OBJETIVO: Os autores examinaram a freqüência de eventos vitais significativos (estressores) durante o ano que antecedeu o transtorno do pânico e sua relação com história de ansiedade na infância, história familiar de ansiedade, comorbidades e curso da doença. MATERIAIS E MÉTODOS: 223 pacientes foram acompanhados em um estudo naturalístico, longitudinal do transtorno do pânico. RESULTADOS: Apesar de 80% dos pacientes com transtorno do pânico referirem a presença de um fator estressor durante o ano anterior ao início da sua doença, sua freqüência é mais elevada em pacientes com história de ansiedade na infância e comorbidade com depressão na vida adulta. CONCLUSÕES: A presença de eventos vitais significativos não está associada com a presença de outros transtornos de ansiedade na vida adulta e nem com história familiar de ansiedade. Apesar de sua associação com história de ansiedade na infância e depressão, a presença de um fator estressor identificável não está associado a severidade ou ao curso do transtorno do pânico.

Panic disorder is a debilitating manifestation of anxiety characterized by frequent panic attacks and intermittent worry about the consequences and meaning of future episodes of panic. Several evidence-based treatment strategies have been identified for panic disorder, which are theorized to ameliorate symptoms by targeting cognitive-behavioral mechanisms. In this review, the following treatment components are reviewed: psychoeducation, interoceptive exposure, in vivo exposure, cognitive restructuring, relaxation training, and mindfulness strategies. The greatest amount of empirical support has been found for interoceptive exposures and cognitive restructuring, whereas relaxation techniques appear to be associated with poorer outcomes. [ Psychiatr Ann . 2021;51(5):216–220.]

Back to table of contents Previous article Next article Ask the ExpertFull AccessAnxiety Treatment With BenzodiazepinesJerrold F. Rosenbaum, M.D.Jerrold F. RosenbaumSearch for more papers by this author, M.D.Published Online:17 Jun 2021https://doi.org/10.1176/appi.focus.20200040AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail What is the role of benzodiazepines in treating anxiety today?For this issue of Focus, I am asked once again to address the issue. I get this request a lot from journal editors, colleagues, and occasionally the media. I thought my recent Commentary in the American Journal of Psychiatry (1) might have closed the book on what I have to say, but the issue keeps arising. Now the U.S. Food and Drug Administration has added new boxed warnings (2), including the known risks of “abuse, misuse, addiction, physical dependence, and withdrawal reactions” to help “improve” their safe use. Of interest, the warnings do not address the consequences of failure to prescribe these agents to those who merit them and the paucity of effective alternatives that work by the same fundamental mechanism to effectively treat disabling anxiety as rapidly, as robustly, and for many in as sustained a way—a Hobson’s choice for sure, but a choice that a well-trained physician must make for the benefit of the patient.Physicians use many treatments that have unwanted and potential risks yet may restore life and function to patients. If fear biology is analogous to the immune system to protect people from external threat, then acute and sustained anxiety is like an autoimmune disorder where the response is inappropriate, sustained, disabling, and associated with life-shortening consequences. The protective system is now punishing the person in the absence of a true biological threat. The dysregulated “protective” response becomes the biological threat itself. In a sense, the benzodiazepine is the prednisone for this autoimmune response to decrease “inflammation” and restore function, carrying with it, however, certain adverse effects and the need for a gradual taper when possible to avoid long-term consequences or withdrawal effects. Severe anxiety and chronic anxiety are not trivial but are viewed as such because many people can tolerate ordinary anxiety. Dismissing more severe forms is just another form of stigma against those who suffer psychiatric distress.After my Commentary was published, I heard from grateful but beleaguered colleagues pleased for some support to take advantage of the mechanism of action of benzodiazepines on fear circuitry (3) to treat their patients. More poignant by far, however, was hearing from patients who felt terrified after a recent change in providers. The typical letter read as follows: “I read your article in the American Journal and will be sending it to my doctor. I have suffered from severe and frequent panic attacks and agoraphobia, and after I started on X, my life was restored. I have a new PCP who insists I get off X, and I am now back to being homebound and fear that I will lose my life that I had fought so hard to regain. I had been on X for 7 years and always took what I was prescribed and had no side-effects that I was aware of.” The doctor might feel a bit better, but the patient would be devastated.If other treatments (such as antidepressants) work for a patient and there is not urgency, then other treatments and approaches could be tried before using a benzodiazepine. But the default option to prescribing a benzodiazepine for a patient with an anxiety disorder should not be “let the patient suffer because I fear I cannot manage the risks of these agents” or “someone might think less of me if I prescribe this drug.”Center for Anxiety and Traumatic Stress Disorders, Department of Psychiatry, Harvard Medical School, and Massachusetts General Hospital, Boston.Send correspondence to Dr. Rosenbaum ([email protected]).Dr. Rosenbaum is cofounder of and holds equity in Psy Therapeutics and is a scientific adviser to Odin (formerly Luminopia) and Terran Biosciences.References1 Rosenbaum JF : Benzodiazepines: a perspective . Am J Psychiatry 2020 ; 177 : 488 – 490 Crossref, Google Scholar2 FDA Requiring Boxed Warning Updated to Improve Safe Use of Benzodiazepine Drug Class. FDA Drug Safety Communication 09-23-2020. Washington, DC, US Food and Drug Administration, 2020. https://www.fda.gov/drugs/drug-safety-and-availability/fda-requiring-boxed-warning-updated-improve-safe-use-benzodiazepine-drug-class Google Scholar3 Hur J , Smith JF , DeYoung KA , et al. : Anxiety and the neurobiology of temporally uncertain threat anticipation . J Neurosci 2020, 40: 7949–7964 Crossref, Google Scholar FiguresReferencesCited byDetailsCited ByNone Volume 19Issue 2 Spring 2021Pages 211Anxiety and Stress-Related Disorders KeywordsAntianxiety AgentsBenzodiazepinesPDF download

