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.

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.

[The "Psychopathologic laboratory" at Burghölzli. Development and termination of the working relationship of C.G. Jung and Eugen Bleuler]. / Das "psychopathologische Laboratorium" am "Burghölzli". Entwicklung und Abbruch der Arbeitsbeziehung C.G. Jung/E.Bleuler.

C.G. Jung was on the staff of the University Psychiatric Clinic in Zurich ("Burghölzli"), headed by Eugen Bleuler, from 1900 to 1909; he became a senior physician in 1905. In correspondence with Sigmund Freud, Jung claimed that he had informed Bleuler about the subject of psychoanalysis and had recruited him for the movement. In fact, it can be shown that Bleuler was familiar with Freud's publications even before Jung came to Burghölzli and that he had written a very positive review of the hysteria study. Jung received his doctorate (1902) and postdoctoral qualification as university lecturer based on Bleuler's reports to the Department of Medicine and continued to give lectures on certain recurring topics, such as the theory of hysteria, until the summer semester of 1914, well after his resignation. Minutes of department meetings that have not previously been evaluated appear to indicate that the department's rejection of the founding of a "psychopathologic research laboratory," expected by Jung,was a major factor leading to his resignation on March 7, 1909. The importance of other events for Bleuler's relationship with Jung--the unsuccessful attempt at an analytical treatment of Otto Gross or Jung's relationship with Sabina Spielrein--cannot be demonstrated based on current sources.

Development and termination of the working relationship of C. G. Jung and Eugen Bleuler 1900-1909.

From 1900 to 1909, C. G. Jung was on the staff of the University Psychiatric Clinic in Zurich ('Burghölzli'), headed by Eugen Bleuler, where he became a senior physician (Sekundararzt) in 1905. Jung received his doctorate (1902) and postdoctoral qualification as a university lecturer (Habilitation) based on Bleuler's reports to the department of medicine, and he continued to give lectures on certain recurring topics, such as the theory of hysteria, until summer semester 1914, well after his resignation. Minutes of department meetings that have not previously been evaluated appear to indicate that a major factor leading to Jung's resignation on 7 March 1909 was the department's rejection of the founding of the 'psychopathologic research laboratory' that he had expected. The importance of other events for Bleuler's relationship with Jung - the unsuccessful attempt at an analytical treatment of Otto Gross, and Jung's relationship with Sabina Spielrein - cannot be determined from current sources.

[The schizophrenic spectrum: an epidemiological viewpoint]. / Gedanken zum schizophrenen Spektrum aus epidemiologischer Sicht.

In epidemiological terms there is no clear demarcation between health and illness. This is also true for the schizophrenic spectrum, where sub-clinical (sub-syndromal, sub-diagnostic) syndromes embrace schizotypical, schizoid and paranoid personality disorders and personality features, which in the general population are much more prevalent than schizophrenias themselves. Early recognition of risk cases and mild cases is decisive for prophylaxis. Several diagnostic instruments are available for this purpose, but satisfactory confirmation of their predictive power and validity by prospective studies is lacking. Alongside traditional, clinical research on schizophrenia, future epidemiological research, focusing increasingly on the whole schizophrenic spectrum, may be expected to yield important new insights confirming a dimensional rather than a categorical distribution of traits and syndromes and providing powerful arguments against the discrimination and stigmatisation suffered by schizophrenic patients.

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.

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.

[Intersubjectivity and interpersonal relations of schizophrenics]. / Intersubjektivität und Interpersonalität bei Schizophrenen.

Original accounts of an introspectively and linguistically highly gifted schizophrenic woman serve as a means to reflect about the meaning of the concept of intersubjectivity in the sense of Husserl, the constitution of self and world and its failure in the schizophrenic ego disorder. Concerning general psychopathology, there can be attempted to propose a typology of disordered intersubjectivity and consequently interpersonality. Psychotherapy of schizophrenics means reconstruction of intersubjectivity.

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.

[Orthodoxy against heretics. Correspondence of Gaupp and Kretschmer to Eugen Bleuler]. / Recht- und Andersgläubige. Briefe von Gaupp und Kretschmer an Eugen Bleuler.

A letter of R. Gaupp to Eugen Bleuler (1906) illustrates the contradictory reception of psychoanalysis. Letters from E. Kretschmer to Eugen Bleuler (1920) reflect the devalorization of Kretschmer by E. Kraepelin. The orthodox systems of the authorities are intolerant towards heretics.

