Anxiety Disorders: Klein DF

Bandelow B, Zohar J, Hollander E, Kasper S, Möller HJ, Anonymous00037, Zohar J, Hollander E, Kasper S, Möller HJ, Bandelow B, Allgulander C, Ayuso-Gutierrez J, Baldwin DS, Buenvicius R, Cassano G, Fineberg N, Gabriels L, Hindmarch I, Kaiya H, Klein DF, Lader M, Lecrubier Y, Lépine JP, Liebowitz MR, Lopez-Ibor JJ, Marazziti D, Miguel EC, Oh KS, Preter M, Rupprecht R, Sato M, Starcevic V, Stein DJ, van Ameringen M, Vega J. · Department of Psychiatry and Psychotherapy, University of Gottingen, Gottingen, Germany. · World J Biol Psychiatry. · Pubmed #18949648 No free full text.

Abstract: 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 substantial number of new randomized controlled studies of anxiolytics have been published. In particular, more relapse prevention studies are now available that show sustained efficacy of anxiolytic drugs. The recommendations, developed by the World Federation of Societies of Biological Psychiatry (WFSBP) Task Force for the Pharmacological Treatment of Anxiety, Obsessive-Compulsive and Post-traumatic Stress Disorders, a consensus panel of 30 international experts, are now based on 510 published randomized, placebo- or comparator-controlled clinical studies (RCTs) and 130 open studies and case reports. First-line treatments for these disorders are selective serotonin reuptake inhibitors (SSRIs), serotonin-noradrenaline reuptake inhibitors (SNRIs) and the calcium channel modulator pregabalin. Tricyclic antidepressants (TCAs) are equally effective for some disorders, but many are less well tolerated than the SSRIs/SNRIs. In treatment-resistant cases, benzodiazepines may be used when the patient does not have a history of substance abuse disorders. Potential treatment options for patients unresponsive to standard treatments are described in this overview. Although these guidelines focus on medications, non-pharmacological were also considered. Cognitive behavioural therapy (CBT) and other variants of behaviour therapy have been sufficiently investigated in controlled studies in patients with anxiety disorders, OCD, and PTSD to support them being recommended either alone or in combination with the above medicines.

Preter M, Klein DF. · New York State Psychiatric Institute, Columbia University College of Physicians & Surgeons, 1160 Fifth Avenue, Suite 112, New York, NY 10029, USA. · Prog Neuropsychopharmacol Biol Psychiatry. · Pubmed #17765379 links to  free full text

Abstract: 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 monitors information about potential suffocation. Panic attacks maladaptively occur when the alarm is erroneously triggered. That panic is distinct from Cannon's emergency fear response and Selye's General Alarm Syndrome is shown by the prominence of intense air hunger during these attacks. Further, panic sufferers have chronic sighing abnormalities outside of the acute attack. Another basic physiologic distinction between fear and panic is the counter-intuitive lack of hypothalamic-pituitary-adrenal (HPA) activation in panic. Understanding panic as provoked by indicators of potential suffocation, such as fluctuations in pCO(2) and brain lactate, as well as environmental circumstances fits the observed respiratory abnormalities. However, that sudden loss, bereavement and childhood separation anxiety are also antecedents of "spontaneous" panic requires an integrative explanation. Because of the opioid system's central regulatory role in both disordered breathing and separation distress, we detail the role of opioidergic dysfunction in decreasing the suffocation alarm threshold. We present results from our laboratory where the naloxone-lactate challenge in normals produces supportive evidence for the endorphinergic defect hypothesis in the form of a distress episode of specific tidal volume hyperventilation paralleling challenge-produced and clinical panic.

