Young people at risk for developing bipolar disorder: Two-year findings from the multicenter prospective, naturalistic Early-BipoLife study.

Early identification and intervention of individuals with an increased risk for bipolar disorder (BD) may improve the course of illness and prevent long­term consequences. Early-BipoLife, a multicenter, prospective, naturalistic study, examined risk factors of BD beyond family history in participants aged 15-35 years. At baseline, positively screened help-seeking participants (screenBD at-risk) were recruited at Early Detection Centers and in- and outpatient depression and attention-deficit/hyperactivity disorder (ADHD) settings, references (Ref) drawn from a representative cohort. Participants reported sociodemographics and medical history and were repeatedly examined regarding psychopathology and the course of risk factors. N = 1,083 screenBD at-risk and n = 172 Ref were eligible for baseline assessment. Within the first two years, n = 31 screenBD at-risk (2.9 %) and none of Ref developed a manifest BD. The cumulative transition risk was 0.0028 at the end of multistep assessment, 0.0169 at 12 and 0.0317 at 24 months (p = 0.021). The transition rate with a BD family history was 6.0 %, 4.7 % in the Early Phase Inventory for bipolar disorders (EPIbipolar), 6.6 % in the Bipolar Prodrome Interview and Symptom Scale-Prospective (BPSS-FP) and 3.2 % with extended Bipolar At-Risk - BARS criteria). In comparison to help-seeking young patients from psychosis detection services, transition rates in screenBD at-risk participants were lower. The findings of Early-BipoLife underscore the importance of considering risk factors beyond family history in order to improved early detection and interventions to prevent/ameliorate related impairment in the course of BD. Large long-term cohort studies are crucial to understand the developmental pathways and long-term course of BD, especially in people at- risk.

Prevention of First-Episode Psychosis in People at Clinical High Risk: A Randomized Controlled, Multicentre Trial Comparing Cognitive-Behavioral Therapy and Clinical Management Plus Low-Dose Aripiprazole or Placebo (PREVENT).

BACKGROUND: There is limited knowledge of whether cognitive-behavioral therapy (CBT) or second-generation antipsychotics (SGAs) should be recommended as the first-line treatment in individuals at clinical high risk for psychosis (CHRp). HYPOTHESIS: To examine whether individual treatment arms are superior to placebo and whether CBT is non-inferior to SGAs in preventing psychosis over 12 months of treatment. STUDY DESIGN: PREVENT was a blinded, 3-armed, randomized controlled trial comparing CBT to clinical management plus aripiprazole (CM + ARI) or plus placebo (CM + PLC) at 11 CHRp services. The primary outcome was transition to psychosis at 12 months. Analyses were by intention-to-treat. STUDY RESULTS: Two hundred eighty CHRp individuals were randomized: 129 in CBT, 96 in CM + ARI, and 55 in CM + PLC. In week 52, 21 patients in CBT, 19 in CM + ARI, and 7 in CM + PLC had transitioned to psychosis, with no significant differences between treatment arms (P = .342). Psychopathology and psychosocial functioning levels improved in all treatment arms, with no significant differences. CONCLUSIONS: The analysis of the primary outcome transition to psychosis at 12 months and secondary outcomes symptoms and functioning did not demonstrate significant advantages of the active treatments over placebo. The conclusion is that within this trial, neither low-dose aripiprazole nor CBT offered additional benefits over clinical management and placebo.

Efficacy of cognitive-behavioral group therapy in patients at risk for serious mental illness presenting with subthreshold bipolar symptoms: Results from a prespecified interim analysis of a multicenter, randomized, controlled study.