Background: We have previously shown that subsyndromal scores on the Child Behavior Checklist (CBCL)Anxiety/Depression (Anx/Dep) scale at baseline predicted the subsequent development of Major Depressive Disorder (MDD) in youth with ADHD. The present study aimed to replicate these findings in a separate, longterm, longitudinal sample of children at high- and low- risk for depression. Methods: 219 children of parents with and without depression and/or anxiety, ages 2-25, were stratified into 3 groups: 1) children with familial risk for depression (by presence of parental MDD) plus subsyndromal scores on the CBCL-Anx/Dep scale, 2) children with familial risk for depression without subsyndromal scores, and 3) children with neither familial risk for depression nor subsyndromal scores. Subjects were reassessed at both 5 and 10 year follow-ups. Results: Children with both subsyndromal scores on the CBCL-Anx/Dep plus a familial risk for depression were at greater risk for developing MDD at the 10 year follow-up when compared with all other groups. Those with familial risk but no subsyndromal scores had an intermediate risk that was greater than the controls, who had the lowest risk. Limitations: The recruitment of the study included families with parental panic disorder, so the sample likely included more families with anxiety disorders than the general population. Conclusions: Our results showed that subsyndromal scores of the CBCL-Anx/Dep scale increased the risk for the subsequent development of MDD, particularly in children at high risk for depression. These results confirm the CBCL-Anx/Dep scale?s utility in identifying children at high risk for developing MDD.

As this special volume indicates, we have multiple modalities and approaches for thinking about anxiety and its therapeu-tics. Our treatment approaches and under-standings vary from the psychological and cognitive to the biological and pharmaco-logical.

