Donald Franklin Klein

NYU Langone Medical Center | NYUMC · Department of Child and Adolescent Psychiatry

Part of Review of Martin Katz to be entered into INHN publication

This Viewpoint opposes adoption of the Research Domain Criteria (RDoC) initiative to replace categorical with dimensional diagnoses.Do we need to replace categorical with dimensional diagnoses to make progress in psychiatry research? No.The release of Research Domain Criteria (RDoC), which occurred coincident with publication of the DSM-5, has been...

The American Psychiatric Association's Diagnostic and Statistical Manual is primarily a diagnostic manual for practitioners. It describes syndromes, domains, and symptoms. The threshold for including objective findings should depend on practical value related to differential diagnosis and most importantly therapeutic relevance. Our suggestion for t...

A knowledgeable, experienced group of experts, willing to disagree, discuss the rationale and practice of monoamine oxidase inhibitor (MAOI) therapy. The goal is to provide a discussion pertinent to clinical practice. The moderator offered participation to researchers and clinicians highly experienced in MAOI therapy. Before the colloquy, all parti...

This article reviews the history of monoamine oxidase inhibitors (MAOIs) from their initial synthesis in the early 1900s until the present. The recognition of their potential psychiatric benefits came when the only available effective treatment for depressed patients was seizure therapy. The introduction of medications to treat depressive illness h...

In 17 healthy young men who had a parent with documented early coronary disease, ratings of type A behaviour correlated with upregulated lymphocyte Beta2 receptor density and inversely with the ratio of platelet Alpha1 to lymphocyte Beta2 receptor density ratio. This indicates a correlation of type A behaviour with receptor based determinations of...

Between 1950 and 1969, on a serendipitous basis, psychiatric drug development flourished. However, there has been a steep decline in the development of new medication classes. Instead of new molecular entities, slight molecular modifications producing "me-too" drugs attempted to garner market share. With failing profitability, industry is now withd...

Clinical trials testing the effectiveness of interventions for addictions, HIV transmission risk, and other behavioral health problems are important to advancing evidence-based treatment. Such trials are expensive and time-consuming to conduct, but the underlying effect sizes tend to be modest, and often findings are disappointing, failing to show...

The false-suffocation hypothesis of panic disorder (Klein, 1993) suggested δ-opioid receptors as a possible source of the respiratory dysfunction manifested in panic attacks occurring in panic disorder (Preter and Klein, 2008). This study sought to determine if a lack of δ-opioid receptors in a mouse model affects respiratory response to elevated C...

Resting-state functional magnetic resonance imaging (fMRI) has provided a novel approach for examining interhemispheric interaction, demonstrating a high degree of functional connectivity between homotopic regions in opposite hemispheres. However, heterotopic resting-state functional connectivity (RSFC) remains relatively uncharacterized. In the pr...

Introduction Panic disorder (PD) is a common and debilitating anxiety disorder, with lifetime prevalence ranging from 1.3% (with agoraphobia) to 4.7% (without agoraphobia). Women are affected more often than men (Kessler et al. 2006). Importantly, many epidemiologic estimates of agoraphobia without panic disorder significantly overestimate prevalen...

Melancholia, a syndrome with a long history and distinctly specific psychopathological features, is inadequately differentiated from major depression by the DSM-IV specifier. It is neglected in clinical assessment (e.g., in STAR*D [1]) and treatment selection (e.g., in the Texas Medication Algorithm Project [2]). Nevertheless, it possesses a distin...

The expanded suffocation false alarm theory (SFA) hypothesizes that dysfunction in endogenous opioidergic regulation increases sensitivity to CO2, separation distress and panic attacks. In panic disorder (PD) patients, both spontaneous clinical panics and lactate-induced panics markedly increase tidal volume (TV), whereas normals have a lesser effe...

Similar patterns of vulnerability to carbon dioxide (CO(2)) inhalation have been reported in adults with panic disorder (PD) and children with separation anxiety disorder (SAD), suggesting a link between the adult and child conditions. This study examines the influence of familial risk for PD on CO(2) responses in children with SAD. We hypothesized...

Functional connectivity analyses of resting-state fMRI data are rapidly emerging as highly efficient and powerful tools for in vivo mapping of functional networks in the brain, referred to as intrinsic connectivity networks (ICNs). Despite a burgeoning literature, researchers continue to struggle with the challenge of defining computationally effic...

Administration to rats of mood stabilizers approved for bipolar disorder (BD) downregulates markers of the brain arachidonic acid (AA, 20:4n-6) metabolic cascade, including phospholipase A(2) (PLA(2)) and cyclooxygenase (COX) expression. We hypothesized that other agents that target the brain AA cascade, nonsteroidal anti-inflammatory drugs (NSAIDs...

