Polypharmacy in psychiatry and weight gain: longitudinal study of 832 patients hospitalized for depression or schizophrenia, along with data of 3180 students from Europe, the U.S., South America, and China.

Epidemiologic data indicate that overweight and obesity are on the rise worldwide. Psychiatric patients are particularly vulnerable in this respect as they have an increased prevalence of overweight and obesity, and often experience rapid, highly undesirable weight gain under psychotropic drug treatment. Current treatment strategies in psychiatry are oriented towards polypharmacy, so that the information on drug-induced weight gain from earlier monotherapy studies is of very limited validity. We have analyzed the longitudinal data of 832 inpatients with ICD-10 diagnoses of either F2 (schizophrenia; n = 282) or F3 (major depression; n = 550) with the goal of ranking treatment regimens in terms of weight gain, side effects, and response to treatment. The patient data were complemented by the data of 3180 students aged 18-22 years, with which we aimed to identify factors that enable the early detection and prevention of obesity and mental health problems. After 3 weeks of treatment, 47.7% of F2 patients and 54.9% of F3 patients showed a weight gain of 2 kg and more. Major predictive factors were "starting weight" (r = 0.115), "concurrent medications" (r = 0.176), and "increased appetite"(r = 0.275). Between 11 and 30% of the observed variance in weight gain could be explained by these factors, complemented by sex and age. The comparison between monotherapy (n = 409) and polypharmacy (n = 399) revealed significant drawbacks for polypharmacy: higher weight gain (p = 0.0005), more severe side effects (p = 0.0011), and lower response rates (F2: p = 0.0008); F3: p = 0.0101). The data of 3180 students made it clear that overweight and obesity often begin early in life among those affected, and are interconnected with personality traits, while increasing the risk of developing psychosomatic disturbances, mental health problems, or somatic illnesses. Although the available data did not readily lead to a comprehensive, clinically applicable model of unwanted weight gain, our results have nevertheless demonstrated that there are ways to successfully counteract such weight gain at early stages of treatment.

Detailing the effects of polypharmacy in psychiatry: longitudinal study of 320 patients hospitalized for depression or schizophrenia.

Current treatment standards in psychiatry are oriented towards polypharmacy, that is, patients receive combinations of several antidepressants, antipsychotics, mood stabilizers, anxiolytics, hypnotics, antihistamines, and anticholinergics, along with other somatic treatments. In tandem with the beneficial effects of psychopharmacological drug treatment, patients experience significant adverse reactions which appear to have become more frequent and more severe with the rise of ubiquitous polypharmacy. In this study, we aimed to assess today's acute inpatient treatment of depressive and schizophrenic disorders with focus on therapeutic strategies, medications, adverse side effects, time course of recovery, and efficacy of treatments. Of particular interest was the weighing of the benefits and drawbacks of polypharmacy regimens. We recruited a total of 320 patients hospitalized at three residential mental health treatment centers with a diagnosis of either schizophrenic (ICD-10: "F2x.x"; n = 94; "F2 patients") or depressive disorders (ICD-10: "F3x.x"; n = 226; "F3 patients"). The study protocol included (1) assessment of previous history by means of the SADS Syndrome Check List SSCL-16 (lifetime version); (2) repeated measurements over 5 weeks assessing the time course of improvement by the Hamilton Depression Scale HAM-D and the Positive and Negative Syndrome Scale PANSS, along with medications and adverse side effects through the Medication and Side Effects Inventory MEDIS; and (3) the collection of blood samples from which DNA and serum were extracted. Polypharmacy was by far the most common treatment regimen (85%) in this study. On average, patients received 4.50 ± 2.68 medications, consisting of 3.30 ± 1.84 psychotropic drugs, plus 0.79 ± 1.13 medications that alleviate adverse side effects, plus 0.41 ± 0.89 other somatic medications. The treating psychiatrists appeared to be the main determining factor in this context, while «previous history¼ and «severity at baseline¼ played a minor role, if at all. Adverse drug reactions were found to be an inherent component of polypharmacy and tended to have a 2-3 times higher incidence compared to monotherapy. Severe adverse reactions could not be attributed to a particular drug or drug combination. Rather, the empirical data suggested that severe side effects can be triggered by virtually all combinations of drugs, provided patients have a respective vulnerability. In terms of efficacy, there were no advantages of polypharmacy over monotherapy. The results of this study underlined the fact that polypharmacy regimens are not equally suited for every patient. Specifically, such regimens appeared to have a negative impact on treatment outcome and to obfuscate the "natural" time course of recovery through a multitude of interfering factors. Evidence clearly speaks against starting just every therapeutic intervention in psychiatry with a combination of psychopharmaceuticals. We think that it is time for psychiatry to reconsider its treatment strategies, which are far too one-sidedly fixated on psychopharmacology and pay far too little attention to alternative approaches, especially in mild cases where psychotherapy without concurrent medication should still be an option. Also, regular exercises and sports can definitely be an effective therapeutic means in a considerable number of cases. General practitioners (GPs) are particularly in demand here.