OBJECTIVE: Most patients with bipolar disorders (BD) exhibit prodromal symptoms before a first (hypo)manic episode. Patients with clinically significant symptoms fulfilling at-risk criteria for serious mental illness (SMI) require effective and safe treatment. Cognitive-behavioral psychotherapy (CBT) has shown promising results in early stages of BD and in patients at high risk for psychosis. We aimed to investigate whether group CBT can improve symptoms and functional deficits in young patients at risk for SMI presenting with subthreshold bipolar symptoms. METHOD: In a multicenter, randomized, controlled trial, patients at clinical risk for SMI presenting with subthreshold bipolar symptoms aged 15-30 years were randomized to 14 weeks of at-risk for BD-specific group CBT or unstructured group meetings. Primary efficacy endpoints were differences in affective symptomatology and psychosocial functioning at 14 weeks. At-risk status was defined as a combination of subthreshold bipolar symptomatology, reduction of psychosocial functioning and a family history for (schizo)affective disorders. A prespecified interim analysis was conducted at 75% of the targeted sample. RESULTS: Of 128 screened participants, 75 were randomized to group CBT (n = 38, completers = 65.8%) vs unstructured group meetings (n = 37, completers = 78.4%). Affective symptomatology and psychosocial functioning improved significantly at week 14 (P < .001) and during 6 months (P < .001) in both groups, without significant between-group differences. Findings are limited by the interim character of the analysis, the use of not fully validated early detection interviews, a newly adapted intervention manual, and the substantial drop-outs. CONCLUSIONS: Results suggest that young patients at-risk for SMI presenting with subthreshold bipolar symptoms benefit from early group sessions. The degree of specificity and psychotherapeutic interaction needed requires clarification.

Relationship between metacognitive beliefs and psychosocial performance in at-risk states of psychosis and patients with first psychotic episodes.

AIMS: Improving diagnostic batteries to identify individuals at-risk for developing psychotic disorders as early as possible is an ongoing challenge in schizophrenia research. Here, we sought to explore whether metacognition in at-risk of developing psychosis would differ from that of first episode psychosis and unaffected controls and whether dysfunctional metacognitive beliefs would be associated with psychosocial functioning in the clinical groups. METHODS: Twenty-three subjects at-risk of psychosis were compared with a group of 15 first psychotic episode patients and 21 healthy controls with regard to their metacognitive beliefs and psychosocial functioning. Metacognition was assessed using the Metacognition Questionnaire (MCQ), psychosocial functioning was rated using the Personal and Social Performance Scale (PSP). Depression and anxiety were also evaluated. RESULTS: The clinical groups differed significantly from controls in several MCQ scores, particularly the subscales "negative beliefs" and "need for control," as well as on all PSP scales. Furthermore, significant correlations emerged between the metacognition and psychosocial functioning. A mediation analysis revealed that dysfunctional metacognitive beliefs had no direct effect on psychosocial functioning, but was mediated by depressive symptoms. CONCLUSIONS: These results corroborate findings assigning depressive symptoms an important role in early recognition of psychosis.

Negative schemata about the self and others and paranoid ideation in at-risk states and those with persisting positive symptoms.

BACKGROUND: The objective of this study is to test the conflicting theories concerning the association of negative self and other schemata and paranoid ideation. METHODS: A risk-based approach, including risk stratification, is used to gain insight into the association of the negative self and other schemata that may be shared by individuals or differentiate between individuals at clinical high risk (CHR) for a first-episode psychosis and those with full-blown psychosis. The dataset includes a sample of individuals at CHR (n = 137) and a sample of individuals with persisting positive symptoms (PPS, n = 211). The CHR sample was subdivided according to a prognostic index yielding 4 CHR sub-classes with increasing risk for transition to psychosis. RESULTS: Negative beliefs about the self were associated with paranoid ideation in CHR and a lower risk state. In the highest risk state and full-blown psychosis, there is an association with negative beliefs about others. CONCLUSION: These findings are in line with theories suggesting a switch from a predominantly activated negative self-schema to a malevolent others-schema in association with paranoid ideation along the risk-continuum. However, due to methodological limitations these results should be replicated by future studies.

Clinical high risk for psychosis: gender differences in symptoms and social functioning.