Klein DF. · Department of Therapeutics, New York State Psychiatric Institute, New York, NY 10032, USA. · Am J Psychiatry. · Pubmed #10910778 links to  free full text

Abstract: OBJECTIVE: The author sought to illustrate the invalidity of meta-analyses that claim to quantitatively compare the benefits of psychotherapy to pharmacotherapy in patients with psychiatric disorders. METHOD: Studies included in four meta-analyses were retrieved and their study designs evaluated. RESULTS: The meta-analyses compared effect sizes from disparate studies that were not uniformly blind, random, controlled, or of high quality. The studies did not directly address the comparative efficacy question or lacked assay sensitivity. CONCLUSIONS: Numerous types of studies exemplify the need for caution in evaluating meta-analytic conclusions without first critically examining the included studies. Estimates of the relative efficacy of different treatments are not well founded when based almost exclusively on indirect, multiply confounded comparisons. Meta-analyses based on flawed studies or studies that lack demonstrated assay sensitivity are also inadequate for the criticism of treatment guidelines. Some bodies of data are inadequate to support a proper meta-analysis.

Martinez JM, Kent JM, Coplan JD, Browne ST, Papp LA, Sullivan GM, Kleber M, Perepletchikova F, Fyer AJ, Klein DF, Gorman JM. · Department of Psychiatry, Columbia University, New York, New York 10032, USA. · Depress Anxiety. · Pubmed #11754131 No free full text.

Abstract: 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 specific to panic disorder and whether effective anti-panic treatment alters respiratory variability. Patients with panic disorder, major depression, or premenstrual dysphoric disorder, and normal control subjects underwent two respiratory exposures (5% and 7% CO(2) inhalation), while in a canopy system. Panic disorder patients returned after 12 weeks of either anti-panic medication or cognitive behavioral therapy, and were retested. Normal control subjects were also retested after a period of 12 weeks. Panic disorder patients had significantly greater respiratory variability at baseline than normal control subjects and patients with major depression. The premenstrual dysphoric patients also had greater variability than the normal control group. Panic disorder patients who panicked to 7% CO(2) inhalation had significantly greater baseline variability than panic disorder patients who did not panic. Anti-panic treatment did not significantly alter baseline respiratory variability. Our data suggest that increased respiratory variability may be an important trait feature for some panic disorder patients and may make them more vulnerable to CO(2)-induced panic.

Lipsitz JD, Mannuzza S, Klein DF, Ross DC, Fyer AJ. · New York State Psychiatric Institute, Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, USA. · Depress Anxiety. · Pubmed #10604083 No free full text.

Abstract: Twenty eight participants, initially treated for specific phobia as part of a comparative treatment study, were evaluated 10 to 16 years (X = 12 years) later. A comprehensive, in-person, semi-structured diagnostic interview was utilized, which also assessed comorbid disorders. Of 21 patients who had been rated as responders (much improved or very much improved) at treatment termination, 13 (62%) had clinically significant avoidance or endurance with dread subsequent to treatment. Among a subgroup of these responders who had been considered completely recovered (n = 11), 5 (45%) had clinically significant symptoms following treatment. None of the seven subjects who had been considered unimproved at treatment termination recovered from phobia symptoms in the intervening years. Positive response to treatment was associated with better long term outcome. Clinical characteristics, such as phobia subtype, age of onset, baseline severity, and lifetime comorbidity of other psychiatric disorders were not associated with long term outcome in this sample. Type of treatment was not associated with long term outcome. Results challenge the notion that recovery from specific phobia following treatment is characterized by complete and enduring cessation of symptoms.

Sinha SS, Coplan JD, Pine DS, Martinez JA, Klein DF, Gorman JM. · Department of Psychiatry, Columbia University College of Physicians and Surgeons and New York State Psychiatric Institute, New York 10032, USA. · Psychiatry Res. · Pubmed #10397411 No free full text.