Inflammatory processes linked to major depression and schizophrenic disorders and the effects of polypharmacy in psychiatry: evidence from a longitudinal study of 279 patients under therapy.

Over the past 2 decades, polypharmacy has become the de-facto standard of acute treatment in psychiatry where patients with psychiatric disorders receive a multiple medication regimen. There is growing evidence for a potential link between major psychiatric disorders and inflammatory processes. Combining these two aspects aims at avoiding polypharmacy attempts among patients with inflammatory activation through alternative treatment strategies. In this study, we addressed the following questions: (1) to what extent can polypharmacy be explained through the factors "diagnosis", "previous history", "severity at baseline", "age", "gender", and "psychiatrist in charge"; (2) what are the differences between polypharmacy and monotherapy regarding efficacy and side effect profiles; and (3) what amount of between-patient variance is explainable by the natural antibody immunoglobulin M (IgM) within each diagnostic group. This naturalistic longitudinal study was comprised of 279 patients under therapy with a clinical diagnosis of depressive (ICD-10: "F3x.x"; n = 195) or schizophrenic disorders (ICD-10: "F2x.x"; n = 84). The study protocol included (1) assessment of previous history by the SADS Syndrome Check List SSCL-16 (lifetime version); (2) repeated measurements over 5 weeks assessing the time course of improvement by the Hamilton Depression Scale HAM-D and the Positive and Negative Syndrome Scale PANSS, along with medication and unwanted side effects through the Medication and Side Effects Inventory MEDIS; and (3) the collection of blood samples from which DNA and serum were extracted. The association between inflammatory response system and psychiatric disorders was detailed by fitting multi-layer Neural Net (NN) models to the observed data ("supervised learning"). The same approach was used to set up prediction models of side effects. Our data showed that polypharmacy was omnipresent. Yet the various polypharmacy regimens had no advantage over monotherapy: we even found slightly larger baseline score reductions under monotherapy, independent of primary diagnoses and for comparable baseline severities. Most patients experienced unwanted side effects. The close link between side effects and treatment regimen was revealed by a linear model in which the mere number of drugs explained a significant (p < 0.001) proportion of the observed variance. As to the inflammatory response system: For the F2 patients, our NN model identified a 22.5% subgroup exhibiting a significant correlation of r = 0.746 (p = 0.0004) between global schizophrenia scores and IgM levels, along with a correct prediction of response of 94.4%, thus explaining 55.7% of the observed between-patient variance. For the F3 patients, our NN model identified a 19.6% subgroup exhibiting a significant correlation of r = 0.644 (p = 0.00003) between global depression scores and IgM levels, along a correct prediction of response of 89.6%, thus explaining 41.4% of the observed between-patient variance. Polypharmacy is omnipresent in today's acute treatment of psychiatric disorders. Given the large proportion of patients with unwanted side effects and the strong correlation between side effects and the number of drugs, polypharmacy approaches are not equally suited for every patient. In terms of efficacy, there are no advantages of polypharmacy over monotherapy. Most notably, our study appears to have cleared the way for the reliable identification of a subgroup of patients for whom the inflammatory response system is a promising target of therapeutic intervention.

Effect of helmet use on maxillofacial injuries due to bicycle and scooter accidents: a systematic literature review and meta-analysis.

