Theory of mind in the early course of schizophrenia: stability, symptom and neurocognitive correlates, and relationship with functioning.

BACKGROUND: Numerous studies have reported links between theory of mind (ToM) deficits, neurocognition and negative symptoms with functional outcome in chronic schizophrenia patients. Although the ToM deficit has been observed in first-episode patients, fewer studies have addressed ToM as a possible trait marker, neurocognitive and symptom correlations longitudinally, and associations with later functioning. METHOD: Recent-onset schizophrenia patients (n = 77) were assessed at baseline after reaching medication stabilization, and again at 6 months (n = 48). Healthy controls (n = 21) were screened, and demographically comparable with the patients. ToM was assessed with a Social Animations Task (SAT), in which the participants' descriptions of scenes depicting abstract visual stimuli 'interacting' in three conditions (ToM, goal directed and random) were rated for degree of intentionality attributed to the figures and for appropriateness. Neurocognition, symptoms and role functioning were also assessed. RESULTS: On the SAT, patients had lower scores than controls for both intentionality (p < 0.01) and appropriateness (p < 0.01) during the ToM condition, at baseline and 6 months. The ToM deficit was stable and present even in remitted patients. Analyses at baseline and 6 months indicated that for patients, ToM intentionality and appropriateness were significantly correlated with neurocognition, negative symptoms and role functioning. The relationship between ToM and role functioning was mediated by negative symptoms. CONCLUSIONS: The ToM deficit was found in recent-onset schizophrenia patients and appears to be moderately trait-like. ToM is also moderately correlated with neurocognition, negative and positive symptoms, and role functioning. ToM appears to influence negative symptoms which in turn makes an impact on role functioning.

Early-onset and very-early-onset bipolar disorder: distinct or similar clinical conditions?

OBJECTIVE: This study aimed to examine differences in the clinical presentation of very-early-onset (VEO) and early-onset (EO) bipolar disorder (BD) not fully explored previously. METHODS: We selected two groups of subjects with BD from the Maritime Bipolar Registry based on age at onset of first major mood episode (VEO with onset prior to age 15 years; EO ranging from 15 to 18 years) and compared them with a reference group (onset after 18 years of age). There were 363 subjects (240 with bipolar I disorder and 123 with bipolar II disorder; mean age 44.2 ± 12.8 (SD) years), with 41 subjects in the VEO and 95 in the EO groups. RESULTS: In comparison with the EO and reference groups, more subjects in the VEO group developed major depression as an index episode (88% for the VEO group versus 61% for the EO group and 54% for the reference group), and had an unremitting clinical course (65% versus 42% and 42%, respectively), rapid cycling (54% versus 34% and 28%, respectively), and comorbid attention-deficit hyperactivity disorder (17% versus 1% and 3%, respectively); a higher proportion of the VEO group had first-degree relatives with affective disorders compared with the EO and reference groups (0.41 versus 0.32 and 0.29, respectively), and they had lower scores on the Global Assessment of Functioning scale (mean scores of 64 versus 70 and 70). Overall, the EO group was similar to the reference group on most measures, except for increased suicidal behavior VEO 53%, EO 44% and reference group 25%). The results of polychotomous logistic regression also support the view that VEO BD represents a rather specific subtype of BD. CONCLUSIONS: Our results suggest the recognized correlates of early-onset BD may be driven by subjects at the lowest end of the age at onset spectrum.

Retinal electrophysiological alterations are associated with cognition in early course psychosis.

Retinal electrophysiological alterations are implicated in psychosis, but their relationship with cognition in early course psychosis (ECP) is understudied. The Brief Assessment of Cognition (BAC) and flash electroretinography (fERG) were conducted in 24 controls (HC) and 27 ECP individuals. Partial Spearman correlations were performed between fERG and BAC. Lower Photopic-1b and Scotopic-3b amplitudes were identified in ECP vs. HCs. Correlations were significant (p<0.05) between BAC Composite score and a-wave S3a and S2a and b-wave S2b and S3b conditions. Thus, ECP was characterized by lower ERG responses, and lower rod/cone/bipolar cell responses were related to poorer cognition.

Prefrontal oscillatory slowing in early-course schizophrenia is associated with worse cognitive performance and negative symptoms: a TMS-EEG study.