Abstract: It has been hypothesized that spontaneous panic is distinct from anticipatory anxiety, which activates the hypothalamic-pituitary-adrenal (HPA) axis. Panic attacks characterized by prominent respiratory symptoms, such as those induced by sodium lactate, are not associated with increases in cortisol. We examined blood cortisol responses to CO2-induced panic. Cortisol levels did not increase and actually decreased significantly in 10 panicking subjects with panic disorder. No reductions were noted after 20 min of CO2 inhalation in either eight normal comparison subjects or six non-panicking panic disorder patients. These results lend support to the hypothesis that the pathophysiological mechanism underlying CO2-induced panic is different from that underlying general or anticipatory anxiety.

Coplan JD, Tamir H, Calaprice D, DeJesus M, de la Nuez M, Pine D, Papp LA, Klein DF, Gorman JM. · College of Physicians and Surgeons of Columbia University, New York State Psychiatric Institute, New York, NY, USA. · Neuropsychopharmacology. · Pubmed #10088140 links to  free full text

Abstract: The psychoneuroimmunology of panic disorder is relatively unexplored. Alterations within brain stress systems that secondarily influence the immune system have been documented. A recent report indicated elevations of serotonin (5-HT) and ganglioside antibodies in patients with primary fibromyalgia, a condition with documented associations with panic disorder. In line with our interest in dysregulated 5-HT systems in panic disorder (PD), we wished to assess if antibodies directed at the 5-HT system were elevated in patients with PD in comparison to healthy volunteers. Sixty-three patients with panic disorder and 26 healthy volunteers were diagnosed by the SCID. Employing ELISA, we measured anti-5-HT and 5-HT anti-idiotypic antibodies (which are directed at 5-HT receptors). To include all subjects in one experiment, three different batches were run during the ELISA. Plasma serotonin anti-idiotypic antibodies: there was a significant group effect [patients > controls (p = .007)] and batch effect but no interaction. The mean effect size for the three batches was .76. Following Z-score transformation of each separate batch and then combining all scores, patients demonstrated significantly elevated levels of plasma serotonin anti-idiotypic antibodies. Neither sex nor age as covariates affected the significance of the results. There was a strong correlation between anti-serotonin antibody and serotonin anti-idiotypic antibody measures. Plasma anti-serotonin antibodies: there was a significant diagnosis effect [patients > controls (p = .037)]. Mean effect size for the three batches was .52. Upon Z-score transformation, there was a diagnosis effect with antibody elevations in patients. Covaried for sex and age, the result falls below significance to trend levels. The data raise the possibility that psychoimmune dysfunction, specifically related to the 5-HT system, may be present in PD. Potential interruption of 5-HT neurotransmission through autoimmune mechanisms may be of pathophysiologic significance in certain patients with panic disorder. It remains to be demonstrated if the peripheral autoimmunity is representative of CNS 5-HT neuronal alterations. Replication appears warranted.

Lee SH, Lim J, Vannucci M, Petkova E, Preter M, Klein DF. · Nathan S. Kline Institute for Psychiatric Research, 140 Old Orangeburg Road, Orangeburg, New York 10962, USA. · Biometrics. · Pubmed #18177460 No free full text.

Abstract: 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 while reducing the dimension of the data. The observed data matrix is projected onto a set of lower rank matrices with a positive constraint. A multivariate testing procedure is then applied in the lower dimension. We use simulated data to illustrate the statistical properties of the proposed testing procedure. Results on the case study confirm the preliminary hypothesis of the investigators and provide critical support to their overall goal of creating an experimental model of the clinical panic attack in normal subjects.

Sinha SS, Goetz RR, Klein DF. · Department of Psychiatry, Columbia University, and New York State Psychiatric Institute, 1051 Riverside Drive, Unit 22, New York, NY 10032, USA. · Psychiatry Res. · Pubmed #17156855 No free full text.