[Dissociation and schizophrenia. Schizophrenias--a dissociative nosopoietic construct?]. / Dissoziation und Schizophrenie. Die Schizophrenien--ein dissoziiertes nosopoietisches Konstrukt?

The historical roots of the nosopoietic construct schizophrenia are traced: the nosographic construction by Kraepelin, an act of unification and split at the same time. The name schizophrenia reflects the tradition of the model of dissociation which is aetiologically connected with the idea of weakness of the synthetic power of the psyche: psychasthenia. In the establishment of the supposed nosological entity schizophrenia, the name-giving idea of dissociation was almost forgotten. Thus, nowadays Dissociative Disorders are classified in ICD and DSM separately from schizophrenic disorders, but it must be borne in mind that the schizophrenic disorders represent the most severe of disorders, hypothetically based on dissociation, namely, fragmentation of the ego.

[Occultism, parapsychology and the esoteric from the perspective of psychopathology]. / Okkultismus, Parapsychologie und Esoterik in der Sicht der Psychopathologie.

The concepts and main themes of occultism, parapsychology and esoterics are set in comparison to religion, spirituality, mysticism. The cultural relativity of these concepts is emphasised. Occultism means dealing with phenomena, processes, and/or powers which are not accessible to "normal perception". The manipulation of such powers is effected via (white, black, grey) magic. Parapsychology, in its popular sense, deals with occult phenomena, whereas scientific parapsychology investigates them empirically. Esoterics is a complex of beliefs within a hermetic tradition about occult processes and about desting after death. Transpersonal psychology deals with these issues while calling them "spiritual". Effects of paranormal experiences and actions on the side of the actor as well as the adept are discussed: personality types, interpersonal effects, crises and psychoses (mediumistic psychoses). The concept of dissociation of subpersonalities (subselves) appears to be a viable perspective to explain these phenomena. In mediumistic psychoses, the splitting of non-ego parts of the psyche leads to a manifestation of schizophrenic symptoms. Dangers for mental health are an ego inflation by self-attribution of "superhuman" power. A personality disposition for parapsychological perception and/or action may be seen in schizotypia and similar near-psychotic "personalities up the border". Adepts of occultism may present with a "false self" in the sense of Winnicott.

Speaking behavior and speech sound characteristics in acute schizophrenia.

Based on a sample of 45 hospitalized, acute-schizophrenic patients and 45 carefully matched controls, we investigated the non-verbal characteristics of schizophrenic speech by means of an 'acoustic' speech analysis and determined the extent to which speaking behavior and speech sound characteristics had adjusted toward normal values at the time of hospital release. Using a multivariate discriminant function derived from a previous study of chronic schizophrenics, totally 77 (85.6%) individuals of our patient and control sample could be correctly classified by a set of 12 acoustic variables at entry into study. At hospital release, the majority of patients (64.4%) still exhibited speech impairment although acute psychopathology had significantly improved. A configuration of 6 acoustic variables, assessed at the time point of entry into study, predicted at high reliability the severity of the negative syndrome at hospital release. Acute medication effects did not explain these findings, thus underlining the potential diagnostic relevance of the speech analysis method. With respect to the relationship between speech characteristics and acute psychopathology throughout the time course of recovery, our results suggest that changes in speaking behavior and speech sound characteristics may be distinct aspects of schizophrenia that can persist in a subgroup of patients over a long period, mostly beyond the time point of hospital release. Accordingly, the speech analysis method might become very useful in detailing the nature and severity of deficits in patients after remission of positive symptoms.

Positron emission tomography and fluorodeoxyglucose studies of metabolic hyperfrontality and psychopathology in the psilocybin model of psychosis.

The effects of the indolehallucinogen psilocybin, a mixed 5-HT2 and 5-HT1 agonist, on regional cerebral glucose metabolism were investigated in 10 healthy volunteers with PET and [F-18]-fluorodeoxyglucose (FDG) prior to and following a 15- or 20-mg dose of psilocybin. Psychotomimetic doses of psilocybin were found to produce a global increase in cerebral metabolic rate of glucose (CMRglu) with significant and most marked increases in the frontomedial and frontolateral cortex (24.3%), anterior cingulate (24.9%), and temporomedial cortex (25.3%). Somewhat smaller increases of CMRglu were found in the basal ganglia (18.5%), and the smallest increases were found in the sensorimotor (14.7%) and occipital cortex (14.4%). The increases of CMRglu in the prefrontal cortex, anterior cingulate, temporomedial cortex, and putamen correlated positively with psychotic symptom formation, in particular with hallucinatory ego disintegration. The present data suggest that excessive 5-HT2 receptor activation results in a hyperfrontal metablic pattern that parallels comparable metabolic findings associated with acute psychotic episodes in chronic schizophrenics and contrasts with the hypofrontality in chronic schizophrenic patients.