AIM: Schizophrenia is a heterogeneous disorder that presents differently in men and women: men show a higher propensity to negative symptoms, lower social functioning, earlier age at onset and co-morbid substance abuse, whereas women display more affective symptoms. It is unknown whether these differences extend to subjects at high risk (HR) of psychosis. Thus, the aim of the present study was to address this question. METHODS: Clinical symptoms and functioning were assessed using structured interviews in 239 HR subjects (female, n = 80). The definition of being at HR was based on the criteria used in the European Prediction of Psychosis Study (EPOS). RESULTS: Men displayed more pronounced negative symptoms, higher rates of past substance abuse disorders and higher deficits in social functioning. No gender difference was found for depression, which affected almost 50% of the cohort, or age at onset for the fulfilment of HR criteria. CONCLUSION: The higher impairment in specific symptoms observed in male schizophrenia patients was also present in subjects at HR for psychosis. Further studies are required to determine whether these symptoms are gender-specific predictors of transition to psychosis and whether they warrant gender-specific interventions. The high propensity to depression in the present cohort, which was particularly pronounced in the male cohort compared with the general population, in conjunction with the observed increase in negative symptoms and functional impairment, should alert clinicians to the necessity for the identification and treatment of HR subjects, irrespective of the degree to which these features are associated with transition risk.

Pathways to care in subjects at high risk for psychotic disorders - a European perspective.

Evidence-based decisions on indicated prevention in early psychosis require large-scale studies on the pathways to care in high-risk subjects. EPOS (The European Prediction of Psychosis Study), a prospective multi-center, naturalistic field study in four European countries (Finland, Germany, The Netherlands and England), was designed to acquire accurate knowledge about pathways to care and delay in obtaining specialized high risk care. Our high risk sample (n=233) reported on average 2.9 help-seeking contacts, with an average delay between onset of relevant problems to initial help-seeking contact of 72.6 weeks, and between initial help-seeking contact and reaching specialized high risk care of 110.9 weeks. This resulted in a total estimated duration of an unrecognized risk for psychosis of 3 ½ years. Across EPOS EU regions, about 90% of care pathway contacts were within professional health care sectors. Between EPOS regions, differences in the pathways parameters including early detection and health-care systems were often very pronounced. High-risk participants who later made transition to a full psychotic disorder had significantly longer delays between initial help-seeking and receiving appropriate interventions. Our study underlines the need for regionally adapted implementation of early detection and intervention programs within respective mental health and health care networks, including enhancing public awareness of early psychosis.

The bipolar disorder prodrome revisited: Is there a symptomatic pattern?

OBJECTIVES: To assess the phenomenology and course of pre-(hypo)manic and pre-depressed prodromal symptoms, including mood swings, as precursors of bipolar disorder (BD) in a German multi-center study. METHODS: Semi-structured interviews [Bipolar Prodrome Symptom Scale-Retrospective (BPSS-R); Semi-structured Interview for Mood Swings] were administered to patients within 8 years of BD (BD I, BD II) onset. RESULTS: Forty two outpatients were included (40.5% male, mean age 35.1±10.0 years, illness onset at 30.5±9.5 years). Feeling extremely energetic (85.7%), racing thoughts (78.6%), physical agitation (76.2%), overtalkativeness (71.4%), and low sleep requirement (71.4%) occurred most frequently prior to the first (hypo)manic episode, whereas depressed mood (83.0%), reduced vitality (81.0%), physical exhaustion (78.6%), tiredness (76.2%), and insomnia (66.7%) preceded pre-depressively. Mood lability (p=.006), odd ideas (p=.003) and the psychosis index score (p=.003) differed significantly in prevalence depending on the episodes' mood. Extremely energetic (p=.046), overtalkativeness (p<.001), and racing thoughts (p=.013) lasted significantly longer prior to depression. Neither severity nor frequency of prodromal symptoms differed significantly. Most of the symptoms emerged during the proximal prodromal phase. Links between mood swings and subsequent BD were found. LIMITATIONS: Symptoms were evaluated retrospectively with self-reporting tools in bipolar patients from academic treatment settings without comparison to clinical controls. CONCLUSIONS: Not only specific depressive or manic but also general symptoms occurred prior to both affective episodes. The pre-depressive prodrome lasted longer than the pre-manic one, but severity and frequency did not differ significantly. Mood swings and disturbed diurnal rhythm occurred prior to both episodes as early signs of BD.

Ventral striatal activation during reward processing in subjects with ultra-high risk for schizophrenia.

