The multifaceted concept of mental disorder.

The concept of mental disorder has many facets. Specific concepts of disease or disorder stand for individual entities, classified as diagnoses. Ideally, they are based on discrete physical, neurobiological or - as is the case with hereditary diseases - genetic findings. However, the majority of mental disorders are still lacking such biological bases of definition. Hence, mental disorders of unknown origin are classified by their patterns of symptoms that show an above-chance co-occurrence and run a similar course.Behind the specific concepts of disease and disorder lies a general concept. It plays a significant role in daily life and underlies the context-specific notions. It defines what constitutes being ill as such independently of diagnosis. In everyday life we frequently experience being ill without at first knowing what we are actually suffering from. Perceivable signs indicating mental disorder in general include pain, fever, physical weakness, irritability, depressiveness, disturbed sleep and cognitive and other types of dysfunction. Various conditions are characterized by a prodromal stage before a sufficient number of typical symptoms permitting a diagnosis appear.Typical of disease or disorder is its progression, a course over time leading to deterioration or improvement, to recovery or a fatal end. Syndromes that show no variation over time are no longer classified as mental disorders, but as personality disorders or disabilities (e. g. mental disability) - formerly infirmities - mostly cognitive in type. Contextual concepts of mental disorder encompass a general concept, used in day-to-day life, and the medical or specific concepts mainly define the individual disorders via diagnoses. The social and legal contexts of mental disorder will also be discussed.

Negative symptoms and their association with depressive symptoms in the long-term course of schizophrenia.

Depressive symptoms abound in schizophrenia and even in subclinical states of the disorder. We studied the frequency of these symptoms and their relationship to negative symptoms from the first psychotic episode on over a long-term course of 134 months on data for 107 patients in our ABC Schizophrenia Study. Prevalence rates of 90 % for presenting at least one negative symptom and of 60 % for presenting at least one depressive symptom in the first psychotic episode illustrate the frequency of these syndromes. After the remission of psychosis the rates fell to 50 % (negative symptoms) and 40 % (depressive symptoms) over a period of 5 years, remaining stable thereafter. After we broke the negative syndrome down into (SANS) subsyndromes, a positive association emerged between anhedonia and depressive symptoms and remained stable over the entire period studied. In contrast, the association between abulia and depression grew increasingly pronounced over the illness course. However, a more detailed look revealed this to be the case in female patients only, whereas male patients showed no such association of these symptom dimensions. We have no explanation at hand for this sex difference yet.

Smaller than expected cognitive deficits in schizophrenia patients from the population-representative ABC catchment cohort.

Most neuropsychological studies on schizophrenia suffer from sample selection bias, with male and chronic patients being overrepresented. This probably leads to an overestimation of cognitive impairments. The present study aimed to provide a less biased estimate of cognitive functions in schizophrenia using a population-representative catchment area sample. Schizophrenia patients (N = 89) from the prospective Mannheim ABC cohort were assessed 14 years after disease onset and first diagnosis, using a comprehensive neuropsychological test battery. A healthy control group (N = 90) was carefully matched according to age, gender, and geographic region (city, rural surrounds). The present sample was representative for the initial ABC cohort. In the comprehensive neuropsychological assessment, the schizophrenia patients were only moderately impaired as compared to the healthy control group (d = 0.56 for a general cognitive index, d = 0.42 for verbal memory, d = 0.61 for executive functions, d = 0.69 for attention). Only 33 % of the schizophrenia patients scored one standard deviation unit below the healthy control group in the general cognitive index. Neuropsychological performance did not correlate with measures of the clinical course including age at onset, number of hospital admissions, and time in paid work. Thus, in this population-representative sample of schizophrenia patients, neuropsychological deficits were less pronounced than expected from meta-analyses. In agreement with other epidemiological studies, this suggests a less devastating picture of cognition in schizophrenia.

Shades of vulnerability: latent structures of clinical caseness in prodromal and early phases of schizophrenia.