Maxillofacial injury is a common injury resulting from bicycle (including e-bike) and scooter accidents. With 80,000 admissions to emergency departments in 2019, bicycle accidents account for more than half of all traffic-related emergency department visits in the Netherlands. The United States reports approximately 130,000 injuries and 1000 fatalities related to cycling annually. This systematic review and meta-analysis was performed to examine the protective effect of helmets against maxillofacial injuries resulting from bicycle and scooter (including e-bike and e-scooter) accidents. After a systematic literature search, 14 studies were found to be eligible for this systematic review. Of these, 11 were included in the meta-analysis. None of the included studies focused on vehicles with motors (e-bikes and e-scooters); all focused only on non-motorized vehicles. All included studies were non-randomized, which could have led to bias in the pooled results. Data from the included studies were tested for heterogeneity using the binary random-effects model (DerSimonian-Laird method), and the odds ratio for the occurrence of maxillofacial injury in cyclists wearing a helmet versus those not wearing a helmet was calculated by random-effects meta-analysis. Patients who had worn a helmet suffered significantly fewer maxillofacial injuries than patients who had not, in bicycle accidents (odds ratio 0.682). In conclusion, wearing a helmet has a significant protective effect against maxillofacial injury, indicating the need for strict helmet legislation.

Analysis of genetic diversity in patients with major psychiatric disorders versus healthy controls: A molecular-genetic study of 1698 subjects genotyped for 100 candidate genes (549 SNPs).

BACKGROUND: This study analyzed the extent to which irregularities in genetic diversity separate psychiatric patients from healthy controls. METHODS: Genetic diversity was quantified through multidimensional "gene vectors" assembled from 4 to 8 polymorphic SNPs located within each of 100 candidate genes. The number of different genotypic patterns observed per gene was called the gene's "diversity index". RESULTS: The diversity indices were found to be only weakly correlated with their constituent number of SNPs (20.5 % explained variance), thus suggesting that genetic diversity is an intrinsic gene property that has evolved over the course of evolution. Significant deviations from "normal" diversity values were found for (1) major depression; (2) Alzheimer's disease; and (3) schizoaffective disorders. Almost one third of the genes were correlated with each other, with correlations ranging from 0.0303 to 0.7245. The central finding of this study was the discovery of "singular genes" characterized by distinctive genotypic patterns that appeared exclusively in patients but not in healthy controls. Neural Nets yielded nonlinear classifiers that correctly identified up to 90 % of patients. Overlaps between diagnostic subgroups on the genotype level suggested that (1) diagnoses-crossing vulnerabilities are likely involved in the pathogenesis of major psychiatric disorders; (2) clinically defined diagnoses may not constitute etiological entities. CONCLUSION: Detailed analyses of the variation of genotypic patterns in genes along with the correlation between genes lead to nonlinear classifiers that enable very robust separation between psychiatric patients and healthy controls on the genotype level.

The Association of Helmet Use with the Occurrence of Maxillofacial Injuries Following Bicycle or Scooter Accidents: A Retrospective Cohort Study.

Study Design: Retrospective Cohort Study. Objective: Yearly, bicycle and scooter accidents in the Netherlands amount to 90 thousand emergency department visits. Maxillofacial injuries are common after cycling or scooter accidents. To prevent these injuries, helmet use might be beneficial. However, the effect of helmet use on maxillofacial injuries remains unclear. The aim of this retrospective study is to assess the effect of helmet use on maxillofacial injuries in patients who had a bicycle or scooter accident. Methods: We collected data from the emergency department of the Erasmus Medical Center in the period from October 2017 to October 2019. Patients that were involved in a bicycle or scooter accident and subsequently received a CT scan of the head were included. We compared the incidence of maxillofacial injuries in helmeted cyclists and scooter users to non-helmeted users. Descriptive and analytic statistics were computed. Level of statistical significance was set at p < 0.05. Results: Helmet use among scooter users was associated with a significant reduction in maxillofacial fractures (p < 0.001) and soft tissue injuries (p < 0.001). Helmet use among cyclists was not associated with a reduction in maxillofacial fractures (p = 0.17) or soft tissue injuries (p = 0.30). Helmet use was not associated with a reduction in soft tissue injuries of the lower face in both cyclists (p = 0.47) and scooter users (p = 0.24). Conclusions: Helmet use should be considered among cyclists and scooter users to prevent maxillofacial injuries. Especially unhelmeted scooter users might benefit from helmet use as this is associated with a lower incidence of maxillofacial injuries.

Predicting response to psychopharmacological treatment: survey of recent results.