Atypical features were incorporated into the American Psychiatric Association's Diagnostic and Statistical Manual, Fourth Edition (DSM-IV, 1994) as an illness specifier for major depression and dysthymia. The validity of depression with atypical features was supported by differences relative to depression with melancholic features in syndromal symp...

The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study was funded by the National Institute of Mental Health to compare the effectiveness of drugs for schizophrenia. The focus here is not on its conclusions but on the knotty issues of design and methods, in order to support appropriate clinical interpretation of the conclusio...

The Social Responsiveness Scale-Adult Version (SRS-A) measures autistic traits that are continuously distributed in the general population. Based on increased recognition of the dimensional nature of autistic traits, the authors examined the neural correlates of these traits in neurotypical individuals using the SRS-A and established a novel approa...

The human brain is a complex dynamic system capable of generating a multitude of oscillatory waves in support of brain function. Using fMRI, we examined the amplitude of spontaneous low-frequency oscillations (LFO) observed in the human resting brain and the test-retest reliability of relevant amplitude measures. We confirmed prior reports that gra...

Functional connectivity (FC) analyses of resting-state fMRI data allow for the mapping of large-scale functional networks, and provide a novel means of examining the impact of dopaminergic challenge. Here, using a double-blind, placebo-controlled design, we examined the effect of L-dopa, a dopamine precursor, on striatal resting-state FC in 19 heal...

In summary, the journal editors' effort to restore faith in science by financial disclosure has been inadequate to the task. The editors could improve matters by demanding access to the raw data supporting claims for product safety and effectiveness. The recent emphasis on a detailed clinical trials registry anteceding the trial is clearly a breakt...

Increased intra-subject response time standard deviations (RT-SD) discriminate children with attention-deficit/hyperactivity disorder (ADHD) from healthy control subjects. The RT-SD is averaged over time; thus it does not provide information about the temporal structure of RT variability. We previously hypothesized that such increased variability m...

This review paper presents an amplification of the suffocation false alarm theory (SFA) of spontaneous panic [Klein DF (1993). False suffocation alarms, spontaneous panics, and related conditions. An integrative hypothesis. Arch Gen Psychiatry; 50:306-17.]. SFA postulates the existence of an evolved physiologic suffocation alarm system that monitor...

In this report, which is an update of a guideline published in 2002 (Bandelow et al. 2002, World J Biol Psychiatry 3:171), recommendations for the pharmacological treatment of anxiety disorder, obsessive-compulsive disorder (OCD) and post-traumatic stress disorder (PTSD) are presented. Since the publication of the first version of this guideline, a...

The paper here presented was motivated by a case study involving high-dimensional and high-frequency tidal volume traces measured during induced panic attacks. The focus was to develop a procedure to determine the significance of whether a mean curve dominates another one. The key idea of the suggested method relies on preserving the order in mean...

Patients present unique combinations of familial relationships, developmental idiosyncrasies, social aberrations, affective states, cognitive abilities, symptoms, defects, and maladaptations. Psychopharmacological treatments form a useful approach to cutting through this complexity to the core pathophysiology. Focusing on disorders that can be brou...

Public concern about serious toxicities from marketed drugs approved by the US Food and Drug Administration (FDA) has led to suspicion of both the pharmaceutical industry and the FDA.1 This has caused the FDA to issue severe, black-box warnings about antidepressant use; however, this action may have been taken based on inadequate grounds.2The centr...

The authors summarize two special sessions focused on the teaching of psychopharmacology at the 2003 and 2004 annual meeting of the American College of Neuropsychopharmacology (ACNP). The focus was on whether "improving the teaching-learning process" in psychiatric residency programs could improve clinical practice. Problems of strategies and pedag...

The Diagnostic and Statistical Manual, Fourth Edition (DSM-IV, 1994) included atypical features as an illness specifier for major depression and dysthymia. We asked whether subsequent literature supported its validity and addressed the relationship between depression with atypical features and melancholia. Literature review focusing on studies addr...

This study investigates whether naloxone, an opioid receptor antagonist, could render normal controls, normally nonresponsive to panic inducing stimuli, sensitive to the physiological and behavioral effects of sodium lactate, a robust panicogen in panic disorder patients. Twelve normal controls received intravenous naloxone followed by sodium lacta...

Because this piece does not have an abstract, we have provided for your benefit the first 3 sentences of the full text. The U.S. Food and Drug Administration (FDA) black box warning that antidepressants increase the risk of suicidal thinking and behavior in children was followed by a sharp fall in antidepressant prescriptions. No procedure for esti...

Panic disorder (PD) is a common illness with a definite but "complex" genetic contribution and estimated heritability of 30-46%. We report a genome scan in 120 multiplex PD pedigrees consisting of 1591 individuals of whom 992 were genotyped with 371 markers at an average spacing of 9cM. Parametric two-point, multipoint, and nonparametric analyses w...