Abstract: 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 lactate. Four of these subjects underwent a separate infusion with naloxone followed by saline. Respiratory physiological symptoms were measured throughout. Clinical symptoms, assessed by the Acute Panic Inventory (API), an Anxiety Scale, and the Borg Breathlessness Scale, were recorded. Eight of the twelve subjects experienced strong physiological reactivity to naloxone-lactate manifested by significantly increased tidal volume. Concomitant increases in the API and Borg scales were demonstrated; however, fear or anxiety was not affected. The four subjects retested with naloxone followed by saline did not experience significant increases on any measure. These results provide preliminary evidence that endogenous opioid system function may be a key modulator of responsivity to sodium lactate. Dysregulation of the opioid system may potentially underlie critical aspects of panic disorder neurobiology, including respiratory abnormalities and suffocation sensitivity.

Fyer AJ, Hamilton SP, Durner M, Haghighi F, Heiman GA, Costa R, Evgrafov O, Adams P, de Leon AB, Taveras N, Klein DF, Hodge SE, Weissman MM, Knowles JA. · Department of Psychiatry, College of Physicians and Surgeons, Columbia University and New York State Psychiatric Institute, New York, New York 10032, USA. · Biol Psychiatry. · Pubmed #16919526 No free full text.

Abstract: BACKGROUND: Panic disorder (PD) is a common illness with a definite but "complex" genetic contribution and estimated heritability of 30-46%. METHODS: 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 were performed using three PD models (Broad, Intermediate, Narrow) and allowing for homogeneity or heterogeneity. The two-point analyses were also performed allowing for independent male and female recombination fractions (theta). Genome-wide significance was empirically evaluated using simulations of this dataset. RESULTS: Evidence for linkage reached genome-wide significance in one region on chromosome 15q (near GABA-A receptor subunit genes) and was suggestive at loci on 2p, 2q and 9p using an averaged theta. Analyses allowing for sex-specific theta's were consistent except that support at one locus on 2q increased to genome-wide significance and an additional region of suggestive linkage on 12q was identified. However, differences in male and female recombination fractions predicted by the sex-specific approach were not consistent with current physical maps. CONCLUSIONS: These data provide evidence for chromosomal regions on 15q and 2q that may be important in genetic susceptibility to panic disorder. Although we are encouraged by the findings of analyses using sex-specific recombination fractions, we also note that further understanding of this analytic strategy will be important.

Goodwin RD, Lipsitz JD, Chapman TF, Mannuzza S, Klein DF, Fyer AJ. · Anxiety Genetics Unit, Department of Psychiatry, Columbia University College of Physicians and Surgeons/New York State Psychiatric Institute, New York, NY 10032, USA. · Compr Psychiatry. · Pubmed #16490565 No free full text.

Abstract: OBJECTIVE: 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. METHOD: Data from a family study of anxiety disorders were used to compare rates of alcohol use disorders in the relatives of 3 proband groups (PD with lifetime alcohol use disorders, PD without lifetime alcohol use disorders, and not-ill controls). RESULTS: There was a significantly higher rate (12%) of alcohol use disorders among the relatives of PD probands compared with relatives of controls (5%), even in the absence of alcohol use disorders in the proband and after adjusting for differences in sociodemographic characteristics and lifetime drug use disorders (chi2 = 5.4; df = 1; P = .02). Anxiety symptoms were more frequent among the male relatives of panic probands who received an alcohol diagnosis, compared with those who did not have alcohol use disorders (10/25 vs 22/111; chi2 = 4.6; df = 1; P = .03). A similar pattern was found in women (8/11 vs 63/156; chi2 = 4.4; df = 1; P = .036). CONCLUSIONS: These findings suggest a familial association between PD and alcohol use disorders. Future studies with more refined alcohol diagnoses are needed to replicate and investigate the mechanism of this association.

Hamilton SP, Slager SL, Mayo D, Heiman GA, Klein DF, Hodge SE, Fyer AJ, Weissman MM, Knowles JA. · Department of Psychiatry, College of Physicians and Surgeons at Columbia University and the New York State Psychiatric Institute, 1051 Riverside Drive, New York, NY 10032, USA. · Am J Med Genet B Neuropsychiatr Genet. · Pubmed #15048659 No free full text.