BACKGROUND: Abnormalities in dorsolateral prefrontal cortex (DLPFC) oscillations are neurophysiological signatures of schizophrenia thought to underlie its cognitive deficits. Transcranial magnetic stimulation with electroencephalography (TMS-EEG) provides a measure of cortical oscillations unaffected by sensory relay functionality and/or patients' level of engagement, which are important confounding factors in schizophrenia. Previous TMS-EEG work showed reduced fast, gamma-range oscillations and a slowing of the main DLPFC oscillatory frequency, or natural frequency, in chronic schizophrenia. However, it is unclear whether this DLPFC natural frequency slowing is present in early-course schizophrenia (EC-SCZ) and is associated with symptom severity and cognitive dysfunction. METHODS: We applied TMS-EEG to the left DLPFC in 30 EC-SCZ and 28 healthy control (HC) subjects. Goal-directed working memory performance was assessed using the "AX" Continuous Performance Task (AX-CPT). The EEG frequency with the highest cumulative power at the stimulation site, or natural frequency, was extracted. We also calculated the local Relative Spectral Power (RSP) as the average power in each frequency band divided by the broadband power. RESULTS: Compared to HC, EC-SCZ had reduced DLPFC natural frequency (p=0.0000002, Cohen's d=-2.32) and higher DLPFC beta-range RSP (p=0.0003, Cohen's d=0.77). In EC-SCZ, the DLPFC natural frequency was inversely associated with negative symptoms. Across all participants, the beta-band RSP negatively correlated with the AX-CPT performance. CONCLUSIONS: A DLPFC oscillatory slowing is an early pathophysiological biomarker of schizophrenia that is associated with its symptom severity and cognitive impairments. Future work should assess whether non-invasive neurostimulation can ameliorate prefrontal oscillatory deficits and related clinical functions in EC-SCZ.

Proof-of-concept evidence for high-density EEG investigation of sleep slow wave traveling in First-Episode Psychosis.

Schizophrenia is thought to reflect aberrant connectivity within cortico-cortical and reentrant thalamo-cortical loops, which physiologically integrate and coordinate the function of multiple cortical and subcortical structures. Despite extensive research, reliable biomarkers of such "dys-connectivity" remain to be identified at the onset of psychosis, and before exposure to antipsychotic drugs. Because slow waves travel across the brain during sleep, they represent an ideal paradigm to study pathological conditions affecting brain connectivity. Here, we provide proof-of-concept evidence for a novel approach to investigate slow wave traveling properties in First-Episode Psychosis (FEP) with high-density electroencephalography (EEG). Whole-night sleep recordings of 5 drug-naïve FEP and 5 age- and gender-matched healthy control subjects were obtained with a 256-channel EEG system. One patient was re-recorded after 6 months and 3 years of continuous clozapine treatment. Slow wave detection and traveling properties were obtained with an open-source toolbox. Slow wave density and slow wave traveled distance (measured as the line of longest displacement) were significantly lower in patients (p < 0.05). In the patient who was tested longitudinally during effective clozapine treatment, slow wave density normalized, while traveling distance only partially recovered. These preliminary findings suggest that slow wave traveling could be employed in larger samples to detect cortical "dys-connectivity" at psychosis onset.

Natural Oscillatory Frequency Slowing in the Premotor Cortex of Early-Course Schizophrenia Patients: A TMS-EEG Study.

Despite the heavy burden of schizophrenia, research on biomarkers associated with its early course is still ongoing. Single-pulse Transcranial Magnetic Stimulation coupled with electroencephalography (TMS-EEG) has revealed that the main oscillatory frequency (or "natural frequency") is reduced in several frontal brain areas, including the premotor cortex, of chronic patients with schizophrenia. However, no study has explored the natural frequency at the beginning of illness. Here, we used TMS-EEG to probe the intrinsic oscillatory properties of the left premotor cortex in early-course schizophrenia patients (<2 years from onset) and age/gender-matched healthy comparison subjects (HCs). State-of-the-art real-time monitoring of EEG responses to TMS and noise-masking procedures were employed to ensure data quality. We found that the natural frequency of the premotor cortex was significantly reduced in early-course schizophrenia compared to HCs. No correlation was found between the natural frequency and age, clinical symptom severity, or dose of antipsychotic medications at the time of TMS-EEG. This finding extends to early-course schizophrenia previous evidence in chronic patients and supports the hypothesis of a deficit in frontal cortical synchronization as a core mechanism underlying this disorder. Future work should further explore the putative role of frontal natural frequencies as early pathophysiological biomarkers for schizophrenia.

