Net gain analysis, an addition to responder analysis--The case of antipsychotic treatment of acute mania.

Net Gain Analysis (NGA) is proposed as an alternative to Responders Analysis (RA) as a more comprehensive method to tap clinical relevance of the effect of treatment. NGA is the group difference in responders minus the group difference in deteriorators; while RA is the group difference in responders. We examined the performance of these two methods in a dataset consisting of individual patient data from 10 randomized controlled trials (N = 2666) of five different antipsychotics in patients with acute mania by comparing the rank ordering of the five compounds according to both systems (NGA and RA). The rank order did not differ between the 2 systems but the inferiority of one compound was revealed more evidently by the NGA in comparison to the RA.

Efficacy of drug treatment for acute mania differs across geographic regions: An individual patient data meta-analysis of placebo-controlled studies.

Given globalization trends in the conduct of clinical trials, the external validity of trial results across geographic regions is questioned. The objective of this study was to examine the efficacy of treatment in acute mania in bipolar disorder across regions and to explain potential differences by differences in patient characteristics. We performed a meta-analysis of individual patient data from 12 registration studies for the indication acute manic episode of bipolar disorder. Patients (n = 3207) were classified into one of three geographic regions: Europe (n = 981), USA (n = 1270), and other regions (n = 956). Primary outcome measures were mean symptom change score on the Young Mania Rating Scale (YMRS) from baseline to endpoint and responder status (50% improvement form baseline). Effect sizes were significantly smaller in the USA (g = 0.203, 95% confidence interval (CI) 0.062-0.344; odds ratio (OR) 1.406, 95% CI 0.998-1.980) than in Europe (g = 0.476, 95% CI 0.200-0.672; OR 2.380, 95% CI 1.682-3.368) or other regions (g = 0.533, 95% CI 0.399-0.667; OR 2.300, 95% CI 1.800-2.941). Regional differences in age, gender, initial severity, body mass index, placebo response, discontinuation rate, and type of compound could not explain the geographic differences in effect. Less severe symptoms at baseline in the US patients did explain some of the difference in responder status between patients in Europe and the USA. These findings suggest that the results of studies involving patients with acute mania cannot be extrapolated across geographic regions. Similar findings have been identified in schizophrenia, contraceptive, and in cardiovascular trials. Therefore, this finding may indicate a more general problem regarding the generalizability of pharmacological trials over geographic regions.

Placebo response in antipsychotic trials of patients with acute mania: Results of an individual patient data meta-analysis.

We examined the role of placebo response in acute mania trials. Specifically, whether placebo response: (1) predicts treatment effect, (2) can be predicted by patient and study characteristics, and (3) can be predicted by a parsimonious model. We performed a meta-analysis of individual patient data from 10 registration studies (n=1019) for the indication acute manic episode of bipolar disorder. We assessed the effect of 14 determinants on placebo response. Primary outcome measures were mean symptom change score (MCS) on the Young Mania Rating Scale (YMRS) and response rate (RR), defined as ≥ 50% YMRS symptom improvement from baseline to endpoint. The overall placebo response was 8.5 points improvement on the YMRS (=27.9%) with a RR of 32.8%. Placebo response was significantly associated with the overall treatment response. Five determinants significantly (p<0.05) predicted the placebo response. The multivariate prediction model, which consisted of baseline severity, psychotic features at baseline, number of geographic regions, and region, explained 10.4% and 5.5% of the variance in MSC and RR, respectively. Our findings showed that the placebo response in efficacy trials of antipsychotics for acute mania is substantial and an important determinant of treatment effect. Placebo response is influenced by patient characteristics (illness severity and presence of psychotic features) and by study characteristics (study year, number of geographic regions and region). However, the prediction model could only explain the placebo response to a limited extent. Therefore, limiting trials to certain patients in certain geographic regions seems not a viable strategy to improve assay sensitivity.

Identifying crime victims who are at high risk for post traumatic stress disorder: developing a practical referral instrument.

