Protecting the privacy of family members in research.
Explore the source record for details and available documents.
Data Collection↗
Biomedical subjects
R R Crowe
Publications and source records attributed to R R Crowe.
Continuation pharmacotherapy in the prevention of relapse following electroconvulsive therapy: a randomized controlled trial.
CONTEXT: Electroconvulsive therapy (ECT) is highly effective for treatment of major depression, but naturalistic studies show a high rate of relapse after discontinuation of ECT. OBJECTIVE: To determine the efficacy of continuation pharmacotherapy with nortriptyline hydrochloride or combination nortriptyline and lithium carbonate in preventing post-ECT relapse. DESIGN: Randomized, double-blind, placebo-controlled trial conducted from 1993 to 1998, stratified by medication resistance or presence of psychotic depression in the index episode. SETTING: Two university-based hospitals and 1 private psychiatric hospital. PATIENTS: Of 290 patients with unipolar major depression recruited through clinical referral who completed an open ECT treatment phase, 159 patients met remitter criteria; 84 remitting patients were eligible and agreed to participate in the continuation study. INTERVENTIONS: Patients were randomly assigned to receive continuation treatment for 24 weeks with placebo (n = 29), nortriptyline (target steady-state level, 75-125 ng/mL) (n = 27), or combination nortriptyline and lithium (target steady-state level, 0.5-0.9 mEq/L) (n = 28). MAIN OUTCOME MEASURE: Relapse of major depressive episode, compared among the 3 continuation groups. RESULTS: Nortriptyline-lithium combination therapy had a marked advantage in time to relapse, superior to both placebo and nortriptyline alone. Over the 24-week trial, the relapse rate for placebo was 84% (95% confidence interval [CI], 70%-99%); for nortriptyline, 60% (95% CI, 41%-79%); and for nortriptyline-lithium, 39% (95% CI, 19%-59%). All but 1 instance of relapse with nortriptyline-lithium occurred within 5 weeks of ECT termination, while relapse continued throughout treatment with placebo or nortriptyline alone. Medication-resistant patients, female patients, and those with more severe depressive symptoms following ECT had more rapid relapse. CONCLUSIONS: Our study indicates that without active treatment, virtually all remitted patients relapse within 6 months of stopping ECT. Monotherapy with nortriptyline has limited efficacy. The combination of nortriptyline and lithium is more effective, but the relapse rate is still high, particularly during the first month of continuation therapy.
Antidepressive Agents↗
Genetic diversity of the human serotonin receptor 1B (HTR1B) gene.
We systematically and comprehensively investigated polymorphisms of the HTR1B gene as well as their linkage disequilibrium and ancestral relationships. We have detected the following polymorphisms in our sample via denaturing gradient gel electrophoresis, database comparisons, and/or previously published assays: G-511T, T-261G, -182INS/DEL-181, A-161T, C129T, T371G, T655C, C705T, G861C, A1099G, G1120A, and A1180G. The results of the intermarker analyses showed strong linkage disequilibrium between the C129T and the G861C polymorphisms and revealed four common haplotypes: ancestral (via chimpanzee comparisons), 129T/861C, -161T, and -182DEL-181. The results of association tests with schizophrenia were negative, although A-161T had a nominal P = 0.04 via ASPEX/sib_tdt. The expressed missense substitutions, Phe124Cys, Phe219Leu, Ile367Val, and Glu374Lys, could potentially affect ligand binding or interaction with G proteins and thus modify drug response in carriers of these variants. On average, the human cSNPs and differences among other primates clustered in the more thermodynamically unstable regions of the mRNA, which suggests that the evolutionary survival of nucleotide sequence variation may be influenced by the mRNA structure of this gene.
Alleles↗
Genomewide survey of panic disorder.