Abstract: 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 disorder. We have employed a family-based design to investigate the role of DNA sequence variations in the gene for CREM in panic disorder. We have genotyped 613 individuals in 70 panic disorder pedigrees, as well as 42 parent/offspring triads. Subjects were genotyped at two informative single nucleotide polymorphisms (SNPs) and three polymorphic microsatellites in the CREM genomic region; and the data were analyzed for genetic association and linkage. Linkage analysis employing several diagnostic/genetic models produced a maximum lod score of 0.63 for SNP-1, located in the 5' UTR of CREM, under a dominant model with a broad diagnostic definition of panic disorder. Non-parametric analysis, using the NPL statistic or FBAT, also did not support any linkage or association between the markers and panic disorder. All five markers (spanning 77 kb) used in the study showed modest, but significant linkage disequilibrium. Analysis of 2-, 3-, 4-, or 5-marker haplotypes using TRANSMIT failed to find any globally significant results; however, individual haplotypes containing a single allele of MS-3 were nominally associated with panic disorder. These findings provide little additional evidence for a susceptibility locus for panic disorder either within the CREM gene or in a nearby region of chromosome 10p11 in our sample.

Hamilton SP, Slager SL, De Leon AB, Heiman GA, Klein DF, Hodge SE, Weissman MM, Fyer AJ, Knowles JA. · Department of Psychiatry, College of Physicians and Surgeons at Columbia University and the New York State Psychiatric Institute, New York City, NY 10032, USA. · Neuropsychopharmacology. · Pubmed #14666117 links to  free full text

Abstract: 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 pedigrees. Individuals from 70 panic disorder pedigrees, and 83 child-parent 'trios', were genotyped at five single-nucleotide polymorphisms (SNPs) in and near the ADORA2A gene and were analyzed for genetic linkage and association. Linkage analysis revealed elevated LOD scores for a silent substitution (1083C/T, SNP-4) in the second coding exon. This SNP has been previously reported to be associated with panic disorder. We observed a maximal heterogeneity LOD score of 2.98 (theta=0) under a recessive genetic model and narrow diagnostic model. Other SNPs showed no evidence for linkage. Association tests were not significant for any of the five ADORA2A SNPs. When SNP haplotypes were assessed in the triads with TRANSMIT, one 3-marker haplotype (SNPs 1, 4, 5) was nominally significantly associated with panic disorder (p=0.029). Pairwise estimations of linkage disequilibrium between the SNPs showed strong patterns of linkage disequilibrium across the ADORA2A locus. Analyses carried out by broadening the panic disorder phenotype to include agoraphobia continued to support linkage to ADORA2A. Our findings provide evidence for a susceptibility locus for panic disorder, and possibly including agoraphobia, either within the ADORA2A gene or in a nearby region of chromosome 22, and serves as the first successful candidate gene replication study in panic disorder.

Donovan SJ, Nunes EV, Stewart JW, Ross D, Quitkin FM, Jensen PS, Klein DF. · Department of Therapeutics, New York State Psychiatric Institute, New York, NY 10032, USA. · J Clin Psychiatry. · Pubmed #12823085 No free full text.

Abstract: OBJECTIVE: 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. METHOD: A sample (N = 20) of disruptive youth (aged 10-18 years) entering a divalproex treatment study of temper and irritable mood swings was compared to normal controls (N = 18) on measures of aggression/irritability directed against others (externalizing symptoms) and on aggression/ irritability against self, anxiety, and depression (internalizing symptoms). All patients met DSM-IV criteria for a disruptive behavior disorder (oppositional defiant disorder of conduct disorder) in addition to research criteria. RESULTS: "Outer-directed irritability" most clearly distinguished patients from controls (effect size 4.1) and did not correlate with other mood measures. Patients and controls showed no to minimal differences on internalizing symptoms. CONCLUSION: Disruptive behavior disordered children and adolescents characterized by outer-directed irritability exist, can be identified, and should be further investigated, especially since they are potentially treatable.

