Preventing the Second Episode: A Systematic Review and Meta-analysis of Psychosocial and Pharmacological Trials in First-Episode psychosis

Objective: The majority of first-episode psychosis (FEP) patients reach clinical remission; however, rates of relapse are high. This study sought to undertake a systematic review and meta-analysis of randomized controlled trials (RCTs) to determine the effectiveness of pharmacological and non-pharmacological interventions to prevent relapse in FEP patients. Methods: Systematic review and meta-analysis of RCTs. Results: Of 66 studies retrieved, 18 were eligible for inclusion. Nine studies investigated psychosocial interventions and 9 pharmacological treatments. The analysis of 3 RCTs of psychosocial interventions comparing specialist FEP programs vs treatment as usual involving 679 patients demonstrated the former to be more effective in preventing relapse (odds ratio [OR] = 1.80, 95% confidence interval [CI] = 1.31–2.48; P < .001; number needed to treat [NNT] = 10). While the analysis of 3 different cognitive-behavioral studies not specifically intended at preventing relapse showed no further benefits compared with specialist FEP programs (OR = 1.95, 95% CI = 0.76–5.00; P = .17), the combination of specific individual and family intervention targeted at relapse prevention may further improve upon these outcomes (OR = 4.88, 95% CI = 0.97–24.60; P = .06). Only 3 small studies compared first-generation antipsychotics (FGAs) with placebo with no significant differences regarding relapse prevention although all individual estimates favored FGAs (OR = 2.82, 95% CI = 0.54–14.75; P = .22). Exploratory analysis involving 1055 FEP patients revealed that relapse rates were significantly lower with second-generation antipsychotics (SGAs) compared with FGAs (OR = 1.47, 95% CI = 1.07–2.01; P < .02; NNT = 10). Conclusions: Specialist FEP programs are effective in preventing relapse. Cognitive-based individual and family interventions may need to specifically target relapse to obtain relapse prevention benefits that extend beyond those provided by specialist FEP programs. Overall, the available data suggest that FGAs and SGAs have the potential to reduce relapse rates. Future trials should examine the effectiveness of placebo vs antipsychotics in combination with intensive psychosocial interventions in preventing relapse in the early course of psychosis. Further studies should identify those patients who may not need antipsychotic medication to be able to recover from psychosis.     

Is there an association between neurocognitive performance and medication adherence in first episode psychosis?

Aim: Medication adherence is a determining factor for symptomatic remission and relapse prevention following a first episode of psychosis (FEP). Neurocognitive abilities have received only scant attention so far as a risk factor for poor adherence but significant impairments with memory and/or planning abilities could play a role. We examined early medication adherence following admission to a specialized clinical programme for FEP. Method: One hundred sixty FEP participants and 35 healthy controls completed an exhaustive neurocognitive assessment. FEP participants were categorized as a function of their medication adherence at 6 months into poor (n = 34), partial (n = 27) and full (n = 99) adherence, respectively. Domain-specific and global measures of cognitive ability were examined. Results: No measure of neurocognition could significantly discriminate amongst the three medication adherence groups. Conclusion: These results suggest no strong associations between neurocognitive abilities and medication adherence in first episode of psychosis.     

Sex Differences in Verbal Memory Predict Functioning Through Negative Symptoms in Early Psychosis

Verbal memory (VM) is one of the most affected cognitive domains in first-episode psychosis (FEP) and is a robust predictor of functioning. Given that healthy females demonstrate superior VM relative to males and that female patients show less-severe illness courses than male patients, this study examined whether normative sex differences in VM extend to FEP and influence functioning. Four hundred and thirty-five patients (299 males, 136 females) with affective or nonaffective psychosis were recruited from a catchment-based specialized FEP intervention service and 138 nonclinical controls (96 males, 42 females) were recruited from the same community. One of the two neurocognitive batteries comprising six cognitive domains (VM, visual memory, working memory, attention, executive function, processing speed) were administered at baseline. In patients, positive and negative symptoms were evaluated at baseline and functioning was assessed at 1-year follow-up. Patients were more impaired than controls on all cognitive domains, but only VM showed sex differences (both patient and control males performed worse than females), and these results were consistent across batteries. In patients, better baseline VM in females was related to better functioning after 1 year, mediated through fewer baseline negative symptoms. Supplemental analyses revealed these results were not driven by affective psychosis nor by age and parental education. Thus, normative sex differences in VM are preserved in FEP and mediate functioning at 1-year follow-up via negative symptoms. This study highlights the importance of investigating sex effects for understanding VM deficits in early psychosis and suggests that sex may be a disease-modifying variable with important treatment implications.     