We completed a genome scan of 23 multiplex families of panic disorder. Ninety family members had DSM-III-R panic disorder, and another 23 had recurrent, spontaneous panic attacks that did not satisfy these criteria. We typed 469 markers from the CHLC map (ver 8c7) with an average intermarker distance of 10.3 cM. Two-point lod scores were calculated with both a dominant and a recessive model, and maps of lod scores < -2.00, assuming genetic homogeneity, were constructed by using DSM-III-R panic disorder as the affected phenotype. Lod scores were < -2.00 over 94-95% of the genome. The greatest lod score was 2.23 (theta = 0.15) at the D7S2846 locus, located at 57.8 cM on chromosome 7 according to the Marshfield Clinic map. Flanking markers analyzed in a nonparametric, multipoint analysis using GENEHUNTER resulted in an NPL score of 2.97 at 63 cM on the Marshfield map. This region lies within 15 cM from the D7S435 locus, where Knowles et al. [1998] obtained a lod score of 1.71 (theta = 0.10) for panic disorder (now 2.45 with the addition of new families; James Knowles, personal communication). Thus, the maximum evidence of linkage from two genome scans of panic disorder lies within a small region of chromosome 7p.
Adult↗
Second stage of a genome scan of schizophrenia: study of five positive regions in an expanded sample.
In a previous genome scan of 43 schizophrenia pedigrees, nonparametric linkage (NPL) scores with empirically derived pointwise P-values less than 0.01 were observed in two regions (chromosomes 2q12-13 and 10q23) and less than 0.05 in three regions (4q22-23, 9q22, and 11q21). Markers with a mean spacing of about 5 cM were typed in these regions in an expanded sample of 71 pedigrees, and NPL analyses carried out. No region produced significant genomewide evidence for linkage. On chromosome 10q, the empirical P-value remained at less than 0.01 for the entire sample (D10S168), evidence in the original 43 pedigrees was slightly increased, and a broad peak of positive results was observed. P-values less than 0.05 were observed on chromosomes 2q (D2S436) and 4q (D4S2623), but not on chromosomes 9q or 11q. It is concluded that this sample is most supportive of linkage on chromosome 10q, with less consistent support on chromosomes 2q and 4q. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:864-869, 2000.
Alleles↗
No support for linkage to the bipolar regions on chromosomes 4p, 18p, or 18q in 43 schizophrenia pedigrees.
Explore the source record for details and available documents.
Bipolar Disorder↗
Family-based study of the association of the dopamine D2 receptor gene (DRD2) with habitual smoking.
A recent study showed an association between the dopamine D2 receptor gene (DRD2) and smoking. The purpose of this study was to determine if the familial transmission of smoking is linked to variation at the DRD2 locus in a genetically informative sample. Subjects were identified in alcohol treatment centers and their relatives were recruited for study. All subjects were interviewed to assess alcohol dependence, smoking habits, and psychiatric disorders. Two polymorphisms within the DRD2 gene were analyzed, including the TaqIA polymorphism. The sample consisted of 138 nuclear families with at least one offspring with habitual smoking, and analysis was by the transmission disequilibrium test (TDT), which avoids problems due to population stratification. There was no significant difference in the frequency between DRD2 alleles transmitted and not transmitted to habitual smokers. There also was no evidence for unequal transmission of DRD2 alleles for the phenotypes "ever smoker" or comorbid alcohol dependence and habitual smoking. This study does not support linkage of the DRD2 with smoking.
Chromosome Mapping↗
Tumor necrosis factor receptor-II: heritability and effect on brain morphology in schizophrenia.
A growing body of research suggests the involvement of immune system factors in central nervous system development and in pathophysiology related to schizophrenia.(1,2) We therefore investigated the Tumor Necrosis Factor Receptor-II (TNF-RII), a TNFalpha receptor expressed in fetal brain, as a candidate disease gene for schizophrenia. We also investigated the relationship between TNF-RII and adult brain morphology. The study sample consisted of 140 probands diagnosed with schizophrenia or schizophreniform disorder, 197 parents of the probands (a subset of which formed 62 proband-parent trios), and 46 psychiatrically normal control subjects. A bi-allelic TNF-RII polymorphism was examined for evidence of association, with none being found between this polymorphism and schizophrenia. Subjects with schizophrenia homozygous for allele 1, however, had larger ventricles and smaller frontal lobes than subjects with at least one copy of allele 2. On follow-up testing, they also had an earlier, less variable age of onset for their illness. We found no support, therefore, for TNF-RII as a disease susceptibility gene for schizophrenia. The gene may, however, modify phenotypic aspects of the disease such as brain morphology and age of onset of illness.