Mannuzza S, Klein RG, Moulton JL, Scarfone N, Malloy P, Vosburg SK, Klein DF. · NYU Child Study Center, New York University School of Medicine, New York, NY, USA. · J Anxiety Disord. · Pubmed #12194540 No free full text.

Abstract: 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. Children were administered the Child Anxiety Sensitivity Index (CASI). There were no significant differences between CASI scores of the offspring of parents with anxiety and/or mood disorders, and offspring of comparison parents. We conclude that parental anxiety or mood disorder does not predispose offspring to high anxiety sensitivity.

Slattery MJ, Klein DF, Mannuzza S, Moulton JL, Pine DS, Klein RG. · Mayo Clinic, Rochester, MN 55905, USA. · J Am Acad Child Adolesc Psychiatry. · Pubmed #12162630 No free full text.

Abstract: OBJECTIVE: 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). METHOD: 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 atopic disorders was determined by parental responses to a clinician-administered questionnaire assessing medical treatment for asthma and allergies. Logistic regression analyses assessed the association between atopic disorders and parental PD, and between atopic disorders and probable or definite childhood SAD. Analyses controlled for age, sex, socioeconomic status, and treatment for other medical illnesses. RESULTS: Increased rates of atopic disorders were found in offspring of parents with PD (odds ratio [OR] = 2.56, 95% confidence interval [CI] = 1.27-5.16, p = .009) and in children with SAD (OR = 2.71, 95% Cl = 1.22-6.03, p = .015). Associations remained significant when both parental PD and SAD were included in the model, suggesting that each contributed independently to increased rates of atopy. The interaction of parental PD and child SAD was not significant. CONCLUSIONS: Atopic disorders in children are associated with parental PD and with childhood SAD. Results do not appear to support that having both childhood SAD and a parent with PD confers increased risk for atopic disorders above and beyond either condition alone.

Marshall RD, Blanco C, Printz D, Liebowitz MR, Klein DF, Coplan J. · New York State Psychiatric Institute, Columbia University College of Physicians and Surgeons, 1051 Riverside Drive, New York, NY 10032, USA. · Psychiatry Res. · Pubmed #12127472 No free full text.

Abstract: 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 disorder group (n = 17) and healthy control subjects (n = 16) on baseline levels of cortisol and 3-methoxy-4-hydroxyphenylglycol (MHPG), and response to clonidine challenge. Despite the small sample size, highly significant differences were found on the following measures: PTSD patients had lower cortisol, lower MHPG, reduced MHPG volatility to clonidine challenge, and marginally reduced cortisol volatility compared to patients with panic disorder. These biological findings support existing clinical, epidemiologic, family study, and clinical trial findings that distinguish these two disorders as distinct syndromes.

Klein DF. · No affiliation provided · Arch Gen Psychiatry. · Pubmed #12044206 No free full text.

This publication has no abstract.

Hamilton SP, Slager SL, Heiman GA, Deng Z, Haghighi F, Klein DF, Hodge SE, Weissman MM, Fyer AJ, Knowles JA. · Department of Psychiatry, College of Physicians and Surgeons at Columbia University, New York, NY, USA. · Biol Psychiatry. · Pubmed #11950461 No free full text.

