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.

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.

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.

[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.

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.

A genome-wide screen on the genetics of atopy in a multiethnic European population reveals a major atopy locus on chromosome 3q21.3.

BACKGROUND: Dissecting complex diseases in underlying distinct traits and studying these for their genetic basis might enhance the power as well as the specificity, of detection of disease genes. These phenotypes are known as intermediate phenotypes. OBJECTIVE: We were interested in the atopic basis of asthma, and used the sensitization to mite (Dermatophagoides pteronyssinus) allergens as a pathophysiologically important intermediate phenotype. METHODS: This time we performed a genome-wide scan based on the same already used multiethnic European population consisting of 82 nuclear families with at least two affected siblings. We carried out nonparametric as well as parametric MOD-score analyses based on the genotypes of 603 microsatellite markers. RESULTS: In comparison with our first genome-wide candidate region search three novel regions additionally appeared to be significant. We obtained significant results for the region 2p12 with a MOD score of 3.35 and for the region 16q21 with a MOD score of 4.18. The most significant result was found for the region 3q21.3 with the same microsatellite marker, which showed significant linkage to atopic dermatitis (AD) in another study with a MOD score of 4.51 and an nonparametric linkage analysis (NPL) of 4.00. CONCLUSION: Our findings indicate that atopy, allergic asthma, allergic rhinitis and AD on the one hand are distinct traits on both the clinical and genetic basis, but on the other hand, our results also underline that these traits are closely related diseases concerning the atopic basis of the traits.

The catechol-O-methyltransferase Val108/158Met polymorphism affects short-term treatment response to mirtazapine, but not to paroxetine in major depression.

The catechol-O-methyltransferase (COMT) is a major degrading enzyme in the metabolic pathways of catecholaminergic neurotransmitters such as dopamine and norepinephrine. This study investigated whether the functionally relevant Val(108/158)Met gene variant is associated with differential antidepressant response to mirtazapine and/or paroxetine in 102 patients with major depression (DSM-IV criteria) participating in a randomized clinical trial with both drugs. In patients treated with mirtazapine, but not paroxetine, allelic variations in the COMT gene were associated with differential response. COMT(VAL/VAL) and COMT(VAL/MET) genotype carriers showed a better response than COMT(MET/MET)-bearing patients in the mirtazapine group. Moreover, carriers of the COMT(VAL/VAL) or COMT(VAL/MET) genotype had significantly greater HAMD-17 (Hamilton Rating Scale for Depression 17 item version) score reductions than COMT(MET/MET) homozygotes from week 2 to 6, respectively, in the mirtazapine group. Time course of response and antidepressant efficacy of mirtazapine, but not paroxetine, seem to be influenced in a clinically relevant manner by this allelic variation within the COMT gene.

Nongenetic pathologic developments of brain-wave patterns in monozygotic twins discordant and concordant for schizophrenia.

Evidence from previous studies has suggested that the inter-individual differences in human brain-wave patterns (EEG) are predominantly determined by genetic factors. In particular, the within-pair EEG concordance of monozygotic (mz) twins was found to be typically as high as r = 0.81 across channels and frequency bands, thus being comparable to that between repeated assessments on the same individual with typically r = 0.83. Yet our investigations into mz twins discordant and concordant for schizophrenia yielded a significantly reduced within-pair EEG concordance for both, the pairs discordant for schizophrenia and the pairs concordant for schizophrenia (with concordance for schizophrenia assessed through a syndrome-oriented approach). A multivariate discriminant function of EEG parameters distinguished in a reproducible way between affected and unaffected subjects at an overall performance of >75% correctly classified subjects, while the severity of illness, as derived from EEG-differences between affected and unaffected subjects, was closely related to the severity of illness as provided by psychopathology syndrome scores. Consequently, EEG anomalies associated with schizophrenia and manifested differently in the mz co-twins concordant for schizophrenia are likely the effect of nongenetic, pathologic processes that evolved independently in the co-twins' genetically identical brains once the illness began to progress. The existence of such nongenetic processes would suggest a modification of the standard phenotype-to-genotype search strategies of molecular-genetic studies that aim to link the schizophrenia phenotype to genetic vulnerability factors.

Ethnicity-independent genetic basis of functional psychoses: a genotype-to-phenotype approach.