Although lithium preparations remain first-line treatment for bipolar disorder, risk for development of renal insufficiency may discourage their use. Estimating such risk could allow more informed decisions and facilitate development of prevention strategies. We utilized electronic health records from a large New England health-care system between 2006 and 2013 to identify patients aged 18 years or older with a lithium prescription. Renal insufficiency was identified using the presence of renal failure by ICD9 code or laboratory-confirmed glomerular filtration rate below 60 ml/min. Logistic regression was used to build a predictive model in a random two-thirds of the cohort, which was tested in the remaining one-third. Risks associated with aspects of pharmacotherapy were also examined in the full cohort. We identified 1445 adult lithium-treated patients with renal insufficiency, matched by risk set sampling 1 : 3 with 4306 lithium-exposed patients without renal insufficiency. In regression models, features associated with risk included older age, female sex, history of smoking, history of hypertension, overall burden of medical comorbidity, and diagnosis of schizophrenia or schizoaffective disorder (p<0.01 for all contrasts). The model yielded an area under the ROC curve exceeding 0.81 in an independent testing set, with 74% of renal insufficiency cases among the top two risk quintiles. Use of lithium more than once daily, lithium levels greater than 0.6 mEq/l, and use of first-generation antipsychotics were independently associated with risk. These results suggest the possibility of stratifying risk for renal failure among lithium-treated patients. Once-daily lithium dosing and maintaining lower lithium levels where possible may represent strategies for reducing risk.

Behavioral inhibition (BI) is a genetically influenced behavioral profile seen in 15–20% of 2-year-old children. Children with BI are timid with people, objects and situations that are novel or unfamiliar, and are more reactive physiologically to these challenges as evidenced by higher heart rate, pupillary dilation, vocal cord tension and higher levels of cortisol. BI predisposes to the later development of anxiety, depression and substance abuse. Reduced hippocampal volumes have been observed in anxiety disorders, depression and posttraumatic stress disorder. Animal models have demonstrated that chronic stress can damage the hippocampal formation and implicated cortisol in these effects. We, therefore, hypothesized that the hippocampi of late adolescents who had been behaviorally inhibited as children would be smaller compared with those who had not been inhibited. Hippocampal volume was measured with high-resolution structural magnetic resonance imaging in 43 females and 40 males at 17 years of age who were determined to be BI+ or BI− based on behaviors observed in the laboratory as young children. BI in childhood predicted reduced hippocampal volumes in the adolescents who were offspring of parents with panic disorder, or panic disorder with comorbid major depression. We discuss genetic and environmental factors emanating from both child and parent that may explain these findings. To the best of our knowledge, this is the first study to demonstrate a relationship between the most extensively studied form of temperamentally based human trait anxiety, BI, and hippocampal structure. The reduction in hippocampal volume, as reported by us, suggests a role for the hippocampus in human trait anxiety and anxiety disorder that warrants further investigation.

Although monoaminergic antidepressants revolutionized the treatment of Major Depressive Disorder (MDD) over a half-century ago, approximately one third of depressed patients experience treatment-resistant depression (TRD). Such patients account for a disproportionately large burden of disease, as evidenced by increased disability, cost, human suffering, and suicide. This review addresses the definition, causes, evaluation, and treatment of unipolar TRD, as well as the major treatment strategies, including optimization, augmentation, combination, and switch therapies. Evidence for these options, as outlined in this review, is mainly focused on large-scale trials or meta-analyses. Finally, we briefly review emerging targets for antidepressant drug discovery and the novel effects of rapidly acting antidepressants, with a focus on ketamine.

Background: Individuals with panic disorder (PD) exhibit a hypersensitivity to inhaled carbon dioxide, possibly reflecting a lowered threshold for sensing signals of suffocation. Animal studies have shown that carbon dioxide-mediated fear behavior depends on chemosensing of acidosis in the amygdala via the acid-sensing ion channel ASIC1a. We examined whether the human ortholog of the ASIC1a gene, ACCN2, is associated with the presence of PD and with amygdala structure and function.Methods: We conducted a case-control analysis (n = 414 PD cases and 846 healthy controls) of ACCN2 single nucleotide polymorphisms and PD. We then tested whether variants showing significant association with PD are also associated with amygdala volume (n = 1048) or task-evoked reactivity to emotional stimuli (n = 103) in healthy individuals.Results: Two single nucleotide polymorphisms at the ACCN2 locus showed evidence of association with PD: rs685012 (odds ratio = 1.32, gene-wise corrected p = .011) and rs10875995 (odds ratio = 1.26, gene-wise corrected p = .046). The association appeared to be stronger when early-onset (age < 20 years) PD cases and when PD cases with prominent respiratory symptoms were compared with controls. The PD risk allele at rs10875995 was associated with increased amygdala volume (p = .035) as well as task-evoked amygdala reactivity to fearful and angry faces (p = .0048).Conclusions: Genetic variation at ACCN2 appears to be associated with PD and with amygdala phenotypes that have been linked to proneness to anxiety. These results support the possibility that modulation of acid-sensing ion channels may have therapeutic potential for PD.

