherwise been a successful implant.
When she was first implanted, in , Wick had been badly depressed for years despite psychotherapy, several antidepressant regimes, and multiple rounds of electroconvulsive therapy. It was like that part in The Wizard of Oz where it goes from black-and-white to color. I felt better right away. They give a taste of how various, variegated, and rich these cases can be, how fickle is fate—and biology.
They speak to the tremendous stakes involved in aiming a treatment so intrusive at an affliction so crushing. And under those terms, each story represents but one point of data among 90; Wick and Ogburn were dots near the opposite ends of a spectrum. But what about the treatment? In the months and years after the halt, as data accrued from patients who continued with the treatment, it became clear that more and more of them were moving toward and past the 40 percent improvement threshold; some were even in remission. Most of the researchers had access to reports about the data as it accrued.
But the first presentation of results—a presentation sharply constrained by journal guidelines, St. The paper, finally published in The Lancet Psychiatry , presented patient data through 24 months of activation. When tracked for two years instead of the six months used for the futility analysis, the percentage of active-treatment patients whose depression scores dropped by at least 40 percent more than doubled, to 50 percent of all those in the original active group.
The remission rate also rose, from 10 percent at six months to 31 percent at 24 months. Also encouraging was the response of patients in the control group when their implants were activated after six months, for they continued to roughly match that of the group whose implants had been active from the start.
Jude nor Abbott has published the individual-patient data. The two-year results for these intensely sick people—half reaching the 40 percent improvement threshold, almost a third in remission—stand sharply at odds with the six-month scores. One is why the trial failed even though the patients got better. The simpler question first: Why did the trial fail even though the patients markedly improved?
A study of her first cohort of patients, operated on in Toronto, found the percentage who markedly improved—that is, cut their depression scores by at least 40 percent—was A study of another 17 open-label patients Mayberg treated at Emory found improvement in 41 percent of patients at six months, which rose to 92 percent at two years; remission rose from 18 percent at six months to 58 percent at two years. Betting the entire Broaden trial on favorable six-month results proved far riskier than anticipated.
So why just six months? A shorter stretch would also save St.
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Jude a lot of money if the trial did need to be stopped. It also meant losing the control group from any analysis beyond six months, making it difficult to assess later progress objectively. One possible contributor is bias. Researcher bias, which can take many forms, is a potential force in any study. As is standard practice, the depression scoring was done by researchers with no ties to her or her lab. Yet Mayberg is a warm, confident, highly engaged clinician, and the bonds she builds with her patients doubtless give many of them more confidence and faith in the procedure.
As some observers have noted, Mayberg had two conflicts of interest that could bias her work: licensing and consulting fees from St. Jude, and part ownership of a patent on the procedure that could generate income should it get approved. During the trial, she and Andres Lozano, the Toronto neurosurgeon who shares the patent with her, received fees from Abbott for a license to use the procedure in the trial. But it is modest next to the shiny-new-Lexus-level fees common in clinical-trial consulting agreements, and it falls far short of what Mayberg could likely demand and receive.
A more obvious difference was that the open-label work had no control groups and the Broaden trial did. As every Broaden patient was told beforehand, one in three of them would start the trial with a device that would be inactive for the first six months. Possibly this knowledge created a sort of bias within them—a reduced confidence and thus response—in both the placebo and the active groups. The factors above may well have contributed to the different responses in the trial and the open-label work.
Even as the Broaden trial was running, Mayberg continued her research, implanting new patients and, in an effort to get ever better results, refining the way she was using DBS. This meant that her work increasingly diverged from the Broaden study in significant ways. She selected patients differently. She sited and managed the electrodes differently. She supported the patients differently. In a sense, that was the point: She wanted to improve on the early protocol on which Broaden was largely based.
The trial and the open-label work differed in how they chose patients. This longer run may have contributed to their reduced response. And while Broaden filtered out people with anxiety or personality disorders as did Mayberg , it did not exclude or prioritize any depressive subtypes. Mayberg now selects for such patients; the Broaden study neither sought nor avoided them.
Another difference was that the Broaden study sited the electrodes by a method that Mayberg happened to abandon as the Broaden study began. That is, they used conventional MRI scans to place the electrodes in a particular spot within the well-defined brain area, visible in any scan, called area B roaden targeted its placements likewise.
Yet even as Broaden launched, Mayberg began using a newer, more detailed imaging tool, diffusion tensor imaging DTI , that could reveal not just distinct brain areas but the white-matter bundles, called tracts, that carry neural traffic from one area to another.
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This DTI work showed that patients responded best if the electrodes sat at particular junctions of white-matter tracts within or next to area Finally, Mayberg has long offered her patients comprehensive, personally tailored programs of psychiatric and social-service support to help them rebuild their lives. The Broaden trial offered only postsurgical support, and to prevent statistical confounds it expressly ruled out the addition of any psycho- or drug therapy not underway before the trial. This successfully isolated the surgical intervention statistically—but likely reduced the chance of recovery.
Running a clinical trial, of course, all but requires that we strip an experimental therapeutic program down to its most basic, reproducible, and scalable parts. But it would be foolish to take the results of that necessarily reductive exercise as a final verdict on all possible versions of the treatment. A trial of aspirin for headache, for instance, could fail if the patients had migraines, took doses too small, or were assessed for effect after five minutes instead of five hours.
Mayberg devised her treatment to test her hypothesis, developed after years of scanning work, that area 25 is a crucial node and thus a possible treatment target in a neural network critical to depression. The encompassing hypothesis—that such networks play a crucial role in at least some mental-health disorders—suggests that other nodes, treated either alone or in combination with area 25, might also be good targets. Neither of these hypotheses comes close to being proven wrong or right by the Broaden trial, any more than a failed aspirin trial would disprove the notion that a headache is at least partly a neurochemical event.
Maureen Meade, a critical-care specialist and researcher in clinical-trial and research methods, put the case against stopping trials for futility in