Abstract: BACKGROUND: 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. METHODS: Subjects from 70 panic disorder pedigrees, and 83 "triads", were genotyped at seven single nucleotide polymorphisms (SNPs), polymorphic microsatellites in the first intron of COMT and approximately 339kb upstream of COMT (D22S944) and analyzed for genetic association and linkage. RESULTS: Linkage analysis showed elevated LOD scores for 472G/A (SNP 8), silent exon 3 substitution (186C/T-SNP 5), and the marker D22S944 (2.88, 2.62, and 2.93, respectively), using a variety of diagnostic and genetic models. Association tests were not significant for the SNPs, but were highly significant for D22S944 (p =.0001-.0003). One three-marker haplotype formed from the above three polymorphisms was significantly associated with panic disorder (p =.0001), as was the "global" p value for this combination (p =.005). In addition, numerous haplotypes with combinations of D22S944 and COMT SNPs were found to be significantly associated with panic disorder. CONCLUSIONS: Our findings provide strong evidence for a susceptibility locus for panic disorder either within the COMT gene or in a nearby region of chromosome 22.

Sheikh JI, Leskin GA, Klein DF. · VA Palo Alto Health Care System, Menlo Park, CA 94025, USA. · Am J Psychiatry. · Pubmed #11772690 links to  free full text

Abstract: OBJECTIVE: 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. METHOD: 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 differences across 18 panic symptoms. RESULTS: Among National Comorbidity Survey respondents with panic disorder or panic attacks, female respondents were more likely than male respondents to experience respiration-related difficulties during panic attacks. CONCLUSIONS: Specific symptoms occurring during panic attacks differ by gender. The pathophysiology of these symptom differences may involve gender differences in sensitivity to CO(2) and in the threshold for panic attacks during hypoxic and hypercapnic states.

Ross DC, Preter M, Klein DF. · Columbia University Department of Psychiatry and The New York State Psychiatric Institute, New York, New York, USA. · Depress Anxiety. · Pubmed #11668670 No free full text.

This publication has no abstract.

Lipsitz JD, Fyer AJ, Paterniti A, Klein DF. · Department of Therapeutics, New York State Psychiatric Institute, New York, New York, USA. · Depress Anxiety. · Pubmed #11668669 No free full text.

Abstract: 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 social, home-marital, and occupational impairment and it causes significant constriction of leisure activities. Nearly half of women avoided or delayed becoming pregnant. About three quarters of respondents have eating rituals or significantly limit the foods they eat. Respondents describe other problems such as depression, panic attacks, social anxiety, compulsions, and frequent history of childhood separation anxiety.

Goetz RR, Klein DF, Papp LA, Martinez JM, Gorman JM. · Department of Clinical Psychobiology, New York State Psychiatric Institute, New York, New York 10032, USA. · Depress Anxiety. · Pubmed #11668665 No free full text.

Abstract: There is scant literature on anxiety symptoms induced during respiratory challenges developed to induce panic symptoms and attacks. Here we report on the prevalence of Acute Panic Inventory (API) symptoms during three consecutive respiratory challenges to patients with panic disorder (PD) and normal controls (NC). The challenges performed using a closed canopy system included voluntary room air hyperventilation (RAH), inhalation of 5% CO(2), and 7% CO(2)-enriched air. The PD patients were 41 men and 53 women whose mean age was 33.4 (SD = 8.55). The normal comparison group consisted of 35 men and 27 women with a mean age of 31.3 (SD = 9.21). The diagnosis of panic disorder was made using the Structured Clinical Interview for DSM-III-R. All potential normal controls underwent structured clinical interview using the Schedule for Affective Disorders and Schizophrenia-Lifetime Version Modified for the Study of Anxiety Disorders (SADS-LA), and must have been free of a lifetime history of anxiety disorders, affective disorders, substance use disorders, and schizophrenia. All participants also had a complete medical evaluation and were in good health. The experiment consisted of seven experimental epochs: three baseline/recovery periods each followed by a respiratory challenge, and then a final recovery epoch. The API was administered at the end of each epoch. Clinical staff trained and experienced in rating panic attacks rated participants' response during each challenge as panic or no panic. Three groups were defined for analysis: PD patients who panicked, PD patients who did not panic, and NC who did not panic. Staff ratings indicated that the 7% CO(2) challenge was the most panicogenic, followed by the 5% CO(2), and the RAH challenges. Conventional statistics (analysis of variance and partial correlations) indicated that many baseline symptoms as well as symptom increments differed across groups, and were associated with the outcome of panic/no panic during each challenge. However, logistic regression analysis indicated that only a few symptoms independently predicted the panic/no panic outcome because many symptoms were redundant. The symptom cluster of fear in general, dizziness, difficulties with concentrating, and doing one's job predicted panic to RAH. The cluster of fear in general, confusion, dyspnea, and twitching/trembling predicted the response to 5% CO(2). Finally, fear in general, confusion, twitching/ trembling and dizziness predicted the response to 7% CO(2). While univariate analyses indicated that many symptoms distinguished between panic and no panic outcome, logistic regression revealed that group differences were subsumed under a few prominent symptoms, namely, fear in general, confusion, dizziness, twitching/trembling, and dyspnea. The results are discussed in the context of patient (having a diagnosis of PD) and panic effects (rated as panicking to a challenge).