The underlying structures of clinical caseness and need of care in prodromal (i.e., at-risk) and early phases of schizophrenia remain poorly characterized in their essential psycho-behavioral coherence. To identify the schizophrenia proneness-related subtypes within a population of young help-seekers referred to a dedicated, community-based early detection program (Programma 2000). A sample of consecutive referrals (n = 168) for suspected psychosis or first-episode schizophrenia spectrum psychosis received a detailed clinical assessment, including the early recognition inventory for the retrospective assessment of the onset of schizophrenia checklist. We used exploratory factor analysis (EFA) to determine the underlying dimensional structure and latent class analysis (LCA) to identify putative vulnerability subtypes. EFA identified four factors: dysphoria (irritability tension), paranoid autocentrism, introversive withdrawal, and disturbed subjective experience. LCA distinguished three classes, interpretable as carrying different degrees of "proneness to schizophrenia psychosis," which best captured the underlying continuum of clinical severity. The validity of the three classes was supported by distinct patterns of association with major clinical variables (i.e., diagnostic staging at referral). Vulnerability to schizophrenia psychosis in young help-seekers may manifest in three major clinical prototypes, presenting common levels of dysphoria and social withdrawal but different degrees of paranoid autocentrism and disturbed subjective experience. Overall, the results provide the empirical background to dissect shared features of clinical caseness from more schizophrenia-specific vulnerability components. This is of value for the refinement of the clinical staging model as well as for the pragmatic implementation of multiple-gate screening programs.

The Bavarian royal drama of 1886 and the misuse of psychiatry: new results.

The deaths of King Ludwig II of Bavaria and Bernhard von Gudden, Professor of Psychiatry in Munich, in Lake Starnberg near Munich on 13 June 1886 have often been mentioned in the psychiatric-historical literature and in fiction. Von Gudden had written a psychiatric assessment of the King, rating him permanently mentally ill and incapable of reigning. Ludwig II was declared legally incapacitated, dethroned and psychiatrically interned. We will report on an interdisciplinary research project conducted at the Heidelberg Academy of Sciences and Humanities. Information was collected from state, local and private archives in Germany and abroad on: (1) the correctness of the psychiatric assessment in form and content; (2) the constitutional basis of the deposition; and (3) its background, motives and execution. The results show that the psychiatric assessment was incorrect in substance and form. They highlight how those in power used psychiatry for their own purposes.

The functional coding variant Asn107Ile of the neuropeptide S receptor gene (NPSR1) is associated with schizophrenia and modulates verbal memory and the acoustic startle response.

Recently, the neuropeptide S (NPS) neurotransmitter system has been identified as a promising psychopharmacological drug target given that NPS has shown anxiolytic-like and stress-reducing properties and memory-enhancing effects in rodent models. NPS binds to the G-protein-coupled receptor encoded by the neuropeptide S receptor gene (NPSR1). A functional variant within this gene leads to an amino-acid exchange (rs324981, Asn107Ile) resulting in a gain-of-function in the Ile107 variant which was recently associated with panic disorder in two independent studies. A potential psychopharmacological effect of NPS on schizophrenia psychopathology was demonstrated by showing that NPS can block NMDA antagonist-induced deficits in prepulse inhibition. We therefore explored a potential role of the NPSR1 Asn107Ile variation in schizophrenia. A case-control sample of 778 schizophrenia patients and 713 healthy control subjects was successfully genotyped for NPSR1 Asn107Ile. Verbal declarative memory and acoustic startle response were measured in subsamples of the schizophrenia patients. The case-control comparison revealed that the low-functioning NPSR1 Asn107 variant was significantly associated with schizophrenia (OR 1.19, p=0.017). Moreover, specifically decreased verbal memory consolidation was found in homozygous Asn107 carriers while memory acquisition was unaffected by NPSR1 genotype. The schizophrenia patients carrying the Ile107 variant demonstrated significantly reduced startle amplitudes but unaffected prepulse inhibition and habituation. The present study confirms findings from rodent models demonstrating an effect of NPS on memory consolidation and startle response in schizophrenia patients. Based on these findings, we consider NPS as a promising target for antipsychotic drug development.

A promoter variant of SHANK1 affects auditory working memory in schizophrenia patients and in subjects clinically at risk for psychosis.