The search for unique biological features of psychiatric disorders, as defined using the reliable symptom clusters of the DSM, has had a disappointing yield in terms of fundamental novel insights to etiology or treatment. Genetic studies reveal a surprising degree of overlap in the genetic variants that confer risk for ostensibly biologically distinct disorders ( 1 Smoller J.W. Craddock N. Kendler K. Lee P.H. Neale B.M. et al. Cross-Disorder Group of the Psychiatric Genomics ConsortiumIdentification of risk loci with shared effects on five major psychiatric disorders: A genome-wide analysis. Lancet. 2013; 381: 1371-1379 Abstract Full Text Full Text PDF PubMed Scopus (2178) Google Scholar ). Thus, National Institute of Mental Health leadership has promulgated the Research Domain Criteria (RDoC), a research roadmap that focuses on dimensions. Neural Antecedents of Emotional Disorders: A Functional Magnetic Resonance Imaging Study of Subsyndromal Emotional Symptoms in Adolescent GirlsBiological PsychiatryVol. 74Issue 4PreviewEmotional symptoms (ES) emerge forme fruste in adolescence, before manifesting as fully fledged emotional disorders. Studies indicate that subsyndromal ES precede the onset of emotional disorders. We hypothesized that adolescents showing subsyndromal ES will show perturbations in the emotion regulatory frontolimbic network (FLN) during emotion processing. Full-Text PDF Patterns of Neural Connectivity During an Attention Bias Task Moderate Associations Between Early Childhood Temperament and Internalizing Symptoms in Young AdulthoodBiological PsychiatryVol. 74Issue 4PreviewBiased attention to threat is found in both individuals with anxiety symptoms and children with the childhood temperament of behavioral inhibition (BI). Although perturbed fronto-amygdala function is implicated in biased attention among anxious individuals, no work has examined the neural correlates of attention biases in BI. Work in this area might clarify underlying mechanisms for anxiety in a sample at risk for internalizing disorders. We examined the relations among early childhood BI, fronto-amygdala connectivity during an attention bias task in young adulthood, and internalizing symptoms, assessed in young adulthood. Full-Text PDF

There has been increasing focus on the population known as transitional aged youth (TAY). Although variably defined, TAY typically refers to the span from older adolescence (e.g., 15–16 years of age) to young adulthood (24–26 years). TAY are navigating the potentially perilous developmental years of growing out of childhood and into adulthood—a time of facing more adult-like challenges without having yet mastered the tools and cognitive maturity of adulthood. Some critical developmental steps occur during the transitional years, reflecting changing neurobiology, the tasks of separation and individuation, and the influences of pre-existing and concurrent mental health and substance use issues. Parents with TAY sustain high burdens of care, particularly for those with very common unmet needs. Indeed, psychopathology and substance abuse are the leading cause of disability worldwide and constitute 45% of disease burden in youth 10 to 24 years of age. 1 Gore F.M. Bloem P.J. Patton G.C. et al. Global burden of disease in young people aged 10-24 years: a systematic analysis. Lancet. 2011; 377: 2093-2102 Abstract Full Text Full Text PDF PubMed Scopus (1265) Google Scholar Child and adolescent psychiatrists are increasingly asked to evaluate or provide care for youth as they emerge into initial independent living settings such as college. Thus, as a field, we must be prepared to address the major concerns and opportunities in focusing on TAY, specifically early recognition of the first signs and symptoms, identifying risk and protective factors, and early and effective intervention for psychopathology and substance abuse.