Age of Onset↗
Electroconvulsive therapy. Potent intervention for the troubled mind.
Explore the source record for details and available documents.
Depression↗
Heritability of BDNF alleles and their effect on brain morphology in schizophrenia.
Accumulating evidence suggests that disturbed brain development may play a role in the etiology of schizophrenia, and that the illness is, to a significant degree, heritable. We therefore investigated brain derived neurotrophic factor (BDNF), a neurotrophin expressed in fetal brain, as a candidate disease gene for schizophrenia. We also investigated the effect of BDNF on adult brain morphology. All subjects were diagnosed by DSM-IIIR or DSM-IV criteria with schizophrenia spectrum disorders. Association of a BDNF polymorphism was examined in 48 proband-parent trios using the haplotype based haplotype relative risk method of case control. In a related group of 63 subjects, relationships between the presence or absence of allele 1 and the volumes of the major cerebral lobes, the ventricles, and the cerebellum were assessed using logistic regression. No association was found between this polymorphism and schizophrenia. Subjects who had at least one copy of allele 1, however, had larger parietal lobes than those who did not when controlling for overall cortical volume and age at the time of magnetic resonance. We did not find support for BDNF as a disease gene for schizophrenia. Allelic variability of the gene may, however, influence brain morphology in these same subjects. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:724-728, 1999.
Adult↗
Follow-up study on a susceptibility locus for schizophrenia on chromosome 6q.
Evidence for suggestive linkage to schizophrenia with chromosome 6q markers was previously reported from a two-stage approach. Using nonparametric affected sib pairs (ASP) methods, nominal p-values of 0.00018 and 0.00095 were obtained in the screening (81 ASPs; 63 independent) and the replication (109 ASPs; 87 independent) data sets, respectively. Here, we report a follow-up study of this 50cM 6q region using 12 microsatellite markers to test for linkage to schizophrenia. We increased the replication sample size by adding an independent sample of 43 multiplex pedigrees (66 ASPs; 54 independent). Pairwise and multipoint nonparametric linkage analyses conducted in this third data set showed evidence consistent with excess sharing in this 6q region, though the statistical level is weaker (p=0.013). When combining both replication data sets (total of 141 independent ASPs), an overall nominal p-value=0.000014 (LOD=3. 82) was obtained. The sibling recurrence risk (lambdas) attributed to this putative 6q susceptibility locus is estimated to be 1.92. The linkage region could not be narrowed down since LOD score values greater than three were observed within a 13cM region. The length of this region was only slightly reduced (12cM) when using the total sample of independent ASPs (204) obtained from all three data sets. This suggests that very large sample sizes may be needed to narrow down this region by ASP linkage methods. Study of the etiological candidate genes in this region is ongoing.
Chromosomes, Human, Pair 6↗
Report of the Chromosome 5 Workshop of the Sixth World Congress on Psychiatric Genetics.
The Chromosome 5 Workshop heard new data on a schizophrenia susceptibility locus in the 5q23.3-q31.1 region. Sixty-two pedigrees from Finland gave a lod score of 1.36 at the CSF1R locus approximately 14 cM distal to IL9/D5S393, where positive results from three pedigree collections converged at the 1997 workshop. Though positive at CSF1R, the new data were only weakly positive at the IL9 (lod 0.46) and D5S393 (lod 0.07) loci themselves. The workshop also reviewed new evidence in the 5p14.1-p13.1 region, where a large pedigree of schizophrenia of Puerto Rican extraction has suggested a susceptibility locus with a maximum lod score at D5S111. Twenty-one new pedigrees multiplex for schizophrenia in African Americans gave positive lod scores at D5S111 and flanking loci. In bipolar illness five genetically related pedigrees from the Saguenay-Lac-St. Jean region of Quebec identified a region of interest at 5q31.3-q35.1. This region overlaps with the D5S423 locus and includes the D5S812 locus and the 5q34 region, all of which are consistent with linkage in at least one other study.