Mutations in postsynaptic scaffolding genes contribute to autism, thus suggesting a role in pathological processes in neurodevelopment. Recently, two de novo mutations in SHANK3 were described in schizophrenia patients. In most cases, abnormal SHANK3 genotype was also accompanied by cognitive disruptions. The present study queries whether common SHANK variants may also contribute to neuropsychological dysfunctions in schizophrenia. We genotyped five common coding or promoter variants located in SHANK1, SHANK2 and SHANK3. A comprehensive test battery was used to assess neuropsychological functions in 199 schizophrenia patients and 206 healthy control subjects. In addition, an independent sample of 77 subjects at risk for psychosis was analyzed for replication of significant findings. We found the T allele of the SHANK1 promoter variant rs3810280 to lead to significantly impaired auditory working memory as assessed with digit span (12.5 ± 3.6 vs. 14.8 ± 4.1, P < .001) in schizophrenia cases, applying strict Bonferroni correction for multiple testing. This finding was replicated for forward digit span in the at-risk sample (7.1 ± 2.0 vs. 8.3 ± 2.0, P = .044). Previously, altered memory functions and reduced dendritic spines and postsynaptic density of excitatory synapses were reported in SHANK1 knock-out mice. Moreover, the atypical neuroleptic clozapine was found to increase SHANK1 density in rats. Our findings suggest a role of SHANK1 in working memory deficits in schizophrenia, which may arise from neurodevelopmental changes to prefrontal cortical areas.

Novel schizophrenia risk gene TCF4 influences verbal learning and memory functioning in schizophrenia patients.

BACKGROUND: Recently, a role of the transcription factor 4 (TCF4) gene in schizophrenia has been reported in a large genome-wide association study. It has been hypothesized that TCF4 affects normal brain development and TCF4 has been related to different forms of neurodevelopmental disorders. Schizophrenia patients exhibit strong impairments of verbal declarative memory (VDM) functions. Thus, we hypothesized that the disease-associated C allele of the rs9960767 polymorphism of the TCF4 gene led to impaired VDM functioning in schizophrenia patients. METHOD: The TCF4 variant was genotyped in 401 schizophrenia patients. VDM functioning was measured using the Rey Auditory Verbal Learning Test (RAVLT). RESULTS: Carriers of the C allele were less impaired in recognition compared to those carrying the AA genotype (13.76 vs. 13.06; p = 0.049). Moreover, a trend toward higher scores in patients with the risk allele was found for delayed recall (10.24 vs. 9.41; p = 0.088). The TCF4 genotype did not influence intelligence or RAVLT immediate recall or total verbal learning. CONCLUSION: VDM function is influenced by the TCF4 gene in schizophrenia patients. However, the elevated risk for schizophrenia is not conferred by TCF4-mediated VDM impairment.

An early improvement threshold to predict response and remission in first-episode schizophrenia.

BACKGROUND: Early improvement with treatment is thought to be important in patients with first-episode schizophrenia, yet a valid definition is still outstanding. AIMS: To develop a valid definition of early improvement and test its predictive validity regarding response and remission. METHOD: We examined 188 in-patients with first-episode schizophrenia. Early improvement was defined as improvement in Positive and Negative Syndrome Scale (PANSS) total score at week 2, response as a 40% PANSS total score improvement at end-point, and remission according to consensus criteria. RESULTS: Reasonable predictive validity of early improvement was found for a 46% PANSS total score improvement at week 2 and a 50% improvement for remission (area under the curve: response 0.707, remission 0.692). Estimated confidence intervals ranged from 26 to 62% PANSS reduction for response and remission. CONCLUSIONS: Patients with a first episode of schizophrenia should improve by at least 30% in PANSS total score at week 2 to achieve response and remission.

From Onset and Prodromal Stage to a Life-Long Course of Schizophrenia and Its Symptom Dimensions: How Sex, Age, and Other Risk Factors Influence Incidence and Course of Illness.