Hamilton SP, Slager SL, Helleby L, Heiman GA, Klein DF, Hodge SE, Weissman MM, Fyer AJ, Knowles JA. · Department of Psychiatry, College of Physicians and Surgeons at Columbia University and the New York State Psychiatric Institute, USA. · Mol Psychiatry. · Pubmed #11244486 No free full text.

Abstract: 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 interest in understanding the molecular genetic component of these observations. Recent association studies using persons with panic disorder described some association between polymorphisms in the genes encoding cholecystokinin and the cholecystokinin B-receptor and panic disorder. In this study, we used a family-based design, employing 596 individuals in 70 panic disorder pedigrees, as well as 77 haplotype relative risk 'triads'. Subjects were genotyped for two polymorphisms: the polymorphic microsatellite marker in the CCK-BR locus using PCR-based genotyping and at a single nucleotide polymorphism in the CCK promoter using a fluorescence polarization detection assay, and the data were analyzed for genetic association and linkage. Employing a variety of diagnostic and genetic models, linkage analysis produced no significant lod scores at either locus. Family-based tests of association, the haplotype-based haplotype relative risk statistic and the transmission disequilibrium test, were likewise non-significant. The results reported here provide little support for the role of these polymorphisms in panic disorder.

Kent JM, Papp LA, Martinez JM, Browne ST, Coplan JD, Klein DF, Gorman JM. · Biological Studies Unit, New York State Psychiatric Institute, New York, NY 10032, USA. · Am J Psychiatry. · Pubmed #11136634 links to  free full text

Abstract: OBJECTIVE: 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) inhalation (patients with major depression and patients with premenstrual dysphoric disorder, respectively). METHOD: The behavioral responses to inhalation of 5% and 7% CO(2), administered by means of a respiratory canopy, were studied in 50 patients with panic disorder, 21 with major depression, and 10 with premenstrual dysphoric disorder and in 34 normal comparison subjects. Occurrence of panic attacks was judged with DSM-IV criteria by a blind rater. Subjects were rated on three behavioral scales at baseline and after each CO(2) inhalation. RESULTS: Panic disorder patients had a higher rate of CO(2)-induced panic attacks than depressed patients and normal subjects, whose panic rates were not distinguishable. The panic rate for patients with premenstrual dysphoric disorder was similar to that for panic disorder patients and higher than that for normal subjects. Subjects with CO(2)-induced panic attacks had similarly high ratings on the behavioral scales, regardless of diagnosis, including the small number of panicking normal subjects. Seven percent CO(2) was a more robust panicogen than 5%, and response to 7% CO(2 )better distinguished panic disorder patients from normal subjects than response to 5% CO(2). CONCLUSIONS: Patients with panic disorder and patients with premenstrual dysphoric disorder are highly susceptible to CO(2)-induced panic attacks, and depressed patients appear to be insensitive to CO(2) inhalation. The symptoms of CO(2)-induced panic attacks have a similar intensity regardless of the subject's diagnosis.