INTRODUCTION: Treatment with antidepressants and antipsychotics, though effective, is unspecific as agents that differ greatly in their biochemical and pharmacological actions have virtually the same efficacy. Half of the patients with initial improvement show incomplete response, while a large proportion of patients exhibit a refractory clinical picture which is resistant to all treatment modalities. METHODS: Our analyses were based on a reference study of 2,848 depressive inpatients under monotherapeutic treatment with 7 different antidepressants or placebo, along with a naturalistic study of depressive and schizophrenic patients (296 inpatients, 363 outpatients) under today's "standard" polypharmaceutic treatment regimens. RESULTS: The empirical data suggested the following predictors of response: (1) severity at baseline, (2) early onset of improvement, (3) unwanted side-effects, and (4) medical comorbidity. A combination of these predictors with Therapeutic Drug Monitoring (TDM) methods has direct clinical relevance. DISCUSSION: Evidence-based approaches to personalized treatment help improving the unsatisfactory situation patients and clinicians are faced with, given today's incomplete treatments and the fact that the mechanisms by which antidepressants and antipsychotics ultimately exert their therapeutic effects are only marginally understood.

Mechanisms for the far-infrared absorption in liquid methane.

The time correlation function for the induced dipole moment in liquid methane was computed from molecular dynamics computer simulations for a thermodynamic state at a temperature of 122.2 K and density of 25.34 mol/l. We included first-order induction mechanisms from the electric fields emanated by octupole and hexadecapole moments, their field gradients, as well as electronic superposition. The octupole-induced dipole represents the most important contribution to the far-infrared absorption spectrum. However, additional mechanisms are important for absorption in liquid methane. By comparing the computed absorption line shape with the experimental spectrum, we found a very satisfactory agreement between the two if we account for detailed balancing.

[Community-based crisis home programme. Cost-efficient alternative to psychiatric hospitalization]. / Gemeindenahe psychiatrische Akutbehandlung in Gastfamilien. Kostengünstige Alternative zum Klinikaufenthalt bei hoher Patientenzufriedenheit.

BACKGROUND: Over recent decades, institutional psychiatric care has shifted its focus from traditional inpatient treatment to a variety of more advanced outpatient services. Within this context, a new "crisis home" programme (CHP) was launched in Zurich on 1 January 2005. With this programme, mentally ill patients can avoid hospitalization by living with a host family for a certain time period while receiving standard outpatient care. In this study we addressed the question of whether the quite substantial financial advantages of the Zurich CHP over traditional inpatient care are achieved at the expense of a reduced quality of care. SAMPLE AND METHODS: Between 1 January 2005 and 30 June 2007, a total of 33 patients enrolled in the Zurich CHP with an average stay of 19 days at host families. The vast majority of the patients (85%) were moderately to severely ill at study entry. Of these patients data were collected in a standardized way on the basis of five rating instruments. The statistical data analysis included cross-comparisons with corresponding inpatient data. RESULTS: Results showed that (1) the CHP works well in a routine setting and provides cost-efficient interventions for patients in acute crises; (2) the financial advantages of the Zurich host family programme over traditional inpatient care do not lead to a reduced quality in patient care; (3) patients suffering from severe mental illnesses clearly benefit from this programme, thus avoiding hospitalization. CONCLUSIONS: The Zurich CHP is a cost-efficient alternative to traditional inpatient treatment. Specifically, our results suggest that this type of acute crisis intervention should be established as a standard psychiatric care service.

Continuous Free Cortisol Profiles-Circadian Rhythms in Healthy Men.

CONTEXT: The pituitary-adrenal axis had historically been considered a representative model for circadian rhythms. A recently developed portable collection device has provided the opportunity to evaluate free cortisol profiles using the microdialysis approach in individuals free to conduct their day-to-day activities in their own surroundings. METHODS: Two separate experiments were conducted in healthy male volunteers. The total and subcutaneous (SC) free cortisol levels were measured at 10-minute intervals for a 24-hour period in one experiment, and the SC free cortisol levels were measured at 20-minute interval for 72 consecutive hours in free-living individuals in the second experiment. RESULTS: The characteristic circadian rhythm was evident in both serum total and SC free cortisol, with the lowest levels achieved and maintained in the hours surrounding sleep onset and the peak levels occurring in every individual around waking. In all free-living individuals, the circadian rhythm was consistent across the 72-hour period, despite a wide range of activities. All the participants also showed increased cortisol after the consumption of lunch. The lowest levels during all 24-hour periods were observed during the hours after lights off, at the onset of sleep. CONCLUSIONS: To the best of our knowledge, the present study is the first to report up to three consecutive 24-hour measurements of SC free cortisol in healthy individuals. We believe our study is a landmark study that paves the way for ambulatory monitoring of free cortisol profiles continuously for a period of 72 hours in free-living individuals performing their day-to-day activities whether healthy or with diseases involving the hypothalamic-pituitary-adrenal axis.