Evidence-based psychotherapy for the prevention and treatment of first-episode psychosis

The aim of psychotherapy among individuals at clinical high risk (CHR) for psychosis is to prevent transition to full-blown psychosis. Psychotherapy in individuals with a first-episode psychosis (FEP) aims to reduce relapse rates. Remission of (pre-) psychotic symptoms, psychosocial functioning, quality of life, comorbid disorders and self-esteem are also important outcomes in individuals at CHR and with FEP. Antipsychotics, Qmega-3-Fatty acids and psychotherapy have been found to be effective in CHR for most of these aims. Thereby psychotherapy presents a better benefit/risk ratio than antipsychotic medication. The most evidence-based intervention is cognitive-behavioral therapy (CBT). Psychotherapy is mostly offered to FEP patients within specialized early intervention services (including assertiveness community treatment and antipsychotic medication). Thereby, CBT is effective for positive symptoms and family intervention is particularly effective for the prevention of relapses. We introduce the principles of CBT for psychosis and suggest adaptions for individuals at CHR and FEP. We conclude that the needs of young people at CHR and with FEP are best met by specially designed, low threshold outpatient clinical services, which include intensive psychotherapy treatment. A number of countries have implemented early detection and intervention services based on this model, while the implementation within in Germany is still marginal.

     

Falling Apart: The Verbalization of Ego Failure

To determine whether evidence-based, psychosocial treatments developed in the United States and England are applicable to Mexican outpatients with schizophrenia, the present study was carried out to evaluate the relative effectiveness of family psycho-education and psychosocial skills training added to customary treatment vs. customary treatment alone. Clinically stable outpatients with schizophrenia participated in a 12-month randomized, controlled trial at the National Institute of Psychiatry in Mexico City. An experimental group (N = 47) received the combination of psychosocial skills training, family psycho-education and customary pharmacotherapy while the comparison group (N = 36) received customary treatment alone. Patients were assessed at baseline and one year after commencement of treatment. Significant differences favoring the group that received psychosocial rehabilitation were found in ratings of adherence to medication, attendance at appointments, symptoms, social functioning, relapse, and re-hospitalization. While some adaptations were made in the psychosocial treatments to resolve cultural differences, the results provide cross-national validation of evidence-based treatments for persons with schizophrenia.     

Electroencephalographic Abnormalities and 5-Year Outcome in First-Episode Psychosis

Objective:

To examine the relation of electroencephalographic abnormalities to 5-year outcomes in first-episode psychosis (FEP).

Methods:

Patients (n = 103) had their baseline electroencephalogram (EEG) classified by modified Mayo Clinic criteria. Symptoms and psychosocial functioning were rated after 5 years of treatment.

Results:

Dysrhythmic EEG was associated with persistence in positive and negative symptoms of psychoses and poorer psychosocial functioning at 5-year follow-up, independently of other characteristics, such as duration of untreated illness or premorbid adjustment. A higher percentage of people with comorbid substance use disorder had normal EEG.

Conclusions:

Abnormal baseline EEG in FEP is associated with poorer 5-year symptomatic and functional outcome.     

Multimodal Cognitive Therapy: Combining Treatments That Bypass Cognitive Deficits and Deal With Reasoning and Appraisal Biases

The process of recovery in schizophrenia involves resolving persistent symptoms, addressing cognitive impairments, and improving functional outcomes. Our research group has demonstrated the efficacy of cognitive adaptation training (CAT)—a home-based psychosocial treatment utilizing environmental supports such as medication containers, signs, checklists, and the organization of belongings to bypass deficits in cognitive functioning and cue and sequence adaptive behavior) for improving adherence to medications and functional outcomes in schizophrenia. Early CAT pilot studies utilizing some therapists with training in cognitive behavior therapy (CBT) techniques for psychosis found significant improvements in positive symptoms. More recent larger scale randomized clinical trials failed to replicate this finding with CAT therapists not trained in CBT techniques. Persistent psychotic symptoms substantially impair patients’ ability to adapt to life in the community. Cognitive behavior therapy for psychosis (CBTp) is an evidence-based practice for addressing persistent positive symptoms and the distress associated with them. CBTp decreases symptomatology and minimizes the negative effect of persisting symptoms upon individuals with this disorder. We now describe a home-delivered, multimodal cognitive treatment targeting functional outcomes and persistent positive symptoms for individuals with schizophrenia by utilizing both CAT and CBT techniques. We discuss the advantages and challenges of combining these 2 interventions, present a small retrospective data analysis to support their combination into a multimodal treatment, and describe the design of an ongoing randomized trial to investigate efficacy.     