Luborsky et al. present meta-meta-analytic analyses of studies contrasting established treatments. Once again, an allegiance effect is found, although methodological problems abound. Allegiance effects may be detected because of clinically insignificant treatment effects.

The FDA (February 3, 2005) issued a black box warning that all antidepressants increase the risk of suicidal thinking and behavior in children and adolescents that must be cited in all advertising as well as included in the package insert. Following this, there was a sharp decrease in antidepressant prescriptions for children with uncertain public...

Neuropsychopharmacology, the official publication of the American College of Neuropsychopharmacology, publishing the highest quality original research and advancing our understanding of the brain and behavior.

The aim of this study was to use data from a family study of anxiety disorders to examine the familial association between alcohol use disorders and panic disorder (PD), controlling for alcohol use disorders in the proband. Data from a family study of anxiety disorders were used to compare rates of alcohol use disorders in the relatives of 3 proban...

This effectiveness study assessed remission rates in patients who had the opportunity to receive up to 3 antidepressant trials if unresponsive. One hundred seventy-one consecutive outpatients entered 1 of 3 studies for the treatment of major depressive disorder (DSM-IV criteria) from January 1999 through December 2001. This group primarily received...

Objective: This effectiveness study assessed remission rates in patients who had the opportunity to receive up to 3 antidepressant trials if unresponsive. Method: One hundred seventy-one consecutive outpatients entered I of 3 studies for the treatment of major depressive disorder (DSM-IV criteria) from January 1999 through December 2001. This group...

The idea of using randomized trials across matched sites for the evaluation of educational practices should meet with a sympathetic audience in academic psychopharmacologists. However, it might be thought too novel to bear fruit. Fortunately, the remarkable book “Evidence Matters: Randomized Trials in Education Research,” edited by Fredrick Mostell...

Treatment outcome and brain laterality differ between early onset (<20 years) chronically (no well-being >2 months) depressed patients with atypical features (early/chronic atypical) and those with either later onset or less chronic illness (late/nonchronic atypical). Because hypothalamic-pituitary-adrenal (HPA) axis abnormalities have been hypothe...

In her article “Volatile chemistry: children and antidepressants” (News Focus, 23 July, p. [468][1]), J. Couzin writes about the complex situation regarding the use of selective serotonin reuptake inhibitors (SSRIs) in children, including the possible initiation of suicidal acts by SSRIs,

Clinical and animal studies suggest a role for pathways regulated by cyclic-AMP in anxiety. Mouse gene deletion studies, our own linkage findings on chromosome 10, and a recently published genetic association study by Domschke et al. [2003: Am J Med Genet 117B:70-78] suggest that the cAMP responsive element modulator (CREM) may be involved in panic...

Data from clinical and behavioral pharmacological studies have implicated adenosine in anxiety behaviors, while genetic studies have suggested that adenosine receptors may be associated with panic disorder. We have undertaken an analysis of several DNA sequence variations in the adenosine 2A receptor (ADORA2A) in a large sample of panic disorder pe...

Psychiatric syndromal nosology is defined in terms of prototypical symptoms and course. Diagnosis does not depend on knowledge of etiology, pathophysiology or objective tests. Of what use is such a nosology? As formulated by Sydenham, and demonstrated by Kraepelin, certain concatenations of signs and symptoms afford improved prognostic ability. Thi...

To examine whether "outer-directed irritability," a mood construct from the adult literature, characterizes a subgroup of disruptive behavior disordered children and adolescents previously shown to improve on divalproex, a mood stabilizer. A sample (N = 20) of disruptive youth (aged 10-18 years) entering a divalproex treatment study of temper and i...

The study examined a large data set to determine whether patients' sex affected the outcome of antidepressant treatment. Data for 1,746 patients aged 18-65 years who had been treated with tricyclic antidepressants, monoamine oxidase inhibitors (MAOIs), fluoxetine, or placebo were examined in a retrospective analysis to determine whether men and wom...

Although reports of childhood status are necessary for making a diagnosis of adult attention deficit hyperactivity disorder (ADHD), systematic investigation of the accuracy of retrospective self-reports has been limited. This study examined accuracy of adult recall of childhood ADHD. Participants were from a controlled, prospective 16-year follow-u...

One reason for failure to find specific treatment effects in drug versus placebo trials with patients who have depression is an insufficient period of observation. Also, differentiating between early fleeting response and maintained response has been shown relevant to detecting specific drug action. A model in which various types of drug and placeb...