BACKGROUND: Early dysfunction of the brain reward system in schizophrenia might be already recognized in the prodromal phase of this illness. We used functional magnetic resonance imaging to assess the blood oxygen level-dependent response in the ventral striatum (VS) of subjects with ultra-high risk for psychosis during the presentation of reward-indicating and loss-indicating stimuli. METHODS: Thirteen prodromal patients (mean age: 25.5 ± 4.6 years) and 13 age-matched healthy volunteers participated in an incentive monetary delay task, in which visual cues predicted that a rapid response to a subsequent target stimulus will gain money, avoid losing money or have no consequence. RESULTS: Compared with the neutral condition, anticipation of reward loss-avoidance elicited significant activation of the VS in both healthy subjects and subjects with ultra-high risk for psychosis, but there was only a statistical tendency for less activation during loss-avoidance anticipation in prodromal compared to healthy subjects. DISCUSSION: This study provides a first weak hint, as revealed by functional magnetic resonance imaging, for impaired activation of a central area of the mesolimbic dopaminergic brain reward system, the VS, already in subjects with ultra-high risk for psychosis, which is in line with results of patients with full-blown schizophrenic psychosis. This pilot study has, however, strong limitations, and its results need to be replicated first before they can be used e.g. for early recognition of patients in the schizophrenic prodrome.

Risk constellations prior to the development of bipolar disorders: rationale of a new risk assessment tool.

BACKGROUND: The precise characterisation of a high risk status for the development of a psychiatric disorder and the question of how well this predicts disease manifestation is of major importance as negative consequences of late diagnosis and treatment have been well demonstrated. In the absence of well defined and disease specific biological markers for bipolar disorder, the recognition of premature stages must rely on combinations of risk factors that have been associated with later disease manifestation. METHODS: A review of the literature and our experience from the Early Recognition Centre led us to identify symptom constellations. RESULTS: Individual categories defined and grouped included: (I) genetic risk, (II) substance use, misuse or dependence, (III) diagnosis/suspected diagnosis of attention deficit hyperactivity disorder, (IV) pronounced creativity, (V) impairment in psychosocial functioning, (VI) subthreshold affective symptoms, and (VII) early symptomatology including (a) changes in sleep and circadian rhythm, (b) changes in mood, mood swings/affective lability, (c) fearfulness/anxiety, and (d) dissociative symptoms. These risk constellations were operationalised and a new risk assessment instrument, the Early Phase Inventory for Bipolar Disorders (EPIbipolar) was developed. LIMITATIONS: Challenges regarding the validity of the data on which the instrument is based, specificity of and correlations between risk categories, and ethical considerations were encountered. CONCLUSIONS: Further use of EPIbipolar in research should help to refine prodromal features and narrow these down to a less cumbersome core that can be used to develop a shortened tool for use in clinical care. Prospective longitudinal research is needed to establish the predictive validity of this novel bipolar disorder risk assessment tool.

Rationale and baseline characteristics of PREVENT: a second-generation intervention trial in subjects at-risk (prodromal) of developing first-episode psychosis evaluating cognitive behavior therapy, aripiprazole, and placebo for the prevention of psychosis.

Antipsychotics, cognitive behavioral therapy (CBT), and omega-3-fatty acids have been found superior to control conditions as regards prevention of psychosis in people at-risk of first-episode psychosis. However, no large-scale trial evaluating the differential efficacy of CBT and antipsychotics has been performed yet. In PREVENT, we evaluate CBT, aripiprazole, and clinical management (CM) as well as placebo and CM for the prevention of psychosis in a randomized, double-blind, placebo-controlled trial with regard to the antipsychotic intervention and a randomized controlled trial with regard to the CBT intervention with blinded ratings. The hypotheses are first that CBT and aripiprazole and CM are superior to placebo and CM and second that CBT is not inferior to aripiprazole and CM combined. The primary outcome is transition to psychosis. By November 2010, 156 patients were recruited into the trial. The subjects were substantially functionally compromised (Social and Occupational Functioning Assessment Scale mean score 52.5) and 78.3% presented with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition axis I comorbid diagnosis. Prior to randomization, 51.5% of the participants preferred to be randomized into the CBT arm, whereas only 12.9% preferred pharmacological treatment. First, assessments of audiotaped treatment sessions confirmed the application of CBT-specific skills in the CBT condition and the absence of those in CM. The overall quality rating of the CBT techniques applied in the CBT condition was good. When the final results of the trial are available, PREVENT will substantially expand the current limited evidence base for best clinical practice in people at-risk (prodromal) of first-episode psychosis.

