Longitudinal study of inflammation and relapse in schizophrenia.

INTRODUCTION: The clinical course of schizophrenia is often characterized by recurrent relapses. Blood inflammatory markers are altered in acute psychosis, and may be state markers for illness relapse in schizophrenia. Few studies have investigated longitudinal, intra-individual changes in inflammatory markers as a predictor of relapse. In the present study, we explored this association in a relapse prevention trial in patients with schizophrenia. METHODS: We analyzed blood inflammatory markers in 200 subjects, with a mean 11 samples per subject, during the 30 month Preventing Relapse in schizophrenia: Oral Antipsychotics Compared to Injectable: eValuating Efficacy (PROACTIVE) trial. Associations between longitudinal changes in inflammatory markers and relapse were analyzed using a within-subjects design. RESULTS: 70 (35 %) of subjects relapsed during the study period. There were no significant differences in mean inflammatory marker levels based on relapse status (yes/no). Baseline levels of inflammatory markers did not predict incident relapse. Among subjects who relapsed, there was a significant decrease in mean blood IL-6 (n = 38, p = 0.019) and IFN-γ (n = 44, p = 0.012) levels from the visit before the relapse to the visit after relapse. CONCLUSION: Although there was some evidence for inflammation as a potential state marker for acute psychosis, we did not find significant evidence for its utility as a relapse-predictive marker.

Continuation Electroconvulsive Therapy for Patients With Clozapine-Resistant Schizophrenia: A Pilot Study.

OBJECTIVES: The risk of relapse after a successful acute course of treatment is a clinical challenge in electroconvulsive therapy (ECT) practice, particularly in patients with a history of marked resistance to previous treatments. Research suggests that a gradual decrease of ECT or its long-term continuation might be the best strategy. Notwithstanding, current studies do not address the role of continuation ECT in the truly refractory cases, that is, the clozapine-resistant patients. Our group published a randomized controlled trial of ECT augmentation of clozapine in clozapine-resistant patients with schizophrenia, where the augmentation was vastly superior in efficacy for the acute treatment. The aim of the current study is to evaluate the efficacy of continuation ECT for patients who showed response to the combination of acute ECT and clozapine for treatment-resistant schizophrenia. METHODS: Continuation ECT was offered to all patients who completed the acute study and who met response criterion. We followed a tapered schedule of 4 weekly ECT sessions, followed by 4 ECT sessions every 2 weeks and 2 monthly ECT sessions for a total of 10 sessions. RESULTS: Patients sustained the gains achieved with the acute course of ECT, and no individual patient presented with clinically relevant worsening of symptoms. Moreover, the long-term use of ECT was not associated with added adverse effects. CONCLUSIONS: This is an open pilot study with a small sample size, and results should be interpreted accordingly, but this report offers a relevant starting point for much needed future studies.

Electroconvulsive Therapy Augmentation in Clozapine-Resistant Schizophrenia: A Prospective, Randomized Study.

(Reprinted with permission from Am J Psychiatry 2015; 172:52-58).

Predicting relapse in schizophrenia: Is BDNF a plausible biological marker?

Understanding the biological processes that underlie why patients relapse is an issue of fundamental importance to the detection and prevention of relapse in schizophrenia. Brain Derived Neurotrophic Factor (BDNF), a facilitator of brain plasticity, is reduced in patients with schizophrenia. In the present study, we examined whether decreases in plasma BDNF levels could be used as a biological predictor of relapse in schizophrenia. A total of 221 patients were prospectively evaluated for relapse over 30months in the Preventing Relapse in Schizophrenia: Oral Antipsychotics Compared to Injectables: eValuating Efficacy (PROACTIVE) study. Serial blood samples were collected at a maximum of 23 time points during the 30-month trial and BDNF levels were measured in plasma samples by ELISA. Receiver Operating Characteristic (ROC) curve analysis indicated that BDNF was not a significant predictor of relapse, hospitalization or exacerbation. Regardless of treatment group (oral second generation antipsychotic vs. long-acting injectable risperidone microspheres), baseline BDNF value did not differ significantly between those who experienced any of the adverse outcomes and those who did not. While contrary to the study hypothesis, these robust results offer little support for the use of plasma BDNF alone as a biomarker to predict relapse in schizophrenia.

Comparison of Injectable and Oral Antipsychotics in Relapse Rates in a Pragmatic 30-Month Schizophrenia Relapse Prevention Study.