Medication adherence in psychosis: predictors and impact on outcome. A 2-year follow-up of first-admitted subjects

OBJECTIVE: To assess the baseline characteristics predicting poor medication adherence following a first admission for psychosis, and the impact of poor medication adherence on outcome. METHOD: First-admitted subjects with psychosis (n = 65) were assessed at 6-month intervals over a 2-year follow-up. Medication adherence was assessed using multiple sources of information. RESULTS: Baseline lower occupational status, alcohol misuse and the intensity of delusional symptoms and suspiciousness predicted poor medication adherence during the 2-year follow-up. Over this period, subjects with poor medication adherence presented more frequently with an episodic course of illness and were more frequently readmitted, especially with regard to involuntary readmission. CONCLUSION: In naturalistic conditions one out of two subjects with psychosis interrupts his/her treatment in the months following his/her first discharge from hospital. Therapeutic programmes aimed at improving medication adherence should be implemented early in the course of psychosis to reduce the deleterious consequences of poor medication adherence on clinical outcome.     

Randomized controlled trial of a cannabis-focused intervention for young people with first-episode psychosis

OBJECTIVE: To evaluate a cannabis-focused intervention (cannabis and psychosis therapy: CAP) for patients continuing to use cannabis following initial treatment for first-episode psychosis (FEP). METHOD: Consecutive admissions to an early psychosis program were screened and consenting individuals using cannabis in the 4 weeks prior to assessment participated. A single-blind randomized controlled trial compared CAP (n = 23) with a clinical control condition (psychoeducation, PE; n = 24). There were no significant differences between the CAP and PE groups on cannabis use at end of treatment and 6 months post-intervention. RESULTS: There were no significant group differences on psychopathology and functional ratings at follow-up. A significant reduction in cannabis use was observed for both groups over time. CONCLUSION: PE and specific cannabis-focused intervention are associated with similar reductions in cannabis use in an FEP cohort. Simple interventions may therefore be worth considering prior to intensive psychotherapeutic efforts with this population.     

On the HORYZON: Moderated online social therapy for long-term recovery in first episode psychosis

BackgroundEarly intervention services have demonstrated improved outcomes in first episode psychosis (FEP); however, recent evidence shows that treatment benefits may not be sustainable over time. These findings have resulted in repeated recommendations for the implementation of longer term treatment programs. An Internet-based intervention specifically designed for young people with psychosis may provide a cost-effective alternative to prevent loss of treatment benefits from early intervention.MethodsOur multi-disciplinary team has developed a highly novel online intervention (HORYZONS) in regular consultation with stakeholders within a specialist early psychosis program. HORYZONS integrates: i) peer-to-peer social networking, ii) individually tailored interactive psychosocial interventions, and iii) expert interdisciplinary and peer-moderation in a coherent platform designed to improve long-term outcomes in FEP. The acceptability, safety and initial clinical benefits of HORYZONS were examined through a 1-month pilot study with 20 participants with FEP.ResultsThere were no dropouts during the pilot study. Seventy per cent of participants utilised the system for at least 3 weeks, 95% used the social networking features, and 60% completed at least 3 therapy modules. System usage was high during the study. There were no incidents and the majority of participants reported feeling safe, empowered and more socially connected using HORYZONS. Analysis revealed a significant reduction in depressive symptoms at follow-up.ConclusionsOur results indicate that HORYZONS is feasible, engaging and safe and may augment social connectedness and empowerment in FEP. These findings have significant implications for the enhancement of specialist FEP services. The potential of HORYZONS to improve long-term recovery is worthy of further investigation.     

Impact of symptom resolution on medication adherence in first episode psychosis

Adequate adherence to medication confers benefits on patients with psychotic illness, but is difficult to achieve. Efficacy of medication influences adherence in patients in advanced phases of illness and may have a similar influence on patients with a first episode of psychosis (FEP). We assessed medication adherence and efficacy in 216 FEP patients at program entry and at 3 and 6 months later. "Efficacy" was evaluated as the ability of medication to reduce positive or negative symptoms to below established thresholds for clinical remission at each evaluation. Adherence was defined as adequate (>75%) or not. Resolution of negative symptoms by month 3 of treatment was associated with inadequate adherence at months 3 and 6. In contrast, rapid resolution of positive symptoms showed no relationship to adherence. In a multivariate analysis taking into account other determinants of adherence in FEP, the role of early negative symptom remission was confirmed, and we found that a 3-month sustained remission of positive symptoms was associated with adequate adherence. Medication efficacy may promote adherence if it produces sustained remission of positive symptoms. However, many patients who benefit from medication, particularly those with rapid improvement of negative symptoms, fail to adhere to the treatment.     