Analysis of verbal communication during teaching in the operating room and the potentials for surgical training.

BACKGROUND: Verbal communication in the operating room during surgical procedures affects team performance, reflects individual skills, and is related to the complexity of the operation process. During the procedural training of surgeons (residents), feedback and guidance is given through verbal communication. A classification method based on structural analysis of the contents was developed to analyze verbal communication. This study aimed to evaluate whether a classification method for the contents of verbal communication in the operating room could provide insight into the teaching processes. METHODS: Eight laparoscopic cholecystectomies were videotaped. Two entire cholecystectomies and the dissection phase of six additional procedures were analyzed by categorization of the communication in terms of type (4 categories: commanding, explaining, questioning, and miscellaneous) and content (9 categories: operation method, location, direction, instrument handling, visualization, anatomy and pathology, general, private, undefinable). The operation was divided into six phases: start, dissection, clipping, separating, control, closing. RESULTS: Classification of the communication during two entire procedures showed that each phase of the operation was dominated by different kinds of communication. A high percentage of explaining anatomy and pathology was found throughout the whole procedure except for the control and closing phases. In the dissection phases, 60% of verbal communication concerned explaining. These explaining communication events were divided as follows: 27% operation method, 19% anatomy and pathology, 25% location (positioning of the instrument-tissue interaction), 15% direction (direction of tissue manipulation), 11% instrument handling, and 3% other nonclassified instructions. CONCLUSION: The proposed classification method is feasible for analyzing verbal communication during surgical procedures. Communication content objectively reflects the interaction between surgeon and resident. This information can potentially be used to specify training needs, and may contribute to the evaluation of different training methods.

Trait-like individual differences in the human sleep electroencephalogram.

We aimed to examine whether commonly observed individual differences in sleep architecture and the sleep electroencephalogram reflect individual traits, which are amenable to a genetic investigation of human sleep. We studied intra-individual stability and inter-individual variation in sleep and sleep electroencephalogram spectra across four baseline recordings of eight healthy young men. A similarity concept based on Euclidean distances between vectors was applied. Visually scored sleep variables served as feature vector components, along with electroencephalogram power spectra in non-rapid-eye-movement and rapid-eye-movement sleep. The distributions of similarity coefficients of feature vectors revealed a clear distinction between high within-subject similarity (i.e. stability), and low between-subject similarity (i.e. variation). Moreover, a cluster analysis based on electroencephalogram spectra in both non-rapid-eye-movement and rapid-eye-movement sleep segregated all four baseline nights of each individual into a distinct cluster. To investigate whether high and low sleep pressure affects the similarity coefficients, normalized non-rapid-eye-movement sleep electroencephalogram spectra of the first and second half of the recordings were compared. Because the electroencephalogram changes systematically in the course of the night, within-subject variation no longer differed from between-subject variation. In conclusion, our data provide evidence for trait-like characteristics in the sleep electroencephalogram. Further studies may help to identify distinct phenotypes to search for genes underlying functional aspects of undisturbed human sleep.

Integration of genetic maps by polynomial transformations.

Currently available genetic maps differ in a variety of basic features; in particular, with respect to the total length of the genome. Consequently, the question arises as to the extent to which genetic maps are compatible to each other, as well as to the methods with which genetic maps can be transformed into one another. We propose a set of nonlinear, polynomial transformations that enable the integration of genetic maps at a sufficiently high overall precision. Our analysis of six major, publicly available maps, and iteratively optimized polynomials of up to degree 5, yielded differences of 90% of points. Similarly, we determined, at a slightly worse overall fit, those polynomials that enabled the reconstruction of sex-specific recombination estimates from sex-averaged data. Our results suggest that polynominal transformations may become a valuable extension of standard map construction methods due to a rapid integration of newly developed markers into existing maps. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:108-113, 2000.