OBJECTIVE: In a pragmatic clinical trial, this study sought to compare relapses among patients receiving either long-acting injectable or oral second-generation antipsychotics. METHODS: PROACTIVE (Preventing Relapse Oral Antipsychotics Compared to Injectables Evaluating Efficacy), a prior 30-month relapse prevention study, compared use of a long-acting injectable second-generation antipsychotic with use of an oral second-generation antipsychotic by 305 patients with schizophrenia or schizoaffective disorder and found similar rates of first relapse between groups (42% with injectable medication, 32% with oral medication). This study examined subsequent relapses among patients who had relapsed in PROACTIVE and who continued in treatment, follow-up, or both. RESULTS: Thirty-two patients (11%) experienced two relapses, and 13 patients (4%) had three relapses. Neither rate of relapse nor time to successive relapses differed between treatment groups. CONCLUSIONS: There was an impressively low rate of subsequent relapses in this pragmatic clinical trial. Because all patients had a clinic visit according to the biweekly long-acting injectable medication administration schedule, frequent contact may have contributed to low relapse rates. Maintaining frequent clinical contact may be a valid psychosocial relapse prevention treatment.

Comparison of SGA oral medications and a long-acting injectable SGA: the PROACTIVE study.

Until relatively recently, long-acting injectable (LAI) formulations were only available for first-generation antipsychotics and their utilization decreased as use of oral second-generation antipsychotics (SGA) increased. Although registry-based naturalistic studies show LAIs reduce rehospitalization more than oral medications in clinical practice, this is not seen in recent randomized clinical trials. PROACTIVE (Preventing Relapse Oral Antipsychotics Compared to Injectables Evaluating Efficacy) relapse prevention study incorporated efficacy and effectiveness features. At 8 US academic centers, 305 patients with schizophrenia or schizoaffective disorder were randomly assigned to LAI risperidone (LAI-R) or physician's choice oral SGAs. Patients were evaluated during the 30-month study by masked, centralized assessors using 2-way video, and monitored biweekly by on-site clinicians and assessors who knew treatment assignment. Relapse was evaluated by a masked Relapse Monitoring Board. Differences between LAI-R and oral SGA treatment in time to first relapse and hospitalization were not significant. Psychotic symptoms and Brief Psychiatric Rating Scale total score improved more in the LAI-R group. In contrast, the LAI group had higher Scale for Assessment of Negative Symptoms Alogia scale scores. There were no other between-group differences in symptoms or functional improvement. Despite the advantage for psychotic symptoms, LAI-R did not confer an advantage over oral SGAs for relapse or rehospitalization. Biweekly monitoring, not focusing specifically on patients with demonstrated nonadherence to treatment and greater flexibility in changing medication in the oral treatment arm, may contribute to the inability to detect differences between LAI and oral SGA treatment in clinical trials.

Electroconvulsive therapy augmentation in clozapine-resistant schizophrenia: a prospective, randomized study.

OBJECTIVE: Up to 70% of patients with treatment-resistant schizophrenia do not respond to clozapine. Pharmacological augmentation to clozapine has been studied with unimpressive results. The authors examined the use of ECT as an augmentation to clozapine for treatment-refractory schizophrenia. METHOD: In a randomized single-blind 8-week study, patients with clozapine-resistant schizophrenia were assigned to treatment as usual (clozapine group) or a course of bilateral ECT plus clozapine (ECT plus clozapine group). Nonresponders from the clozapine group received an 8-week open trial of ECT (crossover phase). ECT was performed three times per week for the first 4 weeks and twice weekly for the last 4 weeks. Clozapine dosages remained constant. Response was defined as ≥40% reduction in symptoms based on the psychotic symptom subscale of the Brief Psychiatric Rating Scale, a Clinical Global Impressions (CGI)-severity rating <3, and a CGI-improvement rating ≤2. RESULTS: The intent-to-treat sample included 39 participants (ECT plus clozapine group, N=20; clozapine group, N=19). All 19 patients from the clozapine group received ECT in the crossover phase. Fifty percent of the ECT plus clozapine patients met the response criterion. None of the patients in the clozapine group met the criterion. In the crossover phase, response was 47%. There were no discernible differences between groups on global cognition. Two patients required the postponement of an ECT session because of mild confusion. CONCLUSIONS: The augmentation of clozapine with ECT is a safe and effective treatment option. Further research is required to determine the persistence of the improvement and the potential need for maintenance treatments.

Randomized comparison of olanzapine versus risperidone for the treatment of first-episode schizophrenia: 4-month outcomes.

OBJECTIVE: The authors compared 4-month treatment outcomes for olanzapine versus risperidone in patients with first-episode schizophrenia spectrum disorders. METHOD: One hundred twelve subjects (70% male; mean age=23.3 years [SD = 5.1]) with first-episode schizophrenia (75%), schizophreniform disorder (17%), or schizoaffective disorder (8%) were randomly assigned to treatment with olanzapine (2.5-20 mg/day) or risperidone (1-6 mg/day). RESULTS: Response rates did not significantly differ between olanzapine (43.7%, 95% CI=28.8%-58.6%) and risperidone (54.3%, 95% CI=39.9%-68.7%). Among those responding to treatment, more subjects in the olanzapine group (40.9%, 95% CI=16.8%-65.0%) than in the risperidone group (18.9%, 95% CI=0%-39.2%) had subsequent ratings not meeting response criteria. Negative symptom outcomes and measures of parkinsonism and akathisia did not differ between medications. Extrapyramidal symptom severity scores were 1.4 (95% CI=1.2-1.6) with risperidone and 1.2 (95% CI=1.0-1.4) with olanzapine. Significantly more weight gain occurred with olanzapine than with risperidone: the increase in weight at 4 months relative to baseline weight was 17.3% (95% CI=14.2%-20.5%) with olanzapine and 11.3% (95% CI=8.4%-14.3%) with risperidone. Body mass index at baseline and at 4 months was 24.3 (95% CI=22.8-25.7) versus 28.2 (95% CI=26.7-29.7) with olanzapine and 23.9 (95% CI=22.5-25.3) versus 26.7 (95% CI=25.2-28.2) with risperidone. CONCLUSIONS: Clinical outcomes with risperidone were equal to those with olanzapine, and response may be more stable. Olanzapine may have an advantage for motor side effects. Both medications caused substantial rapid weight gain, but weight gain was greater with olanzapine.