Predictors of treatment discontinuation during an 18-month multi-site randomized trial of Cognitive Enhancement Therapy for early course schizophrenia.

Treatment discontinuation during clinical trials in schizophrenia is a critical challenge, especially for longer-term interventions in the early course. This research explored predictors of treatment discontinuation in an outpatient early course schizophrenia sample (N = 102) during an 18-month multi-site trial of Cognitive Enhancement Therapy (n = 58) and Enriched Supportive Therapy (n = 44). Fifty-three (52%) participants discontinued, with no significant difference between the treatment groups in discontinuation rate. Univariate and multivariate binary logistic regression models explored differences in key demographic and cognitive and behavioral outcomes between participants who completed and discontinued treatment. Significant multivariate predictors of discontinuation included IQ (linear) and problem solving (curvilinear). The concave shape of the problem solving prediction demonstrated that initially as scores were increasing the probability of non-completion was increasing. However, after a score of 41 (below average problem solving), the probability of being a non-completer decreased as performance increased. Non-completers had significantly lower IQ scores compared to completers. Post-hoc analyses indicated that participants who discontinued prior to mid-treatment exhibited the greatest intellectual challenges, with comparisons moderate-to-large in strength. IQ and problem solving are likely important factors to assess at pre-treatment in early course schizophrenia trials to identify those most vulnerable to discontinuation.

Confirmatory Efficacy of Cognitive Enhancement Therapy for Early Schizophrenia: Results From a Multisite Randomized Trial.

OBJECTIVE: Cognitive enhancement therapy (CET) is an 18-month comprehensive cognitive remediation intervention designed to improve cognition and functioning among patients with schizophrenia. The current study sought to confirm previously observed benefits of CET on cognitive and behavioral outcomes in the early course of the condition in a large multisite trial. METHODS: Overall, 102 outpatients with early-course schizophrenia were randomly assigned to 18 months of CET (N=58) or enriched supportive therapy (EST; N=44). Participants completed cognitive, social adjustment, and symptom assessments at baseline and at 9 and 18 months. Composite indices were calculated for these outcomes. Mixed-effects models investigated differential changes in outcomes between CET and EST. Because of a high attrition rate, sensitivity analyses of data from treatment completers (N=49) were conducted. RESULTS: The effects of CET on improved overall cognition were confirmed and tentatively confirmed for social cognition in both intent-to-treat and completer analyses, and beneficial effects on attention/vigilance were also observed. An effect of CET on social adjustment was not confirmed in the analyses, because both CET and EST groups had considerably improved social adjustment. Although not statistically significant, the between-group effect size for CET's effect on social adjustment doubled from the intent-to-treat (Cohen's d=0.23) to completer analyses (Cohen's d=0.51) (p=0.057). Both groups displayed similar symptom improvements. CONCLUSIONS: CET effectively improved cognition among patients with early-course schizophrenia. The functional benefits of CET appeared to increase with treatment retention. Further research is needed to understand predictors of attrition and mechanisms of change during CET for this population.

Quantifying Retinal Microvascular Morphology in Schizophrenia Using Swept-Source Optical Coherence Tomography Angiography.

BACKGROUND: Retinovascular changes are reported on fundus imaging in schizophrenia (SZ). This is the first study to use swept-source optical coherence tomography angiography (OCT-A) to comprehensively examine retinal microvascular changes in SZ. METHODS: This study included 30 patients with SZ/schizoaffective disorder (8 early and 15 chronic) and 22 healthy controls (HCs). All assessments were performed at Beth Israel Deaconess Medical Center and Massachusetts Eye and Ear. All participants underwent swept-source OCT-A of right (oculus dextrus [OD]) and left (oculus sinister [OS]) eye, clinical, and cognitive assessments. Macular OCT-A images (6 × 6 mm) were collected with the DRI Topcon Triton for superficial, deep, and choriocapillaris vascular regions. Microvasculature was quantified using vessel density (VD), skeletonized vessel density (SVD), fractal dimension (FD), and vessel diameter index (VDI). RESULTS: Twenty-one HCs and 26 SZ subjects were included. Compared to HCs, SZ patients demonstrated higher overall OD superficial SVD, OD choriocapillaris VD, and OD choriocapillaris SVD, which were primarily observed in the central, central and outer superior, and central and outer inferior/superior, respectively. Early-course SZ subjects had significantly higher OD superficial VD, OD choriocapillaris SVD, and OD choriocapillaris FD compared to matched HCs. Higher bilateral (OU) superficial VD correlated with lower Positive and Negative Syndrome Scale (PANSS) positive scores, and higher OU deep VDI was associated with higher PANSS negative scores. CONCLUSIONS AND RELEVANCE: These results suggest the presence of microvascular dysfunction associated with early-stage SZ. Clinical associations with microvascular alterations further implicate this hypothesis, with higher measures being associated with worse symptom severity and functioning in early stages and with lower symptom severity and better functioning in later stages.