1 H-MR spectroscopy in ultra-high risk and first episode stages of schizophrenia.

Using proton magnetic resonance spectroscopy biochemical characteristics in early stages of schizophrenia were examined. N-acetylaspartate, choline and creatine were measured in hippocampus, anterior cingulate gyrus (ACC) and medial prefrontal cortex (mPFC) of 24 first episode and 30 ultra-high risk patients. Careful LCModel analyses revealed no differences between the patient groups and 31 healthy controls, casting doubt upon the idea of metabolic changes in early stages of psychosis.

An fMRI study of "theory of mind" in at-risk states of psychosis: comparison with manifest schizophrenia and healthy controls.

OBJECTIVE: Poor social functioning is a hallmark of schizophrenia and may precede the onset of illness. One of the most robust predictors of social impairment is a deficit in the ability to appreciate the mental states of others ("theory of mind"; ToM). We therefore examined ToM in subjects at risk of developing psychosis using an fMRI paradigm and compared brain activations with those of patients with manifest schizophrenia and healthy controls. METHOD: Ten subjects with at-risk ("prodromal") states of psychosis, 22 schizophrenia patients and 26 healthy controls were recruited. During fMRI scanning, participants were shown a series of cartoons. The task was to infer the mental states of the cartoon characters in terms of beliefs, states of knowledge and intentions. RESULTS: Subjects at risk of psychosis activated the ToM neural network comprising the prefrontal cortex, the posterior cingulate cortex, and the temporoparietal cortex more strongly than patients with manifest schizophrenia, and, in part, also more strongly than healthy controls. Manifest schizophrenia patients and controls activated the ToM neural network differently with little overlap of activated regions, where overall, controls showed stronger activations than schizophrenia patients. CONCLUSIONS: Individuals with at-risk states of schizophrenia activate the ToM neural network differently, and in part, more strongly compared to patients with schizophrenia and controls. This could suggest a compensatory overactivation of brain regions critical for empathic responses during mental state attribution in at-risk subjects for schizophrenia.

Test-performance after cognitive training in persons at risk mental state of schizophrenia and patients with schizophrenia.

This exploratory study aims to examine the differential effects of a computer-based cognitive training in 'prodromal' patients (mean age 27.20 years, S.D. 5.31 years) compared with patients with full-blown schizophrenia (mean age 30.13 years, S.D. 7.77 years). Ten patients at risk for schizophrenia and 16 patients suffering from schizophrenia underwent a computerized cognitive training program (Cogpack). Cognitive functioning before and after a total of 10 training sessions was assessed by different tests controlling for memory, attention, and logical thinking. Prodromal patients turned out to be able to significantly improve their long-term memory functions and their attention after cognitive training with the Cogpack software package whereas in the group of patients with schizophrenia no improvement occurred (e.g. continuous performance test, identical pairs-subtest 'shapes': improvement from 0.73 to 0.88 in persons at risk of schizophrenia vs. no improvement in patients with schizophrenia (0.55 to 0.53). Cognitive training using Cogpack is helpful for the improvement of cognitive functioning in persons at risk of schizophrenia. Thus, the application of cognitive training should be provided as early as possible in the prodromal phases of schizophrenia in order to use the full rehabilitative potential of the patients. These results should be confirmed by further investigations including larger sample sizes.

[Operationalized psychodynamic diagnostics (OPD) in patients in a prodromal state of schizophrenia--an explorative study]. / Operationalisierte Psychodynamische Diagnostik (OPD) bei Patienten im schizophrenen Prodromalstadium--Eine explorative Studie.