The core symptoms of psychosis-delusions, hallucinations, and thought disorders-are not unique to the disorder traditionally called schizophrenia. They occur at the early stages of various brain diseases, too. Psychosis seems to be a preformed pattern of response of the human brain. Most schizophrenia onsets are marked by a prodromal stage extending over several years and producing the maximum of social consequences. Schizophrenia incidence shows a steep increase culminating at age 15 to 25 years in males. In females it reaches a first peak at age 15 to 30 years and a second, flatter peak at menopausal age (44-49 years). Thereafter, incidence declines to a plateau at later ages. Unlike what the findings of most large-scale epidemiological studies applying an upper age limit of 45 to 55 years suggest, schizophrenia is a disorder of all ages. The lifetime risk seems to be the same for both sexes. The lower incidence in premenopausal women is accounted for by the downregulating effect of oestrogen on dopamine receptors. This hormonal protective effect is antagonised by the genetic effect of a high familial load. In the long-term illness course, right-censored to 11.2 years following first admission, the number of psychotic relapse episodes ranges from 0 to 29 with a mean of 3. The positive symptom dimension produces the highest number of relapses and the shortest duration of exacerbations with a mean length of two months. The depressive and negative symptom dimensions show exacerbations extending over nearly six months on average. Following the first illness episode symptom scores decline sharply, reaching a plateau five years after first admission. Negative symptoms come to a plateau after 2 to 3 years in females and after 5 years in males. Depression is the most frequent type of symptom in the long-term course. In the light of these results urgent treatment issues will be discussed.

Predictors of treatment response to psychological interventions in people at clinical high risk of first-episode psychosis.

AIM: Psychological interventions, such as cognitive behavioural therapy (CBT) and supportive counselling (SC), are used to treat people with schizophrenia and people at clinical high risk (CHR) of psychosis. However, little information is available on predictors of treatment response. This study aims to identify such predictors of psychological interventions in CHR. METHODS: A total of 128 help-seeking CHR outpatients were randomized into two groups-integrated psychological intervention (IPI), including CBT, and SC-for 12 months. Multiple regression analysis was used to identify demographic, symptomatic and functional variables that predict improvement in positive (PANSS Positive), negative (PANSS Negative) and basic symptoms (Basic symptom total score) and improvement in functioning (GAF) at 1-year follow up. RESULTS: In the merged group (IPI + SC), people who lived independently, were younger and presented with higher baseline functioning showed more improvement in symptomatic outcomes at follow up. Negative symptoms at baseline predicted less improvement in positive and basic symptoms. Being married or cohabiting and living in the primary family were found to correlate with good functioning at 1-year follow up. CONCLUSIONS: Younger CHR individuals and those who are functioning well may particularly benefit from early intervention. Treatment might need to be modified for low-functioning CHR and those who already display higher scores of negative symptoms. Registration number: NCT00204087.

Further evidence for a functional role of the glutamate receptor gene GRM3 in schizophrenia.

In recent years, evidence has been accumulating indicating a major role of glutamate in the pathogenesis and pathophysiology of schizophrenia. Of particular importance in this regard are the metabotropic glutamate receptors (GRM). Thus, a recently published trial of the amino acid analogue LY2140023, which exerts its effects through the activation of the glutamate receptors GRM3/GRM2, showed an improvement of positive and negative symptoms comparable to treatment with olanzapine. A functional variant of GRM3 has been described which modulates synaptic glutamate levels. We assessed whether this functional variant rs6465084 is related to schizophrenia in a large sample of patients and controls. We found an increased frequency of the A allele (p=0.027) and the AA genotype (p=0.024) in schizophrenia patients. Moreover, in an assessment of schizophrenia endophenotypes, patients of the AA genotype performed poorly in the digit symbol test, a measure of attention (p=0.008). Our results provide further evidence for the potential importance of the glutamate receptor GRM3 in schizophrenia, and indicate that the novel antipsychotic LY2140023 may actually be targeting a pathogenic pathway of schizophrenia.

The early recognition inventory ERIraos assesses the entire spectrum of symptoms through the course of an at-risk mental state.