OBJECTIVE: To construct a practical instrument for the identification and referral of crime victims who are at high risk for post traumatic stress disorder (PTSD). METHOD: Crime victims filing a complaint at a police station were asked to fill out a questionnaire probing risk factors for PTSD (n=126). One and 3 months later, these victims filled out a self-report version of the PTSD Symptom Scale (PSS-SR). RESULTS: The combination of four items predicted persistent PTSD with a sensitivity of 1.00 and a specificity of 0.62. The items were: being victims of a violent crime, knowing the perpetrator, experiencing the results of the crime as worse than was expected, and blaming oneself for the event. Only 25% of PTSD cases received emotional support from a victim assistance organization. CONCLUSION: This study demonstrates that early detection of high-risk victims and their referral to treatment is both necessary and possible.

Relapse and recurrence prevention in major depression: a critical review of placebo-controlled efficacy studies with special emphasis on methodological issues.

This article critically reviews the design and methodology of studies aimed at evaluating relapse and recurrence prevention in major depression. A literature search in MEDLINE was performed with the medical subject headings 'depression', 'recurrence', 'relapse', 'prevention' and 'study'. This search covered the period from January 1990 to July 1999. Only long-term placebo-controlled studies that included patients with non-chronic major depression were selected. Two types of design could be distinguished: randomised withdrawal studies in responders/remitters (N = 11) and extension studies in responders without re-randomisation (N = 3). Randomised withdrawal studies are suitable for demonstrating long-term efficacy for the duration of the study period. However, this design does not permit a clear differentiation between relapse or recurrence and, therefore, is not suitable to demonstrate unequivocally relapse prevention or recurrence prevention. Extension studies in short-term responders without randomisation are not even suitable to demonstrate long-term efficacy.A novel design is proposed that overcomes the weaknesses of designs employed thus far. In essence, this design calls for a long-term randomised placebo-controlled study in patients who are free of medication for a substantial period of time and who fulfil the criteria of major depression (recurrent) in sustained remission (e.g., HDRS < 7) as a possible option.

The relationship between socio-economic inequality and criminal victimisation: a prospective study.

BACKGROUND: This study investigates the relationship of socio-economic inequality (SEI) with criminal victimisation. It is hypothesised that disadvantage in terms of SEI is associated with increased risk of being victimised and with increased distress following victimisation. Two concepts of SEI are applied: social class (measured in terms of relation to work) and SES (measured in terms of education). METHOD: A representative sample of the Dutch population, comprising 3446 individuals, was followed up and incident crime victims were identified (n=179). A matched comparison group was recruited from the same sample (n=266). SEI and potential vulnerability measures were taken at baseline. Distress was measured 1 week following victimisation and at 1-month intervals for the following consecutive 3 months. RESULTS: The probability of becoming victimised was significantly higher among the unemployed and (unexpectedly) among persons with higher education. The unemployed also showed an increased vulnerability for distress following victimisation compared to all other class categories. This increased vulnerability could not be explained by differences in style of information processing, locus of control, hardiness, need for affiliation, or social support. CONCLUSION: The limitations of the study are discussed and recommendations with respect to the special attention required for unemployed persons are offered.

Gene regulation during late embryogenesis: the RY motif of maturation-specific gene promoters is a direct target of the FUS3 gene product.

The Arabidopsis mutants fus3 and abi3 show pleiotropic effects during embryogenesis including reduced levels of transcripts encoding embryo-specific seed proteins. To investigate the interaction between the B3-domain-containing transcription factors FUS3 and ABI3 with the RY cis-motif, conserved in many seed-specific promoters, a promoter analysis as well as band-shift experiments were performed. The analysis of promoter mutants revealed the structural requirements for the function of the RY cis-element. It is shown that both the nucleotide sequence and the alternation of purin and pyrimidin nucleotides (RY character) are essential for the activity of the motif. Further, it was shown that FUS3 and ABI3 can act independently of each other in controlling promoter activity and that the RY cis-motif is a target for both transcription factors. For FUS3, which is so far the smallest known member of the B3-domain family, a physical interaction with the RY motif was established. The functional and biochemical data demonstrate that the regulators FUS3 and ABI3 are essential components of a regulatory network acting in concert through the RY-promoter element to control gene expression during late embryogenesis and seed development.

Social class and substance use disorders: the value of social class as distinct from socioeconomic status.