Bipolar Disorder↗
Acute efficacy of ECT in the treatment of major depression in the old-old.
OBJECTIVE: There are few data addressing the outcome of ECT for persons over 75 years of age. In a prospective, multisite study, the authors compared characteristics and treatment outcomes of adult (59 and younger), young-old (60 to 74 years), and old-old (75 and older) patients treated with ECT for major depression. METHOD: At four hospitals, 268 patients with primary unipolar major depression and scores of at least 20 on the 24-item Hamilton Depression Rating Scale were treated with suprathreshold right unilateral or bilateral ECT in a standardized manner. Demographic variables, clinical characteristics, and short-term outcomes of the three groups were compared. RESULTS: The demographic and clinical characteristics of the old-old patients were similar to those of the young-old patients, whereas both groups differed from the adult patients on these variables. Both older groups had significantly greater burdens from physical illness and global cognitive impairment at baseline than the adult subjects. Both older groups had shorter index depressive episodes and were less likely to have had inadequate responses to adequate medication trials before ECT. The older groups had higher seizure thresholds, but the three groups received similar courses of treatment. The adult patients experienced a significantly lower rate of ECT response (54%) than the young-old patients (73%), while the old-old patients had an intermediate rate of response (67%). CONCLUSIONS: Despite a higher level of physical illness and cognitive impairment, even the oldest patients with severe major depression tolerate ECT in a manner similar to that for younger patients and demonstrate similar or better acute response.
Adult↗
An association of NAG levels and a mutation of the CCK gene in panic disorder patients.
Levels of the enzyme N-acetyl-beta-glucosaminidase (NAG) and a mutation of cholecystokinin (CCK) gene appear to be independently associated with panic disorder. We explored whether there was an association of NAG levels and a CCK mutation identified in a group of panic disorder patients. NAG was measured in 12 panic disorder patients who had a mutation of the CCK gene and 17 who did not. Urine for NAG was collected at baseline and after 3 and 6 weeks of treatment. NAG levels were lower at all three times in the patients that did not have the CCK mutation. The difference between the two groups was significant at week 6 (P < 0.02), and showed a trend toward a difference at baseline (P < 0.15).
Acetylglucosaminidase↗
Possible association of a cholecystokinin promotor polymorphism (CCK-36CT) with panic disorder.
We searched for mutations in the CCK gene in panic disorder with single-strand conformational polymorphism (SSCP) analysis of the three exons and promotor region of the gene. We found a C-->T transition at position -36 (CCK(-36C-->T)) in a GC box, a binding site for transcription factor Sp1, in the promotor region. The allele frequency was 0.168 (95% CI, 0.116-0.221) in 98 persons with panic disorder and 0.083 (95% CI, 0.059-0.107) in 247 geographically matched, unscreened controls. A transmission disequilibrium test based on panic disorder as the affected phenotype was nonsignificant (chi2 = 0.93), but when panic disorder or attacks were considered as affected, statistically significant transmission disequilibrium was detected (chi2 = 4.00, P < 0.05). Linkage analysis was uninformative. In exploratory analyses to search for clinical correlations, the "T" allele was found in 59% of 22 persons with panic attacks but not panic disorder, compared with 31% of those who met the criteria for panic disorder. An association between the CCK polymorphism and panic disorder cannot be considered established due to the inconsistencies in the results noted above, but if the provisional association can be replicated, the findings are consistent with CCK(-36C-->T) being a disease-susceptibility allele that alone is neither necessary nor sufficient to cause panic disorder but that increases vulnerability by acting epistatically.
Adult↗
Genome-wide search for genes affecting the risk for alcohol dependence.