Sarris, Jerome PhD, MHSc; Nierenberg, Andrew A. MD; Schweitzer, Isaac MD; Alpert, Jonathan E. MD, PhD; Rosenbaum, Jerrold F. MD; Iovieno, Nadia MD; Covino, Jennifer MPA; Fava, Maurizio MD; Mischoulon, David MD, PhD Author Information

OBJECTIVE:The authors examined the specificity and course of psychiatric disorders from early childhood through adolescence in offspring of parents with confirmed panic disorder and major depressive disorder.METHOD:The authors examined rates of psychiatric disorders at 10-year-follow-up (mean age, 14 years) in four groups: offspring of referred parents with panic and depression (N=137), offspring of referred parents with panic without depression (N=26), offspring of referred parents with depression without panic (N=48), and offspring of nonreferred parents with neither disorder (N=80). Follow-up assessments relied on structured interviews with the adolescents and their mothers; diagnoses were rated present if endorsed by either.RESULTS:Parental panic disorder, independently of parental depression, predicted lifetime rates in offspring of multiple anxiety disorders, panic disorder, agoraphobia, social phobia, and obsessive-compulsive disorder. Parental depression independently predicted offspring bipolar, drug use, and disruptive behavior disorders. Parental panic and depression interacted to predict specific phobia and major depressive disorder. Phobias were elevated in all at-risk groups, and depression was elevated in both offspring groups of parents with depression (with or without panic disorder), with the highest rates in the offspring of parents with depression only. Parental depression independently predicted new onset of depression, parental panic disorder independently predicted new onset of social phobia, and the two interacted to predict new onset of specific phobia and generalized anxiety disorder.CONCLUSIONS:At-risk offspring continue to develop new disorders as they progress through adolescence. These results support the need to screen and monitor the offspring of adults presenting for treatment of panic disorder or major depressive disorder.

Combination drug therapy is common in psychiatry. It plays a role in the treatment of patients with multiple disorders, in the management of residual symptoms or resistant disease, and in the alleviation of unwanted effects of the primary drug. Coadministration of psychotropic drugs with medications for medical illnesses is becoming more common as well, because as many as half the patients with major depression require long term treatment, and because the number of patients who are elderly is increasing as the population ages. To safely manage multidrug regimens, the clinician must be knowledgeable about drug-drug interaction potential. Drug-drug interactions can produce a change in the pharmacological effect of a drug by altering activity at the site of action (a pharmacodynamic interaction), or by changing the plasma concentrations of a drug (a pharmacokinetic interaction), or both. Selective serotonin reuptake inhibitors (SSRIs) have the potential to impair the oxidative metabolism of several drugs, including tricyclic antidepressants and neuroleptics. However, the SSRIs highlight the maxim that overgeneralisation can be as detrimental to rational co-pharmacy as ignorance of interaction potential. The SSRIs differ in terms of which other drugs they affect, which patients are at risk, and to what extent the effect is clinically important. Clinicians must assess drug combinations on a case-by-case basis. Standard management practices of dose titration, monitoring plasma drug concentrations when the therapeutic index is narrow, and observing for adverse events minimise the clinical impact of potential drug-drug interactions.

Depression and AnxietyVolume 28, Issue 5 p. 355-357 Recollections from the ADAA President Recollections from the ADAA President Jerrold F. Rosenbaum, Corresponding Author Jerrold F. Rosenbaum JRosenbaum@partners.org Psychiatrist-in-Chief, Massachusetts General Hospital, Stanley Cobb Professor of Psychiatry, Harvard Medical School, Boston, MassachusettsPsychiatrist-in-Chief, Massachusetts General Hospital, Stanley Cobb Professor of Psychiatry, Harvard Medical School, 55 Fruit Street, Bulfinch 351, Boston, MA 02114Search for more papers by this author Jerrold F. Rosenbaum, Corresponding Author Jerrold F. Rosenbaum JRosenbaum@partners.org Psychiatrist-in-Chief, Massachusetts General Hospital, Stanley Cobb Professor of Psychiatry, Harvard Medical School, Boston, MassachusettsPsychiatrist-in-Chief, Massachusetts General Hospital, Stanley Cobb Professor of Psychiatry, Harvard Medical School, 55 Fruit Street, Bulfinch 351, Boston, MA 02114Search for more papers by this author First published: 29 March 2011 https://doi.org/10.1002/da.20813Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume28, Issue5May 2011Pages 355-357 RelatedInformation