The functional psychoses schizophrenia, schizoaffective disorder, and bipolar illness represent complex clinical syndromes that are characterized by phenotypic heterogeneity. Yet evidence from numerous studies suggests that (1) the prevalence of schizophrenia and bipolar illness is with 1% very similar across ethnicities, and (2) a strong genetic component is involved in the disorders' pathogenesis. Using data from different US-American ethnicities (77 families with a total of 17 unaffected and 170 affected sib pairs; 276 marker loci), we searched for ethnicity-independent oligogenic susceptibility loci for which the between-sib genetic similarity in affected sib pairs deviated from the expected values. Specifically, we addressed the question of the extent to which genetic risk factors and their interactions constitute multigenic inheritance of functional psychoses across populations and might constitute universal targets for treatment. Our novel multivariate genotype-to-phenotype search strategy was based on a genetic similarity function that allowed us to quantify the inter-individual genetic distances d(x(i), x(j)) between the allelic genotype patterns x(i), x(j) of any two subjects i, j with respect to n loci l(1), l(2), em leader l(n). Thus, we were able to assess the between-ethnicity, the within-ethnicity, and the within-family genetic similarities. The problem of ethnicity-independent vulnerability was addressed by treating the Afro-American families as "training" samples, while the non-Afro-American families served as independent "test" samples. We evaluated the between-sib similarities, which were expected to deviate from "0.5" in affected sib pairs if the region of interest contained markers close to vulnerability genes. The reference value "0.5" was derived from the parent-offspring similarities that are always 0.5, irrespective of the affection status of parents and offspring. We found 12 vulnerability loci on chromosomes 1, 4, 5, 6, 13, 14, 18, and 20, that were reproducible across the two samples under comparison and therefore, likely to constitute an ethnicity-independent, oligogenic vulnerability model of functional psychoses. The elevated vulnerability appeared to be unspecific and to act in such a way that exogenous factors become more likely to trigger the onset of psychiatric illnesses.

Linguistic analysis of the speech output of schizophrenic, bipolar, and depressive patients.

Using speech samples of 100 patients suffering from schizophrenia, bipolar illness and major depression, we addressed the question of the extent to which the linguistic abnormalities in the speech of these patients represent diagnosis-specific characteristics or constitute independent, syndrome-like dimensions of the illnesses. All speech samples were transcribed by a professional linguist who was blind to both identity and diagnosis of the patients. The majority of the deviant linguistic variables was found to be common to all three diagnostic groups under comparison, while only a few linguistic variables exhibited statistically significant between-group differences. On the other hand, when the respective variables were analysed as a multivariate entity, the variety of subtle between-group differences allowed us to discriminate between the diagnostic groups at an overall performance of 72.7% correctly classified patients. There was an almost complete lack of association between linguistic abnormalities and psychopathology syndromes. In particular, we found no correlation between the syndrome 'formal thought disorder' and the large variety of linguistic variables used in this investigation. In consequence, we conjecture that linguistically deviant speech characteristics represent an independent syndrome complex manifested at varying intensities across mental illnesses, and that this syndrome complex deserves greater attention, not only with respect to the principal understanding of the underlying disturbances, but also as a potential target of therapeutical intervention.

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.

Mortality of patients with mood disorders: follow-up over 34-38 years.

BACKGROUND: All follow-up studies of causes of death in affective disordered patients have found they have markedly elevated suicide rates and a less reproducible increased mortality from other causes. The reported rates by gender, disorder type and treatment are more variable. METHODS: Hospitalised affective disordered patients (n=406) were followed prospectively for 22 years or more. Later, mortality was assessed for 99% of them at which time 76% had died. RESULTS: Standardised Mortality Rates (observed deaths/expected deaths) for patients were elevated especially for suicide and circulatory disorders in both men and women. Women actually had higher suicide rates but that did not take into account the twofold increase in general population rates for men. Unipolar patients had significantly higher rates of suicide than bipolar Is or IIs. In all groups long term medication treatment with antidepressants alone or with a neuroleptic, or with lithium in combination with antidepressants and/or neuroleptics significantly lowered suicide rates even though the treated were more severely ill. Although at the age of onset the suicide rates were most elevated, from ages 30 to 70 the rates were remarkably constant despite the different courses of illness. LIMITATIONS: The patients were identified as inpatients and followed prospectively. The treatments were uncontrolled and are not quantifiable but were documented during the follow-up. CONCLUSIONS: Men and women hospitalised for affective disorders have elevated mortality rates from suicide and circulatory disorders. Unipolars have higher suicide rates than bipolar Is or IIs. Long term medication treatment lowers the suicide rates, despite the fact that it was the more severely ill who were treated.