OBJECTIVES: To obtain data and hypotheses regarding the amelioration of risk estimation and preventive psychotherapy in patients in a prodromal state of schizophrenia by using OPD. METHODS: 20 participants with a prodromal condition--6 subjects far from psychosis and 14 close to psychosis--along with 10 patients with paranoid schizophrenia as reference group were examined using the first four OPD axes. RESULTS: Both groups differed considerably in all four axes. Compared to the schizophrenic participants, prodromal probands appear to have more favourable preconditions for therapy. Moreover, they experienced the interaction partners, including the investigator, as less aversive and induced less distanced behaviour in the investigator. Conflicts of self-esteem were prominent in both prodromal subgroups. However, patients farther from psychosis showed less conflicts of autonomy versus dependence and displayed a higher integration in structures such as "defence" and "attachment" when compared to participants closer to psychosis. CONCLUSIONS: Particularly the differences between the prodromal subgroups suggest that application of the OPD may positively complement previous approaches of early detection, prevention,and psychotherapy for prodromal conditions. The hypotheses obtained should be tested in longitudinal studies with larger sample sizes.

Hippocampal subdivision and amygdalar volumes in patients in an at-risk mental state for schizophrenia.

BACKGROUND: Accumulating evidence from postmortem and magnetic resonance imaging (MRI) studies suggests that abnormalities of medial temporal lobe structures are critically involved in the pathogenesis of schizophrenia. It is still unclear, however, whether certain abnormalities are already present in individuals at ultra high-risk (UHR) for transition into psychosis. Recent studies involving patients at UHR showed contradictory results for hippocampal volume, and only 1 study reported that amygdalar volume was unchanged between healthy patients and those at UHR. Furthermore, no subregions of the hippocampus have been investigated in people at UHR. METHODS: We recruited 29 UHR patients, 23 first-episode patients and 29 age- and sex-matched healthy controls. We measured hippocampal and amygdalar volumes from MRI scans by use of BRAINS2 to manually trace the regions of interest. The hippocampi were divided in 2 regions: head and corpus/tail. RESULTS: Patients at UHR had significantly smaller volumes of the hippocampus corpus and tail bilaterally, but not of the head, compared with healthy controls. Group differences for the right hippocampus corpus and tail volume remained significant after we controlled for whole brain volume and other covariates. We found that UHR patients who later developed psychosis had smaller right hippocampus corpus and tail volumes than did those who did not develop psychosis. First-episode patients had significantly smaller left amygdalar volumes than did healthy individuals or those at UHR. LIMITATIONS: Our study had a small sample size, and we were unable to control for the effects of medication. CONCLUSION: Our findings suggest that parts of the hippocampal-amygdalar complex are involved in the pathogenesis of schizophrenia. Reduction of hippocampus corpus and tail volumes may be indicative of the prodromal phase of schizophrenia and represent risk factors for transition into psychosis. Further investigations are needed to determine whether structural changes of the left amygdala play a role during transition from the prodromal phase to the first manifest episode of schizophrenia.

Early mood swings as symptoms of the bipolar prodrome: preliminary results of a retrospective analysis.

BACKGROUND/AIMS: Temperament and mood swings are promising indicators for the characterization of mood spectrum vulnerability. The aim of this study was to investigate the relationship between affective temperament and mood swings in bipolar disorder. We explored these clinical features retrospectively. METHODS: Patients who met the criteria for bipolar I disorder were enrolled in the study. Exclusion criteria were partial remittance and a full affective or psychotic episode. Data concerning illness and family history, mood swings (semistructured interview for mood swings) and depression (Beck, Depression Inventory) were obtained. We examined premorbid temperament with the validated German version Temps-M of the original version Temps-A. Patients with and without mood swings were compared with respect to the dominant temperament. RESULTS: Out of 20 bipolar patients, 6 subjects reported mood swings prior to the onset of affective disorder. Subjects with mood swings prior to the onset of bipolar disorder significantly correlated with a positive family history of affective disorders. Concerning cyclothymic and irritable temperament, bipolar affective patients with mood swings had higher scores. No differences were found between males and females. CONCLUSION: Our findings go in line with previous results that mood swings, as represented by the cyclothymic temperament, are present prior to the first onset of bipolar disorder in a subset of patients. These traits may represent vulnerability markers and could presumably be used to identify individuals at high risk for developing bipolar disorder in order to prevent this illness. Further studies are indicated to clarify the correlation with genetic risk factors.

