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Biomedical subjects

Donald F Klein

Publications and source records attributed to Donald F Klein.

At least 19 recordsLinked to original sources
PubMed2006

Physiological and behavioral effects of naloxone and lactate in normal volunteers with relevance to the pathophysiology of panic disorder.

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.

Acute Disease↗
PubMed2006

A third-pass genome scan in panic disorder: evidence for multiple susceptibility loci.

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.

Chromosomes, Human, Pair 15↗
PubMed2006

The flawed basis for FDA post-marketing safety decisions: the example of anti-depressants and children.

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 health impact. The current black box does not claim that these medications increase the risk of completed suicides, although this is the clear implication of the term 'suicidality'. The interpretation by the press is unequivocal that lethal outcomes prompted this action. This review concludes the following: (1) Since no suicide occurred in clinical trials of approximately 4400 children, the analyses relied upon 'suicidality' as a surrogate. (2) The classification of adverse events by the Columbia group necessarily relied on inferences, because the available evidence was not prospectively collected for this purpose. (3) The data analysis relied on a composite variable labeled 'suicidality', an unvalidated, inappropriate surrogate. Specific criticisms of analytic procedures and inferences are presented. The failure of the FDA's post-marketing surveillance system is reviewed. The data necessary for objective evaluations of possible post-marketing harm cannot be gathered by the current process. Proper prospective post-marketing surveillance by linked computerized medical records is a crucial issue that deserves major public and political attention and prompt action.

Adverse Drug Reaction Reporting Systems↗
PubMed2005

Defining the boundaries of atypical depression: evidence from the HPA axis supports course of illness distinctions.

BACKGROUND: 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 hypothesized to distinguish atypical depression from melancholia, we examined whether HPA measures would also differentiate these two groups of depressed patients with atypical features. METHODS: Three-hour afternoon cortisol levels, stimulation of cortisol by afternoon dextroamphetamine, and suppression of cortisol by dexamethasone were investigated in 85 depressed patients with atypical features. The latter group was divided into early/chronic atypical and late/nonchronic atypical based on chart review of course of illness. RESULTS: Patients with early/chronic atypical had significantly lower mean 3 h afternoon cortisol levels (N=21) and 4:00 p.m. post-dexamethasone cortisol levels (N=20) than did those with late/nonchronic atypical (N=43 with afternoon cortisol; N=26 with post-dexamethasone cortisol). Post-dextroamphetamine cortisol levels were numerically higher in the early/chronic atypical group (N=15 vs. 19), but this failed to reach conventional significance (0.05<p<0.1). Arbitrary categorical distinctions of normal and abnormal did not separate these groups on any of the tests. LIMITATIONS: Lack of demonstrated reliability of the chart review and retrospective determination of atypical features and course of illness limit the generalizability of these findings. CONCLUSIONS: These HPA data are consistent with earlier treatment and brain laterality findings that course of illness distinguishes biologically distinct groups within depressed patients with atypical features. The DSM should consider adding course of illness requirements to its criteria for atypical features.

Adult↗
PubMed2005

Remission rates with 3 consecutive antidepressant trials: effectiveness for depressed outpatients.

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 1 of 3 studies for the treatment of major depressive disorder (DSM-IV criteria) from January 1999 through December 2001. This group primarily received fluoxetine as a first treatment in trials lasting 6 to 12 weeks (a small number received gepirone). If unimproved, patients received a second or third trial (primarily clinician's choice). A standard criterion to determine remission-a score of 7 or less on the 17-item Hamilton Rating Scale for Depression-was used. In order to contrast remission rates with first-generation antidepressants, patients' outcomes in a previously published study that compared placebo, phenelzine, and imipramine were also examined (N = 420). RESULTS: In an intent-to-treat analysis, 66% (113/171) of patients who were treated with second-generation antidepressants and 65% (275/420) of patients who were treated with first-generation antidepressants eventually achieved remission. CONCLUSIONS: Remission rates in the effectiveness study are approximately 20% higher than the rates usually cited, a result of our choice to examine outcome following 3 treatment trials. This choice is dictated by good clinical practice. The usual procedure when comparing treatment modalities is to assess outcome after a single anti-depressant trial. The cumulative high remission rates suggest antidepressants are effective and should encourage more patients to seek treatment and physicians to develop techniques to improve patient adherence.

Adult↗
PubMed2004

Investigation of polymorphisms in the CREM gene in panic disorder.

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.

5' Untranslated Regions↗
PubMed2004

Genes and environment: nosology and psychiatry.

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. This is highly desirable, especially when treatment is ineffective. More recently, syndromes have provided some guidance for therapeutic choice. However, a syndrome has no claim for etiological homogeneity. Therefore, linkage studies are plagued by phenocopies that amount to false positives. An attempt to deal with the phenocopy problem in the area of depression is presented.

Antidepressive Agents↗
PubMed2004

Evidence for genetic linkage between a polymorphism in the adenosine 2A receptor and panic disorder.

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.

Female↗
PubMed2003

"Outer-directed irritability": a distinct mood syndrome in explosive youth with a disruptive behavior disorder?

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.

Adolescent↗
PubMed2002

A pilot study of noradrenergic and HPA axis functioning in PTSD vs. panic disorder.

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.

Adolescent↗
PubMed2002

Evidence for a susceptibility locus for panic disorder near the catechol-O-methyltransferase gene on chromosome 22.

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.

Adult↗
PubMed2002

Improving clinical trials: American Society of Clinical Psychopharmacology recommendations.

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 experts who repeatedly had difficulty pursuing scientific, public health--relevant goals. Many approaches to improving the detection of potentially beneficial agents were reviewed. In this article, we discuss technically feasible study improvements. The scope of inquiry included identifying means of shifting institutional and regulatory assumptions and processes, even to the point of seeking appropriate national incentives.

Clinical Trials as Topic↗