Oligogenic approaches to the predisposition of asthma in ethnically diverse populations.

Using the genome-wide screening data of the Collaborative Study on the Genetics of Asthma (CSGA) (226 families, 1,461 genotyped subjects, 323 marker loci) and Hutterite studies (129 families, 690 genotyped subjects, 365 marker loci), we applied a genetic similarity function in order to quantify the inter-individual genetic distances d(xi,xj) between feature vectors xi, xj made up by the allelic patterns of subjects i,j with respect to loci li, l2,..., ln. Based on this similarity function, we structurally decomposed the genetic diversity of the CSGA population in order to address the question of ethnicity-related asthma vulnerability for genetically homogenous CSGA subgroups. The question of ethnicity-independent asthma vulnerability was investigated with all CSGA families as training and the Hutterite families as replication samples. We evaluated the between-sib similarities, which were expected to deviate from "0.5" in affected sib pairs if the region of interest contained markers close to disease-causing genes. The reference value 0.5 was derived by determining the parent-offspring similarities, which are always 0.5, irrespective of the affection status of parents and offspring. We found 18 vulnerability loci on chromosomes 1, 3, 4, 5, 6, 8, 12, 13, and 14, which were remarkably reproducible in the CSGA and the Hutterite data and constituted an ethnicity-independent oligogenic model.

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.

Intraindividual specificity and stability of human EEG: comparing a linear vs a nonlinear approach.

We have applied the so-called "unfolding dimension approach" to reanalyze an earlier longitudinal EEG study. Both linear and nonlinear approaches show that the EEG comprises a static, person-specific part upon which nonstatic and state-specific parts are superimposed. The intraindividual specificity and stability of the genetic part are similar between methods. This is assessed by comparing the outcome of a person to his own outcomes at later times (14 days and 5 years later). The nonlinear method revealed a median correlation coefficient rho = 0.55, whereas advanced linear methods showed a median rho = 0.84. An apparent effect for the 5-year interval was detected with the nonlinear method and is discussed in terms of the different assumptions of the two approaches concerning EEG signal generation.

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.

Structural decomposition of genetic diversity in families with alcoholism.

Using genotypes of 280 marker loci on the 22 autosomes of 105 alcohol-dependent probands, their affected and unaffected sibs, as well as their parents, we iteratively constructed a genetic similarity function that enabled us to quantify the interindividual genetic distances d(x(i), xj) between feature vectors x(i), xj made up by the allelic patterns of individuals i, j with respect to loci l1, l2,...,ln. Based on this similarity function, we investigated the sib-sib similarities that are expected to deviate from "0.5" in affected sib pairs if the region of interest contains markers close to disease-causing genes. The reference value "0.5" was derived from the parents-offspring similarities, because these are independent of the affection status. The question of population admixture was addressed by means of multivariate structural analyses. These analyses led to four "natural" groups whose validity was tested through the father-mother similarities. Additionally, we determined the eigenvectors that optimally represented the genetic variation and found several marker configurations on chromosomes 1, 3, 7, 15, and 17 that reproducibly discriminated (p < or = 0.01) affected probands/sibs from unaffected sibs, while no such differences were found between affected probands and affected sibs.

Fluoxetine versus moclobemide: cross-comparison between the time courses of improvement.

Competitive statistical methods were used in a meta-analysis of the data of 440 fluoxetine-treated and 437 moclobemide-treated patients in order to address the issue of the timing of recovery from depression, and to elucidate potential differences in the onset of action between the two different classes of antidepressants. In spite of large biochemical and pharmacological differences, fluoxetine and moclobemide turned out to be virtually identical with regard to the overall efficacy, proportions and time characteristics of premature withdrawal, and most notably, the time course of recovery. The onset of improvement occurred in the majority of cases within the first two weeks of treatment and was highly predictive for the outcome after six weeks. The analyses yielded no indication of a delayed onset of action of antidepressants. Given the apparent nonspecificity of antidepressants, together with their relatively modest response rates, future research will need consider whether mechanisms different from those related to the monoaminergic systems may be involved in the pathogenesis of depression.

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.