AIM: Functional disability and social consequences frequently occur at the prodromal stage of schizophrenia. Efforts to recognize an increasing risk of psychosis onset have thus become a topical issue worldwide. This is to introduce the English version of the ERIraos early-recognition inventory. METHODS: The ERIraos, developed in a systematic, empirical approach from the Instrument for the Retrospective Assessment of the Onset of Schizophrenia, incorporates basic symptoms from the Cologne Early Recognition Study. The research version also includes as further predictive items so-called brief limited intermittent psychotic symptoms and attenuated psychotic symptoms from the Comprehensive Assessment of At-Risk Mental States instrument. RESULTS: The ERIraos with its 15-item screening Checklist and 50-item Symptom List permits early recognition of psychosis risk in three steps of decreasing sensitivity and increasing specificity. Step 1 relies on patients' self-perception of symptoms, which prompt them to contact a primary health service. There, in Step 2, at-risk individuals are identified using the Checklist, characterized by a low-risk threshold, and referred to further examination using the Symptom List (Step 3). Information on symptom accumulation and increasing symptom severity enhances the instrument's predictive power. In a validation test, psychotic transitions increased linearly up to 50% over 2 years. Compared with other instruments and on the prodromal stage of depressive disorder, the ERIraos has shown good predictive capacity. CONCLUSIONS: The ERIraos has been successfully employed as a two-step tool for the early recognition of psychosis risk in several German studies and translated into several foreign languages.

The course of schizophrenia: progressive deterioration, amelioration or both?

BACKGROUND: Schizophrenia may follow a course of amelioration, deterioration or stability. It is possible that deterioration at the aggregate level may be due to a sub-group of patients with a tendency to deteriorate. AIMS: To examine the course of schizophrenia in a national population-based cohort. METHODS: All first admissions for schizophrenia in Israel 1978-1986 were followed for readmissions in the Israeli psychiatric hospitalization registry for 10 years (n=6865). Readmission rates were examined using cluster analysis. This was followed by an examination of changes in readmission patterns. RESULTS: Cluster analysis identified a small cluster of patients who spent more days in the hospital over time and two clusters that improved. A priori classification of the patients into deteriorating, improving and stable (based on days hospitalized per year) revealed that approximately 75% of patients improved over time. CONCLUSIONS: Over time a majority of patients appear to improve and a minority appear to deteriorate.

A population based elaboration of the role of age of onset on the course of schizophrenia.

BACKGROUND: Despite suggestions that an earlier age of onset and being male confer to a poorer course of schizophrenia, evidence regarding when these effects are most salient appears to be ambiguous. AIMS: To examine the relationship of age of first hospitalization and sex with the course of hospitalization in a population based cohort. METHOD: All first admissions for schizophrenia in a national population based cohort in Israel from 1978 to 1992 were followed through 1996 (n=12,071) using data from the National Psychiatric Hospitalization Case Registry of the State of Israel, a complete national registry of psychiatric admissions. Recursive partitioning was conducted to empirically determine cut-off points for age groups showing the greatest difference on the variables of interest. RESULTS: A younger age of first hospital admission was associated with a greater likelihood of having more than one hospital admission, longer first admissions, more hospital admissions and more inpatient days per year. Of patients with age of first admission below 17, 82.5% had more than one admission which decreased for subsequent age groups to 73.54% (18-28), 69.36% (29-31), 62.88% (32-45), and 50.77% (over 45). Men had an earlier first admission than women, and had slightly more cut-off values. Irrespective of sex, the relationship between age at first admission and later hospitalization conformed to a linear trend. CONCLUSIONS: An earlier onset corresponds linearly with the severity of the course of illness and appears to have prognostic value.

The German Research Network on Schizophrenia--impact on the management of schizophrenia.

The German Research Network On Schizophrenia (GRNS) is a nationwide network currently comprising 16 psychiatric university departments and 14 state and district hospitals, as well as six local networks of psychiatric practices and general practitioners collaborating on about 25 interrelated, multicenter projects on schizophrenia research. The GRNS aims to intensify collaboration and knowledge exchange between leading research institutions and qualified routine care facilities, both within (horizontal network) and between (vertical network) the two levels of research and care, in order to create the scientific preconditions for optimization of the management of schizophrenia. The concept and the first results of studies aiming at the investigation of (i) strategies for early detection and early intervention in the prodromal stage of psychosis; (ii) treatment in first-episode schizophrenia; (iii) quality management; and (iv) destigmatization, are described as examples of this effort.

In vitro gender differences in neuronal survival on hypoxia and in 17beta-estradiol-mediated neuroprotection.