To test the hypotheses that rates of atopic disorders are elevated in offspring of parents with panic disorder (PD) and in children with separation anxiety disorder (SAD). Rates of atopic disorders were assessed in 343 offspring (aged 6-17 years) of parents with PD, nonpanic psychiatric disorders, and no psychiatric disorder. Lifetime history of at...

"Anxiety" is a key term for behavioral, psychoanalytic, neuroendocrine, and psychopharmacological observations and theories. Commenting on its historical aspects is difficult, since history is properly a study of primary data. Unfortunately, much clinical anecdote does not correspond to factual records of a long time ago. Even reports of objective...

The biological literature in the anxiety disorders has focused on comparisons between patient groups and normal volunteers, with relatively little comparative study of the anxiety disorders. We therefore conducted this pilot study to compare a group of patients with post-traumatic stress disorder (PTSD) (n = 7) to a contiguously studied panic disor...

Specifying exact selection pressures for identifying adaptations is unnecessary. Novel behaviors are not spandrels since they can only develop because of prior functions. An adaptationist approach has a high prior probability, whereas spandrel hypotheses attempt to prove a negative. The concept of maladaptive spandrel is criticized. The utility of...

One reason for failure to find specific treatment effects in drug versus placebo trials with patients who have depression is an insufficient period of observation. Also, differentiating between early fleeting response and maintained response has been shown relevant to detecting specific drug action. A model in which various types of drug and placeb...

A well-characterized single nucleotide polymorphism (472G/A-Val/Met-SNP8) in the coding sequence of the catechol-O-methyltransferase (COMT) gene leads to a three- to fourfold difference in enzymatic activity and clinical and animal studies suggest a role in anxiety states like panic disorder. Subjects from 70 panic disorder pedigrees, and 83 "triad...

The major purpose of this American Society of Clinical Psychopharmacology-sponsored meeting was to identify strategies for more efficiently detecting clinical drug effects, thus reducing the economic and scientific risks of investigating new chemical entities in psychiatric disorders. The meeting consisted of presentations and discussions by expert...

Luborsky et al. present meta-meta-analytic analyses of studies contrasting established treatments. Once again, an allegiance effect is found, although methodological problems abound. Allegiance effects may be detected because of clinically insignificant treatment effects.

We investigated whether parental anxiety was related to anxiety sensitivity (AS) in offspring. Subjects were 261 offspring (aged 6-17 years) of parents with lifetime DSM-IV anxiety and/or mood disorders, and 79 offspring of parents with no lifetime anxiety, mood, or psychotic disorder. Parents and offspring were interviewed by blind clinicians. Chi...

Comments on the G. J. Meyer et al (see record 2001-00159-003) summary of evidence and issues associated with psychological assessment. H. N. Garb et al conclude that Meyer et al did not establish that psychological test validity is comparable to medical test validity. By focusing on meta-analyses, they ignored results for most medical tests and psy...

Several epidemiological studies have demonstrated a higher prevalence of panic disorder in women than in men. This study explored whether the prevalence of specific panic symptoms differs by gender. National Comorbidity Survey data from 609 respondents who met DSM-III-R criteria for panic disorder or panic attacks were analyzed to test for gender d...

Using a high throughput method for genotyping SNPs based on a single base extension reaction, we have employed a family-based design to investigate the role of the genes for Neuropeptide Y (NPY) and the Y1 Neuropeptide Y receptor (NPY1R) in the development of panic disorder. We have genotyped 613 individuals in 70 pedigrees, as well as 83 triads. S...

There is now more information to assimilate in clinical psychopharmacology and newer ways to acquire this information. Educational materials should be designed for and targeted to meet the diverse needs of such groups as medical students, psychiatry residents, clinical practitioners, industry and federal scientists, and clinical research organisati...

Growing animal data implicate cholecystokinin in the regulation of anxiety, while human clinical research confirms the role of cholecystokinin in the provocation of panic attacks. Antipanic medications suppress the ability of cholecystokinin to induce panic attacks, and may alter the expression of the cholecystokinin gene. Thus, there is increased...

The behavioral response to CO(2) inhalation has been used to differentiate panic disorder patients from normal subjects and other clinical populations. This study extended examination of the diagnostic specificity of CO(2)-induced anxiety by testing panic disorder patients and clinical populations with reported low and high sensitivity to CO(2) inh...

Through electronic mail, we surveyed members of an internet support group for emetophobia (fear of vomiting). Respondents were 50 women and 6 men with a mean age of 31 years. Results suggest that, for this sample, emetophobia is a disorder of early onset and chronic course, with highly persistent and intrusive symptoms. Emetophobia is implicated in...

Disordered breathing may play an important role in the pathophysiology of panic disorder. Several studies have now indicated that panic disorder patients have greater respiratory variability than normal controls. In this study, we examine baseline respiratory measures in four diagnostic groups to determine whether greater respiratory variability is...