A Randomized, Double-Blind, Controlled Trial of Lithium Versus Quetiapine for the Treatment of Acute Mania in Youth with Early Course Bipolar Disorder.

Objective: To compare the efficacy and tolerability of lithium versus quetiapine for the treatment of manic or mixed episodes in youths with early course bipolar I disorder. Methods: Six-week, randomized, double-blind clinical trial of lithium versus quetiapine for the treatment of adolescents with acute manic/mixed episode. Target dose of quetiapine dose was adjusted to a target dose of 400-600 mg and target serum level for lithium was 1.0-1.2 mEq/L. Primary outcome measure was baseline-to-endpoint change in the Young Mania Rating Scale (YMRS). Secondary outcomes were treatment response (50% or more decrease from baseline in YMRS score) and remission (YMRS score ≤12, Children's Depression Rating Scale-Revised [CDRS-R] total score ≤28 and Clinical Global Impression Bipolar Severity Scale [CGI-BP-S] overall score of ≤3, respectively). Results: A total of 109 patients were randomized (quetiapine = 58 and lithium = 51). Participants in the quetiapine treatment group showed a significantly greater reduction in YMRS score than those in the lithium group (-11.0 vs. -13.2; p < 0.001; effect size 0.39). Response rate was 72% in the quetiapine group and 49% in the lithium group (p = 0.012); no differences in remission rates between groups were observed. Most frequent side effects for lithium were headaches (60.8%), nausea (39.2%), somnolence (27.5%), and tremor (27.5%); for quetiapine somnolence (63.8%), headaches (55.2%), tremor (36.2%), and dizziness (36.2%) were evidenced. Participants receiving quetiapine experienced more somnolence (p < 0.001), dizziness (p < 0.05), and weight gain (p < 0.05). Conclusions: Treatment with both lithium and quetiapine led to clinical improvement. Most study participants in this study experienced a clinical response; however, less than half of the participants in this study achieved symptomatic remission. The head-to-head comparison of both treatment groups showed quetiapine was associated with a statistically significant greater rate of response and overall symptom reduction compared with lithium. Trial registration: clinicaltrials.gov NCT00893581.

Substance Misuse Trajectories and Risk of Relapse in the Early Course of Bipolar Disorder.

Substance misuse is highly prevalent in bipolar disorder even in the early illness phases. However, the trajectories of misuse of different substances after treatment initiation is not well-studied. Also, knowledge on how substance misuse trajectories influence the early course of bipolar disorder is limited. We recruited 220 individuals in first treatment of bipolar disorder of which 112 participated in a 1-year follow-up study at the NORMENT center in Oslo, Norway. Misuse was defined as having scores above cut-off for harmful use on the Alcohol or Drug Use Disorders Identification Tests (AUDIT or DUDIT). We investigated rates of stopping and continuing misuse of alcohol, cannabis and other illicit substances and daily nicotine use over the follow-up period, and whether such misuse trajectories predicted the risk for affective relapse. The prevalence of cannabis misuse was reduced from 29 to 15% and alcohol misuse was reduced from 39 to 21% during follow-up. Continuing alcohol misuse significantly and independently predicted affective relapse, whereas there was no difference in relapse risk between individuals stopping alcohol misuse and never misusing alcohol. Cannabis misuse trajectories did not significantly predict relapse risk although we cannot exclude interactions with alcohol misuse. In conclusion, substance misuse decreased in the early phase of bipolar disorder treatment but should be further reduced with interventions specifically addressing substance misuse. Stopping alcohol misuse is likely to yield substantial benefit on the clinical course of bipolar disorder.

Electroencephalogram Microstate Abnormalities in Early-Course Psychosis.