Background. Some personality characteristics have previously been associated with an increased risk for psychiatric disorder. Longitudinal studies are required in order to tease apart temporary (state) and enduring (trait) differences in personality among individuals with bipolar disorder (BD). This study aimed to determine whether there is a characteristic personality profile in BD, and whether associations between BD and personality are best explained by state or trait effects.Method. A total of 2247 participants in the Systematic Treatment Enhancement Program for Bipolar Disorder study completed the NEO Five-Factor Inventory administered at study entry, and at 1 and 2 years.Results. Personality in BD was characterized by high neuroticism (N) and openness (O), and low agreeableness (A), conscientiousness (C) and extraversion (E). This profile was replicated in two independent samples, and openness was found to distinguish BD from major depressive disorder. Latent growth modeling demonstrated that manic symptoms were associated with increased E and decreased A, and depressed symptoms with higher N and lower E, A, C and O. During euthymic phases, high N and low E scores predicted a future depression-prone course.Conclusions. While there are clear state effects of mood on self-reported personality, personality variables during euthymia predict future course of illness. Personality disturbances in extraversion, neuroticism and openness may be enduring characteristics of patients with BD.

Back to table of contents Previous article Next article CommentaryFull AccessAssuring That Double-Blind Is BlindRoy H. Perlis, M.D., M.Sc., Michael Ostacher, M.D., M.P.H., Maurizio Fava, M.D., Andrew A. Nierenberg, M.D., Gary S. Sachs, M.D., and Jerrold F. Rosenbaum, M.D.Roy H. Perlis, M.D., M.Sc., Michael Ostacher, M.D., M.P.H., Maurizio Fava, M.D., Andrew A. Nierenberg, M.D., Gary S. Sachs, M.D., and Jerrold F. Rosenbaum, M.D.Published Online:1 Mar 2010https://doi.org/10.1176/appi.ajp.2009.09060820AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail The gold standard for evidence in psychiatry, as elsewhere in medicine, is often considered to be the randomized, placebo-controlled, double-blind study. The use of blinding or masking plays a key role in these designs by addressing the problem of expectancy. First, if participants anticipate greater benefit from a particular treatment, they may be more likely to respond to it, which is considered a component of placebo response. Not surprisingly, participants have been found to report greater anticipated benefits when they were randomized to enter an active-comparator, versus a placebo-comparator, study (1). Likewise, raters may anticipate greater benefit from active drug and thus favor it in their ratings, whether consciously or unconsciously. Greater response rates in both active and placebo arms occur when a greater proportion of participants receive active treatment—that is, when patients (1) or raters (2) expect more participants to benefit.Double-blinding, typically by providing drug and placebo in identical capsules, is intended to minimize the impact of expectancy and the related concept of credibility. The blind may be compromised in a variety of ways, however, beginning with differences in medication taste or smell. Of particular concern may be the emergence of adverse effects, particularly when those adverse effects are known to be associated with a specific medication. The requirement that informed consent forms delineate common adverse effects may increase this risk (3). Indeed, when the degree of unblinding is assessed in antidepressant trials, multiple reports suggest that it is extensive: at least three-quarters of patients are typically able to correctly guess at their treatment assignment (4, 5). Moreover, even the sudden absence of adverse effects may contribute to unblinding, as might occur when a participant stabilized on a sedating medication is abruptly switched to placebo at randomization in a relapse-prevention study.If such unblinding occurs, does it meaningfully affect trial results? A meta-analysis of antidepressant trials using active placebos, such as those with antihistaminergic or anticholinergic effects, suggested smaller effect sizes than those observed in the presumably less blinded trials with inert placebo (6). Estimating the potential impact in published studies is difficult, but certain findings when results are stratified by potentially unblinding adverse effects raise concern. In a trial of quetiapine in bipolar depression (7), for example, when investigators examined only the groups reporting sedation, mean change in the Montgomery-Åsberg Depression Rating Scale total score at week 8 was –18.8 in the quetiapine groups (N=195) and –18.9 in the placebo group (N=24). Conversely, when the subset of participants without sedation were examined, the mean change in the Montgomery-Åsberg Depression Rating Scale total score was –19.3 and –11.7 in the quetiapine and placebo groups, respectively. While only a small subset of patients were in the placebo/sedation arm, the disparity in placebo response might suggest that clinical raters were attempting to "guess" at treatment assignment.Unfortunately, for psychotropic drugs, CNS side effects may be inevitable. Therefore, we call for more uniform application of standards in the design, reporting, and review of clinical trials.1. Consistent with CONSORT (8) and international guidelines (9), participants and raters should be asked to guess treatment assignment, and the degree of true and false unblinding should be reported in the primary publication of results. Statistical techniques to formally test for unblinding have been described and are readily available (10). However, while this approach may help to identify flawed trials, it does nothing to prevent them, and guesses at the end of a trial may be confounded by "true" efficacy.2. To minimize the impact of adverse effects on efficacy ratings, one rater should evaluate symptoms but not side effects, while another rater scores side effects and not symptoms.3. Where the risk of unblinding through adverse effects is substantial, the use of an "active" placebo should be considered, with adverse effects mimicking those of the active drug. This design is rarely used in modern psychotropic studies: A MEDLINE search for "active placebo" identified only one randomized controlled antidepressant trial since 2000 with this design. However, the ethical problem of deliberately inducing risk for adverse effects, even if they are benign or even potentially therapeutic, requires further study.All of these recommendations are reflected in existing guidance documents for clinical trial design and analysis, and some date back more than 25 years. If readers, reviewers, and journal editors ensure that they are applied where appropriate, confidence in the gold standard for determining clinical efficacy could be enhanced.Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, BostonAddress correspondence and reprint requests to Dr. Perlis, Bipolar Clinic and Research Program, Massachusetts General Hospital, 50 Staniford St., 5th Floor, Boston, MA 02114; [email protected]org (e-mail). Editorial accepted for publication November 2009.Dr. Fava has received research support or advisory, consulting, speaking, or publishing fees from Abbott Laboratories, Advanced Meeting Partners, Alkermes, Amarin, APA, Aspect Medical Systems, AstraZeneca, Auspex Pharmaceuticals, Bayer AG, Belvoir Publishing, Best Practice Project Management, Inc., BioMarin Pharmaceuticals, Inc., Bio Research, BrainCells, Biovail Pharmaceuticals, Boehringer-Ingelheim, BrainCells, Bristol-Myers Squibb Company, Cephalon, Clinical Trial Solutions, CNS Response, Compellis, Cypress Pharmaceuticals, Dov Pharmaceuticals, Eli Lilly, EPIX Pharmaceuticals, Euthymics Bioscience, Fabre-Kramer Pharmaceuticals, Forest Pharmaceuticals, Ganeden, GlaxoSmithKline, Grunenthal GmbH, Imedex, J&J Pharmaceuticals, Janssen Pharmaceutica, Jazz Pharmaceuticals, Knoll Pharmaceutical Company, Labopharm, Lichtwer Pharma GmbH, Lorex Pharmaceuticals, Lundbeck, MedAvante, Merck, Methylation Sciences, MGH Psychiatry Academy/Primedia, MGH Psychiatry Academy/Reed-Elsevier, NARSAD, National Center for Complementary and Alternative Medicine, National Institute on Drug Abuse, Neuronetics, NIMH, Novartis, Nutrition 21, Organon, PamLab, Pfizer, PharmaStar, Pharmavite, Precision Human Biolaboratory, PsychoGenics, Roche, Sanofi-Aventis, Sepracor, Schering-Plough, Shire, Solvay Pharmaceuticals, Somaxon, Somerset Pharmaceuticals, Synthelabo, Takeda, Tetragenex, TransForm Pharmaceuticals, Transcept