Metabolic hyperfrontality and psychopathology in the ketamine model of psychosis using positron emission tomography (PET) and [18F]fluorodeoxyglucose (FDG).

To date, the ketamine/PCP model of psychosis has been proposed to be one of the best pharmacological models to mimic schizophrenic psychosis in healthy volunteers, since ketamine can induce both positive and negative symptoms of schizophrenia. At subanesthetic doses, ketamine has been reported to primarily block N-methyl-D-aspartate (NMDA) receptor complex giving support to a glutamate deficiency hypothesis in schizophrenia. Positron emission tomography was used to study ketamine-induced psychotic symptom formation in relation to cerebral metabolic alterations in healthy volunteers. Our study shows that NMDA receptor blockade results in a hyperfrontal metabolic pattern. Increased metabolic activity in the frontomedial and anterior cingulate cortex correlated positively with psychotic symptom formation, in particular with ego pathology. Analysis of correlations between syndrome scores and metabolic rate of glucose (CMRglu) or metabolic gradients (ratios) revealed that each psychopathological syndrome was associated with a number of metabolic alterations in cortical and subcortical brain regions, suggesting that not a single brain region, but distributed neuronal networks are involved in acute psychotic symptom formation.

[Harmony--idea and ideal]. / Das Ganze--Idee und Ideal.

The concept of the whole as an ideal of gestalt and value is sketched. In the concrete situation of healer and patient a multiperspective approach rather than a realization of wholeness has to be enough, taking into account somatic, physiological, intraindividual-psychological, interpersonal-social and transpersonal aspects of personalities in diagnosis and treatment.

Speaking behavior and voice sound characteristics associated with negative schizophrenia.

Based on a sample of 42 chronic schizophrenic patients and 42 carefully matched controls, we investigated potential relationships between acoustic variables on the one hand, and negative syndromes, positive syndromes and affective disturbances, on the other. A set of 12 acoustic variables automatically assessed in a standardized experimental setting allowed an almost perfect discrimination between schizophrenic patients and normal subjects. Acute side-effects of medication did not explain this finding. However, the question of whether the observed changes in speaking behavior and voice sound characteristics were caused by long-term neuroleptic treatment, for example, as a consequence of tardive dyskinesia, could not be answered by our investigation. In view of a biological validation of the negative-positive model of schizophrenia, the reliability of various psychopathological subscales was tested through repeated assessments at 14 day intervals. We found most psychopathology scores to be sufficiently stable and reproducible over time, thus representing a suitable basis for the estimation of severity with respect to the negative and positive component of schizophrenia. Using the first measurements as training samples and the second measurements of 14 days later as test samples, discriminant analysis yielded conclusive proof of a close relationship between acoustic variables and the severity of the negative and positive component of schizophrenia. In particular, by means of "objective" acoustic variables and under the constraint of reproducibility, 75.9% of patients were correctly classified as low or high scorers with respect to the negative syndrome, 71.9% of patients with respect to the positive syndrome, and 79.4% of patients with respect to their depressive symptomatology.

[The ego/self experience of schizophrenic patients]. / Die Ich/Selbst-Erfahrung Schizophrener.

The self experience of schizophrenics (i.e. their ego-pathology) is conceptualized in a theoretical model of five basic dimensions of ego consciousness (identity, activity, demarcation, consistence/coherence, vitality). A systematic empirical study uses the Ego-pathology-Inventory (with 53 items, Interraterreliability Kappa 0.9, Retestreliability 0.65). The study population consists of 552 schizophrenics, 25 borderline personality disorders, 87 depressive disorders. Ego-pathology clearly differs the three diagnostic groups. Confirmatory factorial analysis allows to accept the theoretical model. Various external measurements correlate with ego pathology. Three empirical syndromes resulted from statistical search for data-structures. A series of arguments for validation of the concept allow the conclusion the the proposed ego pathology concept is a viable approach for empirically studying the experimental core of the schizophrenias.