The relationship between social class and substance use disorders (SUDs) is explored and compared to the relationship between SES and SUDs. Social class and SES are two different conceptualizations of socioeconomic inequality (SEI) which emanate from two different theoretical orientations in sociology. SES is commonly used in epidemiological research and is usually measured in terms of education, income or occupational prestige. Social class is less known and less used. Here, following the work of Wright et al. (Wright, E. O., Hachen, D. and Costello, C. et al. (1982) The American class structure. American Sociological Review 47, 709-726) it is measured in terms of four types of control people have in their work place: ownership, control over budget decisions, control over other workers, and control over one's own work. Data are derived from an epidemiological survey, conducted in Israel, using a two stage sampling procedure for the identification of cases. In the first stage 4914 respondents were screened with the Psychiatric Epidemiological Research Interview (PERI). In the second stage (n = 2741), those who screened positive (and a sample of the negatives) were diagnosed by psychiatrists using a structured interview that yielded diagnoses according to the Research Diagnostic Criteria (RDC). The results indicate that those who are advantaged in terms of ownership, i.e. self-employed, have higher rates of SUDs compared to employees. Furthermore, it appears that most disorders have an onset subsequent to entry into the current job, indicating that ownership plays a causal role in the onset of SUDs rather than the other way around. These results are contrasted with those of a previous report from the same study by Dohrenwend et al. (Dohrenwend, B. P., Levav, I. and Shrout, P. E. et al. (1992) Socioeconomic status and psychiatric disorders: the causation selection issue. Science 255, 946-952) which showed just the opposite association between SES and SUDs, i.e. those who are advantaged in terms of SES have lower rates of SUDs. As an explanation of these apparently conflicting results, the possibility is entertained that social class and SES represent independent causal pathways to the onset of SUDs with social class mainly related to primary SUDs and SES mainly to secondary SUDs.

Ectopic expression of a novel MYB gene modifies the architecture of the Arabidopsis inflorescence.

The Arabidopsis thaliana mutants fus3, lec1 and abi3 have pleiotropic defects during late embryogenesis. Mutant embryos fail to enter the maturation programme and initiate a vegetative germination pathway instead. Screening for genes which are differentially expressed in the fus3 mutant of Arabidopsis resulted in the isolation of several members of the MYB family. MYB domain proteins in plants represent an extended gene family of transcription factors, suggesting their participation in a variety of plant specific cellular functions. Here, the authors describe one of these genes, designated AtMYB13, representing a novel member of the MYB gene family. The structure of the gene as well as its genomic organisation and localisation are reported. The expression of the gene is regulated by dehydration, exogenous abscisic acid, light and wounding. A chimeric AtMYB13 promoter/GUS gene is tissue-specifically expressed in transgenic Arabidopsis plants. The GUS staining was predominantly detected in the shoot apex zone and at the basis of developing flowers. In addition, the AtMYB13 gene promoter is active at branching points of the inflorescence. Furthermore, ectopic expression of the AtMYB13 gene has a characteristic impact on the architecture of the inflorescence leading to peculiar hook structures at pedicel branching points. In addition, some transgenic plants exhibit a reversed order of first flowers and axillary buds. These data suggest a function of the AtMYB13 gene product in linking shoot morphogenic activity with environmental as well as intrinsic signals.

Socioeconomic inequality and psychopathology: are socioeconomic status and social class interchangeable?

Two different ways of conceptualizing and measuring socioeconomic inequality (SEI) are described and contrasted: the commonly used socioeconomic status (SES) measures and a neo-Marxist measure of social class. It is argued that SES and social class stem from two different theoretical orientations towards socioeconomic inequality and that they focus on different aspects of inequality. These differences have implications for the role of SEI in relation to psychopathology. Using data from a large scale epidemiological survey that was conducted in Israel, it is shown that SES and social class measures are empirically distinct and that they explain different parts of the variance of psychopathology. It is concluded that since social class is theoretically as well as empirically distinct from SES, it has potential for contributing to our understanding of psychopathological phenomenon.

Pyruvate decarboxylase from Pisum sativum. Properties, nucleotide and amino acid sequences.