Pharmaceuticals, UBC, Vanda Pharmaceuticals, and Wyeth-Ayerst; he has equity holdings in Compellis, has patent applications for "sequential parallel comparison of design" (SPCD) and for a combination of azapirones and bupropion in major depression, and receives royalties for the Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire, the Discontinuation-Emergent Signs and Symptoms scale, and SAFER. Dr. Ostacher has received research support or advisory, consulting, or speaking fees from AstraZeneca, Bristol-Myers Squibb, Concordant Rater Systems, Eli Lilly, Forest Pharmaceuticals, GlaxoSmithKline, Janssen Pharmaceutica, Pfizer, and Massachusetts General Hospital Psychiatry Academy (lectures supported through Independent Medical Education grants from AstraZeneca, Eli Lilly, and Janssen Pharmaceuticals). Dr. Perlis has received research support or advisory, consulting, or speaking fees from AstraZeneca, Bristol-Myers Squibb, Elan/Eisai, Eli Lilly, GlaxoSmithKline, Pfizer, and Proteus Biomedical, and has equity holdings and patents for Concordant Rater Systems, LLC. Dr. Sachs has received research support or advisory, consulting, or speaking fees from Abbott, AstraZeneca, Bristol-Myers Squibb, Cephalon, CNS Response, Elan Pharmaceuticals, Eli Lilly, GlaxoSmithKline, Janssen, Memory Pharmaceuticals, Merck, NIMH, Novartis, Organon, Pfizer, Repligen, Sanofi-Aventis, Shire, Sigma-Tau, Solvay, and Wyeth; his spouse is a shareholder with Concordant Rater Systems. Dr. Nierenberg has received research support or advisory or consulting fees or honoraria from American Drug Utilization Review, American Society for Clinical Psychopharmacology, APA (travel expenses), Appliance Computing Inc. (Mindsite), Baystate Medical Center, Belvoir Publishing, Brain Cells, Inc., Brandeis University, Columbia University, Eli Lilly, Hillside Hospital, IMEDEX, MBL Publishing, MJ Consulting, New York State, NIMH, Novartis, PamLabs, Pfizer Pharmaceuticals, Physicians Postgraduate Press, PGx Health, Schering-Plough, Shire, SUNY Buffalo, Targacept, Takeda Pharmaceuticals, University of Texas Southwestern Dallas, University of Wisconsin, and University of Pisa; he is a presenter for the Massachusetts General Hospital Psychiatry Academy, which has been supported through Independent Medical Education grants from Astra Zeneca, Bristol-Myers Squibb, Eli Lilly, and Janssen Pharmaceuticals; he owns stock options in Appliance Computing, Inc., and Brain Cells, Inc.; through Massachusetts General Hospital (MGH), he is named for copyrights to the Clinical Positive Affect Scale and the MGH Structured Clinical Interview for the Montgomery-Åsberg Depression Rating Scale exclusively licensed to the MGH Clinical Trials Network and Institute; also through MGH, he has a patent extension application for the combination of buspirone, bupropion, and melatonin for the treatment of depression. Dr. Rosenbaum has consulted for or is a member of scientific advisory boards for Auspex, Medavante, Neuro­netics, and Supernus, and he holds equity in Compellis and Medavante. Dr. Freedman has reviewed this editorial and found no evidence of influence from these relationships.References1 Rutherford BR , Sneed JR , Roose SP : Does study design influence outcome? the effects of placebo control and treatment duration in antidepressant trials. Psychother Psychosom 2009; 78:172–181 Crossref, Medline, Google Scholar2 Papakostas GI , Fava M : Does the probability of receiving placebo influence clinical trial outcome? a meta-regression of double-blind, randomized clinical trials in MDD. Eur Neuropsychopharmacol 2009; 19:34–40 Crossref, Medline, Google Scholar3 Brownell KD , Stunkard AJ : The double-blind in danger: untoward consequences of informed consent. 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Kellner, M.D., Dennis M. Popeo, M.D., and Amy S. Aloysi, M.D.1 September 2010 | American Journal of Psychiatry, Vol. 167, No. 9Response to Kellner et al. LetterMarc Zisselman, M.D., and Richard Jaffe, M.D.1 September 2010 | American Journal of Psychiatry, Vol. 167, No. 9Medication Guesses in Double-Blind StudiesKarl Rickels, M.D.1 September 2010 | American Journal of Psychiatry, Vol. 167, No. 9 Volume 167Issue 3 March 2010Pages 250-252 Metrics PDF download History Accepted 1 November 2009 Published online 1 March 2010 Published in print 1 March 2010