Feasibility and Effectiveness of a Multi-Element Psychosocial Intervention for First-Episode Psychosis: Results From the Cluster-Randomized Controlled GET UP PIANO Trial in a Catchment Area of 10 Million Inhabitants

Integrated multi-element psychosocial interventions have been suggested to improve the outcomes of first-episode psychosis (FEP) patients, but they have been studied primarily in experimental settings and in nonepidemiologically representative samples. Thus, we performed a cluster-randomized controlled trial, comparing an integrated multi-element psychosocial intervention, comprising cognitive behavioral therapy, family intervention, and case management, with treatment as usual (TAU) for FEP patients in 117 community mental health centers (CMHCs) in a large area of northern Italy (10 million inhabitants). The randomized units (clusters) were the CMHCs, and the units of observation the patients (and, when available, their family members). The primary hypotheses were that add-on multicomponent intervention: (1) results in greater improvements in symptoms, as assessed with positive and negative syndrome scale and (2) reduces in-hospital stay, based on days of hospitalization over the 9-month follow-up. Four hundred and forty-four FEP patients received the intervention or TAU and were assessed at baseline and 9 months. Based on the retention rates of patients (and families) in the experimental arm, multi-element psychosocial interventions can be implemented in routine mental health services. Regarding primary outcomes, patients in the experimental arm showed greater reductions in overall symptom severity, while no difference could be found for days of hospitalization. Among the secondary outcomes, greater improvements were detected in the experimental arm for global functioning, emotional well-being, and subjective burden of delusions. No difference could be found for service disengagement and subjective burden of auditory hallucinations. These findings support feasibility and effectiveness of early interventions for psychosis in generalist mental health services.Key words: schizophrenia, early psychosis, outcome assessment, cognitive behavioral therapy, family intervention     

A review of second-generation antipsychotic discontinuation in first-episode psychosis

"All-causes discontinuation" refers to discontinuation of treatment for any reason, and adherence to medication is an important component of this measure. Two recent landmark studies suggest that adherence is a major issue in patients with first-episode psychosis (FEP) right from the onset of treatment. In this review, the incidence, reasons for, and clinical outcomes of medication discontinuation in FEP are considered. More than 40% of patients with FEP discontinue medication during the first 9 months of treatment, at which point the chances of relapse increase dramatically. Findings concerning predictors of medication discontinuation in this patient population that have been replicated in more than one study include severity of psychopathology, lack of insight into illness, negative attitudes towards medications, comorbid substance use, and medication side effects. Interventions that have the potential to decrease discontinuation rates in patients with psychotic disorders include orally disintegrating tablets, long-acting injectable drugs, cognitive-behavioral therapy, compliance therapy, family support/intervention, and peer support, although these strategies have largely been unexplored in FEP. In addition to the question of medication discontinuation in the acute treatment of FEP, another important issue is how long patients with FEP should be treated with antipsychotics once they have achieved remission; unfortunately, little evidence is available to guide the decision as to whether medication should be discontinued or maintenance treatment provided in this situation. Studies are therefore needed to identify predictors of patients with remitted FEP who are less likely to relapse when medication is discontinued. Taken together, the findings presented in this article underscore the importance of addressing issues related to medication discontinuation as a means of preventing long-term morbidity and enhancing remission and functional recovery in FEP.     

Cognitive Efficacy of Quetiapine and Olanzapine in Early-Onset First-Episode Psychosis

The primary purpose of this study was to compare changes in cognition in early-onset psychosis after 6-months treatment with quetiapine or olanzapine. This is a randomized, single-blind, 6-month study in 50 adolescents with a diagnosis of early-onset psychosis. Patients were randomized to quetiapine (n = 24) or olanzapine (n = 26). A thorough neuropsychological battery was administered at baseline and after 6-month treatment. Out of the total sample included in the study, 32 patients completed at least 6-months treatment with the assigned medication (quetiapine, n = 16; olanzapine, n = 16). No changes were observed in cognitive performance after 6-month treatment with quetiapine or olanzapine. Although some trends toward cognitive improvement were observed for the olanzapine group after 6-month treatment, neither group showed statistically significant gains. Furthermore, there was no evidence of any differential efficacy of olanzapine or quetiapine on cognitive improvement in this sample of adolescents with psychosis.     