Gray matter abnormalities in subjects at ultra-high risk for schizophrenia and first-episode schizophrenic patients compared to healthy controls.

Neuroimaging studies have revealed gray matter abnormalities in schizophrenia in various regions of the brain. It is, however, still unclear whether such abnormalities are already present in individuals at ultra-high risk (UHR) for transition into psychosis. We investigated this issue using voxel-based morphometry of structural magnetic resonance images (MRI) and compared UHR patients with first-episode patients with schizophrenia and healthy controls. Gray matter volume maps from high-resolution MR T1-weighted whole brain images were analyzed in a cross-sectional study in 30 UHR patients, 23 first-episode schizophrenic patients and 29 controls. UHR patients showed significantly lower gray matter volume in the cingulate gyrus bilaterally, in the right inferior frontal and right superior temporal gyrus, as well as in the left and right hippocampus in comparison to healthy subjects. First-episode patients with schizophrenia showed smaller gray matter volume in the cingulate cortex bilaterally, in the left orbitofrontal gyrus, in the right inferior frontal and superior temporal gyrus, in the right temporal pole, in the left and right hippocampus, in the left parahippocampus, left amygdala, and in the left fusiform gyrus compared to the UHR patients. This study provides further evidence that gray matter brain volume, especially in the anterior cingulate cortex, is already reduced in the prodromal state of schizophrenia.

Serotonergic dysfunction in the prodromal, first-episode and chronic course of schizophrenia as assessed by the loudness dependence of auditory evoked activity.

Recent studies revealing evidence of increased serotonergic neurotransmission in schizophrenia has generated substantial interest in the role of serotonin in its pathophysiology. None of these studies, however, have queried whether dysfunctional serotonergic activity might already have been present in subjects of at-risk mental state for schizophrenia before the onset of psychotic symptoms, and whether serotonergic activity further increases during the development of schizophrenia and the chronic course. Although no valid indicator for measuring the activity level of serotonergic neurotransmission has yet been found, a series of evidence from human and animal studies suggests that a weak loudness dependence of auditory evoked potentials (LDAEP) indicates high serotonergic activity and vice versa. We examined the LDAEP (N1/P2 component) in 60 patients with at-risk mental state for schizophrenia who showed characteristic prodromal symptoms, 34 first-episode patients, 28 patients with a chronic course of schizophrenia and 57 healthy controls. Prodromal patients showed significantly weaker LDAEP in comparison to healthy volunteers, but similarly to that in first-episode and chronic patients. None of the covariates such as age, gender, medication, age of onset, or psychopathology had an influence on this finding. In a subsample of prodromal patients, LDAEP values remain the same after retesting 10 months later. These results indicate that serotonergic neurotransmission had already increased before the onset of the full-blown psychosis of schizophrenia and remains enhanced in the further course of the disease. A weak LDAEP may therefore represent a vulnerability marker rather than an expression of illness progression.

Neurocognitive performances in participants of at-risk mental state for schizophrenia and in first-episode patients.

As suggested by the neurodevelopmental model, neurocognitive disturbances are core features of schizophrenia spectrum disorders. The aim of the present study was to explore the neurocognitive performance of symptomatically defined high-risk participants as well as first-episode patients on tests of verbal memory, executive functioning, working memory, and attention. The sample consisted of 54 participants at risk for schizophrenia and 37 patients with a first episode of psychosis. The high-risk group exhibited a similar cognitive performance profile to that of the first-episode participants when compared with normative data. The neurocognitive functioning of both patient groups were within standard average range at most of the cognitive domains. Moreover the intellectual functioning of both groups was within higher average level, while decreased "hit rates" could be observed within both subtests "Figures" and "Symbols" of the Continuous Performance Test-Identical Pairs Version (CPT-IP) in the group of first-episode patients. Direct comparison between the clinical groups did show increasing impairments of these parameters in first-episode patients compared to high-risk participants. Results suggest that high-risk participants do perform at average neurocognitive performance levels at all tested domains compared with normative data. Compared to norm values first-episode patients showed decreased attention abilities.