BACKGROUND: Microstates are periods of characteristic electroencephalographic signal topography that are related to activity in brain networks. Previous work has identified abnormal microstate parameters in individuals with psychotic disorders. We combined microstate analysis with sample entropy analysis to study the dynamics of resting-state networks in patients with early-course psychosis. METHODS: We used microstate analysis to transform resting-state high-density electroencephalography data from 22 patients with early-course psychosis and 22 healthy control subjects into sequences of characteristic scalp topographies. Sample entropy was used to calculate the complexity of microstate sequences across a range of template lengths. RESULTS: Patients and control subjects produced similar sets of 4 microstates that agree with a widely reported canonical set (A, B, C, and D). Relative to control subjects, patients had decreased frequency of microstate A. In control subjects, sample entropy decreased as template length increased, suggesting that sequence of microstate transitions is self-similar across multiple transitions. In patients, sample entropy did not decrease, suggesting a lack of self-similarity in transition sequences. This finding was unrelated to data length or microstate topography. Entropy was elevated in unmedicated patients, and it decreased in patients who were administered medication. We identified patterns of transitions between microstates that were overrepresented in control data compared with representation in patient data. CONCLUSIONS: Our findings suggest that patients with early-course psychosis have abnormally chaotic transitions between brain networks. This chaos may reflect an underlying abnormality in allocating neural resources and effecting appropriate transitions between distinct activity states in psychosis.

Effectiveness of Cognitive Remediation in Early Versus Chronic Schizophrenia: A Preliminary Report.

Background: Many evidences have demonstrated the effectiveness of cognitive remediation on cognition and functioning in patients with schizophrenia. Some researchers speculate that cognitive deficits are more amenable to remediation during earlier phases of illness than in chronicity. Therefore, cognitive rehabilitation should be used as an early intervention, seeking to produce durable functional changes in the early course of schizophrenia. Although there is strong evidence that cognitive remediation is effective in adult schizophrenia, there is little evidence about its efficacy and long-term generalized effectiveness in the early course of the disease. In this paper, we intended to investigate the possibility that cognitive remediation may produce more beneficial effects when applied in the early phase of the illness compared to chronic patients. Materials and methods: Data were gathered from a database used for a previous study performed by our group, in which 56 patients with schizophrenia received a cognitive remediation intervention. In a post hoc analysis, patients with a duration of illness shorter than 5 years were defined as "early course" patients, while patients with a duration of illness longer than 5 years were defined as "chronic." Clinical, neuropsychological, and functional outcome variables were assessed at baseline and after treatment. Result: Of the 56 patients included in the study, 11 were "early course" and 45 were "chronic." Both the early course group and the chronic group showed significant improvements in all the clinical, neurocognitive, and functional parameters analyzed. A significantly greater improvement in early course patients compared with chronic patients emerged in clinical and functional measures. No differential change was observed between early course patients and chronic patients in the cognitive composite score. Conclusion: Our study confirms the effectiveness of cognitive remediation in improving clinical, cognitive, and functional parameters in patients with schizophrenia, both in patients in the early course and in chronic patients. However, patients in the early course showed a differential, greater change in clinical and functional parameters compared to chronic patients. Although this study has some limitations, it confirms the effectiveness of cognitive remediation interventions, particularly if applied in the early course of the illness.

Objective psychosocial function vs. subjective quality-of-life in schizophrenia within 5-years after diagnosis: A study from southern India.

There is increasing interest from treaters and patients alike in subjective quality-of-life (sQOL) and objective psychosocial function as indices of treatment outcome in studies of schizophrenia. With the emergence of evidence-based treatment protocols (e.g., NIMH-funded Recovery after Initial Schizophrenia Episode Initiative) these outcomes are of particular significance in treatment studies of samples early in the course of their illness. Few studies have investigated demographic, clinical and cognitive factors associated with sQOL in samples early in the course of their illness and compared these factors to objective measures. We administered measures of sQOL or satisfaction with life, and objective psychosocial function to 59 people with schizophrenia within 5-years of diagnosis, along with standardized measures of symptoms and cognition. Results revealed that symptoms, rather than cognitive or demographic variables, were the best independent predictors of both subjective QOL and objective functioning. Positive symptoms were independent predictors of sQOL, while positive and negative symptoms were independent predictors of objective psychosocial status. Depression and cognition were also linked to sQOL. These findings point to the importance of attending to residual positive symptoms early in the treatment of schizophrenia as a means of possibly enhancing both subjective and objective outcome in early course schizophrenia.

Altered resting state functional connectivity in early course schizophrenia.

