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.

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.

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.

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.