Dynamic Interplay Between Insight and Persistent Negative Symptoms in First Episode of Psychosis: A Longitudinal Study

Persistent negative symptoms (PNS) are an important factor of first episode of psychosis (FEP) that present early on in the course of illness and have a major impact on long-term functional outcome. Lack of clinical insight is consistently associated with negative symptoms during the course of schizophrenia, yet only a few studies have explored its evolution in FEP. We sought to explore clinical insight change over a 24-month time period in relation to PNS in a large sample of FEP patients. Clinical insight was assessed in 515 FEP patients using the Scale to assess Unawareness of Mental Disorder. Data on awareness of illness, belief in response to medication, and belief in need for medication were analyzed. Patients were divided into 3 groups based on the presence of negative symptoms: idiopathic (PNS; n = 135), secondary (sPNS; n = 98), or absence (non-PNS; n = 282). Secondary PNS were those with PNS but also had clinically relevant levels of positive, depressive, or extrapyramidal symptoms. Our results revealed that insight improved during the first 2 months for all groups. Patients with PNS and sPNS displayed poorer insight across the 24-month period compared to the non-PNS group, but these 2 groups did not significantly differ. This large longitudinal study supported the strong relationship known to exist between poor insight and negative symptoms early in the course of the disorder and probes into potential factors that transcend the distinction between idiopathic and secondary negative symptoms.     

Treating co-occurring first-episode psychosis and borderline personality: a pilot randomized controlled trial

Aim: First‐episode psychosis and borderline personality disorder are severe mental disorders that have their onset in youth. Their co‐occurrence is clinically well recognized, is associated with significant risks and is complex to treat. Yet, there is no published specific intervention for this problem. This study reports a pilot randomized controlled trial comparing combined specialist first‐episode treatment plus specialist early intervention for borderline personality, entitled Helping Young People Early, with specialist first‐episode treatment alone. We aimed to evaluate the safety and feasibility of adding early intervention for borderline personality. Methods: The study investigated the safety of specialist first‐episode treatment plus specialist early intervention for borderline personality in relation to deterioration in psychosis, aggression, self‐harm and suicidality, and feasibility in relation to the completion of therapy phases. Sixteen patients meeting Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition‐Text Revision (DSM‐IV‐TR) criteria for first‐episode psychosis and borderline personality (four or more DSM‐IV criteria) were randomized either to specialist first‐episode treatment alone or specialist first‐episode treatment plus specialist early intervention for borderline personality and were followed up at the end of treatment and 6 months later. Results: The results showed that it was feasible to recruit and assess a high risk and complex group of patients who were agreeable to study participation. Specialist first‐episode treatment plus specialist early intervention for borderline personality was an acceptable and safe treatment. Conclusion: A larger‐scale randomized controlled trial of early intervention for borderline personality for young first‐episode psychosis patients with co‐occurring full or subsyndromal borderline personality is warranted.     

Profile and Determinants of Disability in Psychotic Disorders in Nigeria

We compared profile and predictors of disability among 210 patients with schizophrenia, schizoaffective disorder, bipolar I disorder with psychosis and depression with psychosis, respectively in a Nigerian clinical population, using the WHO Disability Assessment Schedule, (2.0). Severity of psychosis was determined with Positive and Negative Symptoms Scale, functioning was assessed using the Global Assessment of Functioning Scale, medication adherence with the Medication Adherence Questionnaire. Analyses were by SPSS 20.0. There were remarkable differences in the predictors of disability across these psychotic disorders. The findings strengthens the significance of psychosocial rehabilitation in patients with psychosis as clinical remission and medication adherence did not equate functional recovery.     

Neural correlates of aberrant emotional salience predict psychotic symptoms and global functioning in high-risk and first-episode psychosis

Neurobiological and behavioral findings suggest that psychosis is associated with corticolimbic hyperactivity during the processing of emotional salience. This has not been widely studied in the early stages of psychosis, and the impact of these abnormalities on psychotic symptoms and global functioning is unknown. We sought to address this issue in 18 patients with first-episode psychosis (FEP), 18 individuals at ultra high risk of psychosis (UHR) and 22 healthy controls (HCs). Corticolimbic response and subjective ratings to emotional and neutral scenes were measured using functional magnetic resonance imaging. The clinical and functional impact of corticolimbic abnormalities was assessed with regression analyses. The FEP and UHR groups reported increased subjective emotional arousal to neutral scenes compared with HCs. Across groups, emotional vs neutral scenes elicited activation in the dorsomedial prefrontal cortex, inferior frontal gyrus/anterior insula and amygdala. Although FEP and UHR participants showed reduced activation in these regions when viewing emotional scenes compared with controls, this was driven by increased activation to neutral scenes. Corticolimbic hyperactivity to neutral scenes predicted higher levels of positive symptoms and poorer levels of functioning. These results indicate that disruption of emotional brain systems may represent an important biological substrate for the pathophysiology of early psychosis and UHR states.