The utility of intramuscular ziprasidone in the management of acute psychotic agitation.

Many psychiatric illnesses, including chronic schizophrenia, bipolar disorder, and dementia, are characterized by episodes of acute agitation, making administration of oral agents difficult or impossible. Ziprasidone, the first atypical antipsychotic available in both intramuscular (IM) and oral formulations, has demonstrated significant control of acute agitation within 15 minutes, as seen in two 24-hour studies in patients with schizophrenia. Improvement was maintained for > or = 4 hours, and a low incidence of extrapyramidal symptoms, akathisia, and dystonia as well as no excessive sedation were observed Also, two 7-day studies (n = 132 and n = 306) and one 6-week study (n = 567) of sequential IM/oral ziprasidone versus IM/oral haloperidol in patients with psychotic disorders found IM ziprasidone more effective than IM haloperidol within 3 days of IM treatment; both drugs produced further comparable improvements in efficacy parameters after transition to oral therapy. IM ziprasidone was associated with a lower incidence of movement disorders than was haloperidol in all of these studies. Overall, discontinuations were similar for IM ziprasidone and haloperidol in the comparative trials, including the sequential IM/oral studies. However, in the 6-week sequential IM/oral trial, the rate of discontinuation due to adverse events was twice as high among haloperidol vs ziprasidone patients. This report focuses on the pharmacology, clinical efficacy, and tolerability of IM ziprasidone, and provides an overview of the utility of other commonly used antipsychotics in the management of acute psychotic agitation.

Symptomatic and functional recovery from a first episode of schizophrenia or schizoaffective disorder.

OBJECTIVE: Follow-up studies have found that a substantial number of patients with schizophrenia achieve full recovery (i.e., sustained improvement in both symptoms and social/vocational functioning) when examined decades after an index admission. This study addressed recovery during the crucial early course of the illness. METHOD: Subjects in their first episode of schizophrenia or schizoaffective disorder (N=118) were assessed at baseline and then treated according to a medication algorithm. Full recovery required concurrent remission of positive and negative symptoms and adequate social/vocational functioning (fulfillment of age-appropriate role expectations, performance of daily living tasks without supervision, and engagement in social interactions). RESULTS: After 5 years, 47.2% (95% CI=36.0%-58.4%) of the subjects achieved symptom remission, and 25.5% (95% CI=16.1%-34.7%) had adequate social functioning for 2 years or more. Only 13.7% (95% CI=6.4%-20.9%) of subjects met full recovery criteria for 2 years or longer. Better cognitive functioning at stabilization was associated with full recovery, adequate social/vocational functioning, and symptom remission. Shorter duration of psychosis before study entry predicted both full recovery and symptom remission. More cerebral asymmetry was associated with full recovery and adequate social/vocational functioning; a schizoaffective diagnosis predicted symptom remission. CONCLUSIONS: Although some patients with first-episode schizophrenia can achieve sustained symptomatic and functional recovery, the overall rate of recovery during the early years of the illness is low.

Best clinical practice with ziprasidone: update after one year of experience.

This article presents clinical recommendations for using ziprasidone based on information from a year of post-marketing experience. The recommendations are based on the clinical literature, the package insert, presentations at recent meetings, data on file with the manufacturer, and the consensus of a panel of expert psychiatrists. The article provides updates on efficacy and safety data and gives recommendations for dosing and switching strategies. With regard to the QTc issue, there has not been any case of torsades de pointes reported in the more than 150,000 patients who have received ziprasidone since its approval. Ziprasidone is weight neutral and does not appear to cause increases in glucose or lipid levels or in insulin resistance. The panel generally recommends beginning with an initial dose of 80 mg/day (40 mg b.i.d.) rather than the 40 mg/day dose recommended in the package insert. The ability to begin with a therapeutic dose and to titrate up rapidly is an advantage of ziprasidone, especially in treatment settings where admission time is short. In making an elective switch to ziprasidone, the panel recommends a variety of different switching strategies but stresses the importance of trying to maintain a therapeutic dose of one antipsychotic at all times.