Reliable computer-assisted classification of the EEG: EEG variants in index cases and their first degree relatives.

A method which optimizes on global properties of sample recordings is proposed for the definition of and the discrimination between electroencephalogram (EEG) classes. The sample was drawn from students at the University of Heidelberg from 1974 to 1978 and consists of 15 healthy index cases clinically ascertained as belonging to the low voltage EEG group. In addition, the three clinically defined groups: diffuse beta (18 index cases), borderline alpha (12 index cases) and monomorphous alpha (18 index cases) have been included in the study, as well as the first degree relatives of the index cases, thus providing a clinical classification into four groups. The proposed method provides an automatic and reliable classification algorithm using discriminant and cluster analysis. The relation between such an automatized classification and clinical classification schemes is investigated. In particular, the inheritance of the low voltage EEG, the question on sex differences and the question of a simple Mendelian mechanism had been examined. The method of random splittings had been applied for discriminant and cluster analysis. Our findings can be summarized as follows: (1) except for the monomorphous alpha EEG group, the clinical classification shows rather marginal separation (discriminating performance 60% to 75%), while a new and more reliable grouping scheme improves the discriminating performance up to 87% to 91%. The latter scheme leads to the concept of personal channel pattern (PCP) and was compared to the clinical classification scheme by means of contingency tables; (2) only a weak correlation between the clinically and PCP-based groups could be found (Cramér Index: 0.27). Accordingly, we continued to investigate the extent to which the proposed EEG classification scheme can nevertheless explain the genetic mechanisms apparently involved in the low voltage EEG. We thus considered the role of sex differences manifest in our proposed new grouping scheme; (3) males occurred more frequently in the new group 3 and females more frequently in the new group 1. In this regard, a much better correlation of the new groups between mothers and children than between fathers and children was observed; and (4) with help of our new PCP scheme, we have been able to reproduce a simple two gene Mendelian scheme to explain inheritance of the clinical low voltage EEG group. In this PCP-based scheme, the low voltage property does not occur when dominance of a certain gene (called gene A) is absent.

Schizophrenia and smoking: evidence for a common neurobiological basis?

Several previous investigations have suggested that the gene for the alpha 7-nicotinic receptor may play a role in the pathogenesis of schizophrenia and may be responsible for the heavy smoking among schizophrenic patients. In a study of 129 healthy controls and 127 schizophrenic, schizoaffective, and bipolar patients we have aimed 1) to confirm the potential association between schizophrenia and the alpha 7-nicotinic receptor, 2) to test the diagnostic specificity of alpha 7-receptor subunits with respect to psychiatric diagnoses, and 3) to investigate potential receptor differences between smokers and nonsmokers in the general population. Our analysis included the two dinucleotide polymorphisms D15S1360 and L76630 that are localized in a genomic fragment containing the alpha 7-nicotinic receptor gene CHRNA7. Highly significant differences (P < 0.0001) between the allele distributions of patients and controls were detected for these two markers with all three diagnostic subgroups contributing to the discrimination. An independently ascertained replication sample of 24 patients confirmed this finding. Our results suggested an unspecific vulnerability that depended on the severity of overall psychopathology in terms of the co-occurrence of psychopathology with no clear-cut boundary between the diagnostic entities. In comparison with healthy controls, this vulnerability was lowest among schizophrenics, intermediate among bipolars, and highest among schizoaffectives. As to the question of alpha 7-receptor differences between smokers and nonsmokers among the healthy control subjects, our analysis revealed no significant differences, thus indicating that the differences between patients and controls are more than just a smoker/nonsmoker distinction. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:173-177, 2000.

Suicide risk in patients with major depressive disorder.

Understanding the origins of suicide is the first step in preventing it. Review of the current literature has revealed only limited data from general practice and community samples; most research has been performed on inpatient psychiatric populations, and extended follow-ups are rare. Mood disorders were found to be highly associated with suicide, especially in patients with major depressive disorder. Depression is an important factor in suicides of adolescents and the elderly, but those with late-onset depression are at higher risk. Both comorbidity with other disorders, such as anxiety and agitation, and rapid changes in the depressive state, for instance after release from the hospital, increase the risk for suicide.