Gender differences in neuropsychiatric disease are recognized but not well understood. Investigating the survival of primary rat hippocampal neurons in culture, we found significant and inverted gender differences on normoxia versus hypoxia. Male cells were more resistant under normoxia but more vulnerable under hypoxia than female cells. Male vulnerability pattern was acquired in cells from neonatally testosterone-primed females. Estrogens, acting via membrane receptors, had a higher neuroprotective power in male neurons, explained at least in part by the pronounced increase in estrogen receptor beta/alpha ratio during hypoxia in male cells only.

Khat use as risk factor for psychotic disorders: a cross-sectional and case-control study in Somalia.

BACKGROUND: Little is known about the prevalence of khat-induced psychotic disorders in East African countries, where the chewing of khat leaves is common. Its main psycho-active component cathinone produces effects similar to those of amphetamine. We aimed to explore the prevalence of psychotic disorders among the general population and the association between khat use and psychotic symptoms. METHODS: In an epidemiological household assessment in the city of Hargeisa, North-West Somalia, trained local interviewers screened 4,854 randomly selected persons from among the general population for disability due to severe mental problems. The identified cases were interviewed based on a structured interview and compared to healthy matched controls. Psychotic symptoms were assessed using the items of the WHO Composite International Diagnostic Interview and quantified with the Positive and Negative Symptoms Scale. Statistical testing included Student's t-test and ANOVA. RESULTS: Local interviewers found that rates of severe disability due to mental disorders were 8.4% among males (above the age of 12) and differed according to war experiences (no war experience: 3.2%; civilian war survivors: 8.0%; ex-combatants: 15.9%). The clinical interview verified that in 83% of positive screening cases psychotic symptoms were the most prominent manifestations of psychiatric illness. On average, cases with psychotic symptoms had started to use khat earlier in life than matched controls and had been using khat 8.6 years before positive symptoms emerged. In most cases with psychotic symptoms, a pattern of binge use (> two 'bundles' per day) preceded the onset of psychotic symptoms, in contrast to controls of the same age. We found significant correlations between variables of khat consumption and clinical scales (0.35 to 0.50; p < 0.05), and between the age of onset of khat chewing and symptom onset (0.70; p <0.001). CONCLUSION: Evidence indicates a relationship between the consumption of khat and the onset of psychotic symptoms among the male population, whereby not the khat intake per se but rather early onset and excessive khat chewing seemed to be related to psychotic symptoms. The khat problem must be addressed by means other than prohibition, given the widespread use and its role in Somali culture.

Schizophrenia and depression: challenging the paradigm of two separate diseases--a controlled study of schizophrenia, depression and healthy controls.

BACKGROUND: We studied descriptive and causal associations between schizophrenia, depressive symptoms and episodes of depression. METHODS: Untreated psychotic, depressive and negative symptoms were assessed retrospectively from onset until first admission using the IRAOS in a population-based sample of 232 first episodes of schizophrenia. A representative subsample of 130 patients, studied retrospectively until onset and followed up prospectively over 6 months after first admission, were compared with 130 age- and sex-matched healthy population controls and with 130 equally matched first admissions for unipolar depressive episodes. RESULTS: The lifetime prevalence of depressive mood (>or=2 weeks) at first admission for schizophrenia was 83%. The most frequent initial symptom of schizophrenia was depressive mood, appearing more than 4 years before first admission and followed by negative symptoms and functional impairment. Showing considerable overlap in symptoms and functional impairment at their initial stages, schizophrenia and unipolar depression became clearly distinguishable with the emergence of psychotic symptoms. In the first psychotic episode 71% presented clinically relevant depressive symptoms, 23% fulfilled the ICD-10 criteria for a depressive episode. With remitting psychosis the prevalence of depression, too, decreased. The high frequency of depressive symptoms at the prepsychotic prodromal stage and their increase and decrease with the psychotic episode suggests that depression in schizophrenia might be expression of an early, mild stage of the same neurobiological process that causes psychosis. CONCLUSIONS: The high prevalence of depression in the population and the diversity of its causes prompted us to speculate about a hierarchical model of preformed dimensional patterns of psychopathology.