Alcohol dependence is a leading cause of morbidity and premature death. Several lines of evidence suggest a substantial genetic component to the risk for alcoholism: sibs of alcoholic probands have a 3-8 fold increased risk of also developing alcoholism, and twin heritability estimates of 50-60% are reported by contemporary studies of twins. We report on the results of a six-center collaborative study to identify susceptibility loci for alcohol dependence. A genome-wide screen examined 291 markers in 987 individuals from 105 families. Two-point and multipoint nonparametric linkage analyses were performed to detect susceptibility loci for alcohol dependence. Multipoint methods provided the strongest suggestions of linkage with susceptibility loci for alcohol dependence on chromosomes 1 and 7, and more modest evidence for a locus on chromosome 2. In addition, there was suggestive evidence for a protective locus on chromosome 4 near the alcohol dehydrogenase genes, for which protective effects have been reported in Asian populations.
Adolescent↗
Familial transmission of substance dependence: alcohol, marijuana, cocaine, and habitual smoking: a report from the Collaborative Study on the Genetics of Alcoholism.
BACKGROUND: Alcoholism and substance dependence frequently co-occur. Accordingly, we evaluated the familial transmission of alcohol, marijuana, and cocaine dependence and habitual smoking in the Collaborative Study on the Genetics of Alcoholism. METHODS: Subjects (n=1212) who met criteria for both DSM-III-R alcohol dependence and Feighner definite alcoholism and their siblings (n=2755) were recruited for study. A comparison sample was also recruited (probands, n=217; siblings, n=254). Subjects were interviewed with the Semi-Structured Assessment for the Genetics of Alcoholism. The familial aggregation of drug dependence and habitual smoking in siblings of alcohol-dependent and non-alcohol-dependent probands was measured by means of the Cox proportional hazards model. RESULTS: Rates of alcohol, marijuana, and cocaine dependence and habitual smoking were increased in siblings of alcohol-dependent probands compared with siblings of controls. For siblings of alcohol-dependent probands, 49.3% to 50.1% of brothers and 22.4% to 25.0% of sisters were alcohol dependent (lifetime diagnosis), but this elevated risk was not further increased by comorbid substance dependence in probands. Siblings of marijuana-dependent probands had an elevated risk of developing marijuana dependence (relative risk [RR], 1.78) and siblings of cocaine-dependent probands had an elevated risk of developing cocaine dependence (RR, 1.71). There was a similar finding for habitual smoking (RR, 1.77 in siblings of habitual-smoking probands). CONCLUSIONS: Alcohol, marijuana, and cocaine dependence and habitual smoking are all familial, and there is evidence of both common and specific addictive factors transmitted in families. This specificity suggests independent causative factors in the development of each type of substance dependence.
Adolescent↗
Chromosome 5 workshop.
In schizophrenia, evidence consistent with linkage in the 5q23.3-q31.1 region emerged from three independent samples. In addition, a moderately retarded woman with schizophrenia with an interstitial deletion overlapping this region was reported at the workshop. A second region of interest for schizophrenia is the 5p14.1-p13.1 region, where lod scores as high as 4.37 were found in one pedigree. Chromosome 5p15 gave a non-parametric linkage (NPL) score of 2.18 (p < 0.02) in one study. Several genome scans have not found evidence of excess allele sharing in these regions, although in most cases the genome scans did not include the markers that had resulted in provisional evidence of linkage. A large pedigree of bipolar illness has shown provisional evidence of linkage at, or near, the dopamine transporter locus at 5p15.3; the maximum lod score obtained was 2.72 at D5S417. In other regions, a genome scan of bipolar disorder gave NPL scores of 2.98 at D5S812 and 3.76 at D5S423. The third disorder of interest is attention deficit hyperactivity disorder (ADHD) because two studies have reported an association with the 480 bp allele at the dopamine transporter locus. A poster presented at the Congress reported a failure to replicate the association in a sample with considerable power to detect the effect size previously reported.
Attention Deficit Disorder with Hyperactivity↗