Selecting methodologies for the evaluation of differences in time to response between antidepressants.

BACKGROUND: The delay in the therapeutic effect of antidepressants is a considerable impediment to their successful clinical use, and attention has recently been focused on antidepressant drugs that may have a faster onset of action. DATA SYNTHESIS: Several methodologies exist for evaluating differences in time to response between antidepressants including the identification of the timepoint at which statistically or clinically significant differences between treatment groups emerge, pattern analysis, and survival analytical approaches. All have conceptual as well as practical advantages and disadvantages. CONCLUSION: The survival analytical approach is generally considered to be the most rigorous and sensitive in detecting differences in the speed of response of antidepressants, but the other methodologies provide useful information.

Effect of neuroleptics on positive and negative symptoms and the deficit state.

The concept of negative symptoms tries to operationalize a deficit syndrome observed in schizophrenia, but also in other disorders. The instruments for the measurement developed so far are unclear in their dimensional structure and validity. Further methodological development is needed. A new scale for measuring negative symptoms was derived from the AMDP-system and applied to results of drug trials with clozapine, fluperlapine, and haloperidol. The three drugs were equally effective on negative symptoms of acute and chronic schizophrenics.

Familial brain wave patterns: study of a 12-sib family.

In the sense of a paradigm for the heritability of complex psychiatric disorders, we compared the brain wave patterns of a 12-sib family with those of 144 unrelated controls and with those of 14 pairs of monozygotic twins. Under constant experimental conditions, electroencephalogram (EEG) parameters generally displayed a broad range of inter-individual differences, but were also remarkably stable over time within each subject, thus suggesting that the variation of EEG parameters forms a continuous phenotypic range rather than discrete phenotype classes. The distributions of all EEG parameters were found to be unimodal but significantly different from a normal distribution. Although an unimodal distribution speaks in favor of a polygenic additive mode of inheritance, this may not necessarily be true. Our findings might reflect the fact that a symmetric environmental distribution is converted through the underlying genotypes' norm of reaction into an asymmetric phenotype distribution. On the other hand, the distributions of the power-related EEG parameters were not that clearly unimodal, and with a larger sample size a trimodal solution might have become significant. With respect to the between-sib EEG similarity, we found the empirically derived value to be approximately half that of the within-subject similarity at 14-day intervals and of the within-pair similarity of monozygotic twins. This finding confirmed earlier results on monozygotic twins brought up together and reared apart, concerning the estimated value of h2. All in all, the EEG paradigm has clearly demonstrated that the methods of quantitative genetics represent a powerful tool once phenotypes designed to assess the variation of a trait are based on dimensional quantities.

Age-of-onset or age-cohort changes in the lifetime occurrence of depression?

In a re-investigation of the NIMH Psychobiology of Depression data, we have studied the question of shifts towards earlier onset together with the question of steadily increasing lifetime risk of major depression in successive birth-cohorts. Using a contingency-table approach, it turned out that inhomogeneities with respect to successive birth-cohorts exclusively showed up in the neighborhood of principally unobservable combinations of the variables under investigation. Standard approaches to testing independence in cross-classified data, such as the quasi-independence model, yielded highly significant results. Through the definition of a log-linear model with weights which replaces the 'discrete' truncation of the quasi-independence approach by a 'smoothed' truncation, it was possible to fully explain the observed age-of-onset shifts, thus supporting the hypothesis that age-of-onset and birth-cohort are independent. With respect to the question of generational changes in the lifetime risk of depression this independence implied that such changes should occur at equal rates across all ages of onset. The analysis yielded significantly larger cohort sizes for the two youngest birth-cohorts, a fact which might be interpreted as an indication of increasing environmental impacts on the genetically predisposed vulnerability during recent years. However, our cross-sectional survey data were, by design, not an optimal basis for a reliable assessment of changes in the lifetime risk of depression, because the risk estimate derived from affected-only survey data corresponds to the probability that a depressive belongs to a certain birth-cohort and is only loosely related to the lifetime risk of this cohort (which is the probability that a person belonging to a certain birth-cohort develops depression). We therefore conclude, firstly, that method effects are likely to explain a major portion of secular trends thus far reported in the literature, and, secondly, that there appears to be no clear necessity to include changing environmental effects into quantitative genetic modelling.