To study the molecular structure and function of pyruvate decarboxylase (PDC) from plants the protein was isolated from pea seeds and partially characterised. The active enzyme which occurs in the form of higher oligomers consists of two different subunits appearing in SDS/PAGE and mass spectroscopy experiments. For further experiments, like X-ray crystallography, it was necessary to elucidate the protein sequence. Partial cDNA clones encoding pyruvate decarboxylase from seeds of Pisum sativum cv. Miko have been obtained by means of polymerase chain reaction techniques. The first sequences were found using degenerate oligonucleotide primers designated according to conserved amino acid sequences of known pyruvate decarboxylases. The missing parts of one cDNA were amplified applying the 3'- and 5'-rapid amplification of cDNA ends systems. The amino acid sequence deduced from the entire cDNA sequence displays strong similarity to pyruvate decarboxylases from other organisms, especially from plants. A molecular mass of 64 kDa was calculated for this protein correlating with estimations for the smaller subunit of the oligomeric enzyme. The PCR experiments led to at least three different clones representing the middle part of the PDC cDNA indicating the existence of three isozymes. Two of these isoforms could be confirmed on the protein level by sequencing tryptic peptides. Only anaerobically treated roots showed a positive signal for PDC mRNA in Northern analysis although the cDNA from imbibed seeds was successfully used for PCR.

Comparative analysis of chromosomal HMG proteins from monocotyledons and dicotyledons.

Chromosomal high-mobility-group (HMG) proteins occur ubiquitously in eukaryotes and their common structural and biochemical features indicate a critical role. In this context, we compared structural and functional aspects of HMG proteins from the monocotyledonous plant maize and the dicotyledonous plant Vicia faba. Besides biochemical similarities and immunological differences found between these proteins, the isolation and characterization of a cDNA encoding the V. faba homologue of the maize HMGa protein revealed great similarities between these two proteins, including the HMG-box DNA-binding motif and an acidic domain. Therefore, like the maize HMGa protein, the V. faba HMG protein belongs to the vertebrate HMG1 family, which consists of HMG proteins and transcription factors of various eukaryotes.

The relationship between social dysfunctioning and psychopathology among primary care attenders.

The extent of social dysfunctioning and its relationship to psychological disorders among Dutch primary care patients was examined. Social dysfunctioning in these patients was rather limited, but was more pronounced in patients with a psychological disorder than in those without. Disabilities were largely restricted to the occupational and social roles, with family role functioning and self-care relatively intact. Social dysfunctioning was moderately related to psychopathology, with higher levels of dysfunctioning in more severe and depressed cases. The extent of social dysfunctioning among patients with both anxiety and depression was similar to that of patients with a single diagnosis of depression. Depressed patients had a similar level of dysfunctioning to non-psychotic psychiatric out-patients. Analyses regarding the effects of diagnosis and severity on social dysfunctioning revealed considerable overlap between these two aspects of psychopathology. This study supports the need for a simultaneous but separate assessment of psychopathology and social dysfunctioning. However, future research should incorporate additional predictors of social dysfunctioning (e.g. personality, life events, long-term difficulties, physical disorders), and prospective studies should be conducted to clarify the temporal sequences of symptom severity, diagnosis, and comorbidity on the one hand, and social dysfunctioning on the other.

How neuroticism, long-term difficulties, and life situation change influence psychological distress: a longitudinal model.

The causal relationships between neuroticism (N), long-term difficulties (LTDs), life situation change (LSC), and psychological distress (PD) were examined using self-report and interview data from a 7-year, 3-wave study in a general population sample (N = 296). LTDs were classified as either endogenous (dependent) or exogenous (independent). We found that earlier neuroticism had a strong direct and a moderate indirect effect (through endogenous LTDs) on PD. The direct effect was strikingly stronger than those of LTDs and LSC. In addition, much correlation between endogenous LTDs, LSC, and PD could be attributed to the confounding effects of earlier neuroticism. High neuroticism tended to strengthen the effect of LSC on PD. These findings suggest that temperamental dispositions are more powerful than environmental factors in predicting PD.

Psychiatric diagnosis in an outpatient population. A comparative study of PSE-Catego and DSM-III.

Two diagnostic systems are compared in a psychiatric outpatient population of 175 patients. The Present State Examination (PSE)-Catego system identified 121 patients (69%) as "cases," whereas DSM-III identified 152 patients (87%) as cases. The two systems converged in 115 patients, yielding a kappa coefficient of only .32. Approximately one third of the DSM-III cases that were not detected by the PSE-Catego system was due to the restricted coverage of the latter system; the remaining two thirds could be attributed to differences in threshold and time framing. Compared with DSM-III, the PSE-Catego system showed a strong bias toward depression, and the system was extremely insensitive to the detection of social phobias and obsessive-compulsive disorders. Only 58% of cases of depression and 46% of cases of anxiety were diagnosed by both systems. The results are compared with other studies, and some consequences are discussed.