Impaired connectivity is proposed to underlie pathophysiology of schizophrenia. Existing studies on functional connectivity show inconsistent results. We examined functional connectivity in a clinically homogenous sample of 34 early course schizophrenia patients compared with/to 19 healthy controls using resting state functional magnetic resonance imaging (rsfMRI). Mean duration of illness for schizophrenia patients was 4 ± 1.78 years. Following a comprehensive clinical assessment, rsfMRI data were acquired using a 3.0 T magnetic resonance imaging scanner, and analyzed using FSL version 5.01 software (FMRIB's Software Library, www.fmrib.ox.ac.uk/fsl). Compared to healthy controls, schizophrenia patients had significantly decreased functional connectivity in the left fronto-parietal network, lateral and medial visual network, motor network, default mode network and auditory network. Our data suggests significant functional hypoconnectivity in selected brain networks in early schizophrenia patients compared to controls. It is likely that the observed functional hypoconnectivity may be associated with features of schizophrenia other than those examined in this study. It is possible that hypoconnectivity is necessary but not sufficient to the clinical manifestation of schizophrenia. The examination of functional connectivity as a biomarker should be extended to a wider array of disease phenotypes to better understand its significance.

The clinical trajectory of emerging bipolar disorder among the high-risk offspring of bipolar parents: current understanding and future considerations.

BACKGROUND: Relatively little is known about the onset of bipolar disorder, yet the early illness course is already associated with significant morbidity and mortality. Therefore, characterizing the bipolar illness trajectory is key to risk prediction and early intervention advancement. MAIN BODY: In this narrative review, we discuss key findings from prospective longitudinal studies of the high-risk offspring of bipolar parents and related meta-analyses that inform us about the clinical trajectory of emerging bipolar disorder. Challenges such as phenotypic and etiologic heterogeneity and the non-specificity of early symptoms and syndromes are highlighted. Implications of the findings for both research and clinical practice are discussed. CONCLUSION: Bipolar disorder in young people at familial risk does not typically onset with a hypomanic or manic episode. Rather the first activated episode is often preceded by years of impairing psychopathological states that vary over development and across emerging bipolar subtype. Taking heterogeneity into account and adopting a more comprehensive approach to diagnosis seems necessary to advance earlier identification and our understanding of the onset of bipolar disorder.

Prediction and prevention of schizophrenia: what has been achieved and where to go next?

In modern medicine, vigorous efforts are being made in the prediction and prevention of diseases. Mental disorders are suitable candidates for the application of this program. The currently known neurobiological and psychosocial risk indicators for schizophrenia do not have a predictive power sufficient for selective prevention in asymptomatic patients at risk. However, once predictive basic and later pre-psychotic high risk symptoms of psychosis develop into the five-year initial prodrome, the impending outbreak of the disease can be predicted with high accuracy. Research findings suggest a differential strategy of indicated prevention with cognitive behavioral therapy in early initial prodromal states and low dosage atypical antipsychotics in late initial prodromal states. The most important future tasks are the improvement of the predictive power by risk enrichment and stratification, as well as the confirmation of the existing and the development of new prevention strategies, with a stronger focus on the etiology of the disorder. In addition, the prediction and prevention approach would benefit from the inclusion of risk symptoms in the DSM-5 criteria.

Indicated prevention of schizophrenia.

INTRODUCTION: Despite recent advances in their treatment, schizophrenic disorders are still among the diseases that most severely impair patients' quality of life. For this reason, centers for the early recognition of schizophrenic disorders have come into existence worldwide. In these centers, much effort is devoted to the development and testing of suitable preventive strategies. METHODS: In this article, we selectively review the literature on the currently available means of assessing the individual risk of becoming ill with schizophrenia and of preventing the imminent onset of the disease. RESULTS: The currently recognized neurobiological and psychosocial risk factors are not predictive enough to enable the development and application of selective prevention measures for asymptomatic persons at risk. The imminent onset of schizophrenia can be predicted with high accuracy, however, in cases where an initially non-psychotic patient develops early cognitive symptoms that imply a risk of schizophrenia and then, later on in the prodrome of the disease (which typically lasts about five years), goes on to develop high-risk symptoms with mild psychosis. At this point, a differential strategy of indicated prevention can be put into action, including cognitive behavioral therapy, atypical antipsychotics in low doses, and neuroprotective agents. DISCUSSION: The current state of knowledge in this innovative field of research leads us to expect that it will soon be possible to offer individually tailored preventive measures to persons seeking medical help and advice because of the early warning signs of schizophrenia.