Takefumi Suzuki

Defining treatment-resistant schizophrenia and response to antipsychotics: A review and recommendation

Treatment-resistant schizophrenia (TRS) has been defined mainly by severity of (positive) symptoms and response to antipsychotics derived from a relative change in the representative scales (most frequently ≥ 20% decrease in the Positive and Negative Syndrome Scale: PANSS), but these definitions have not necessarily been consistent. Integrating past evidence and real-world practicability, we propose that TRS be defined by at least two failed adequate trials with different antipsychotics (at chlorpromazine-equivalent doses of ≥ 600mg/day for ≥ 6 consecutive weeks) that could be retrospective or preferably include prospective failure to respond to one or more antipsychotic trials. In addition, our proposed criteria require both a score of ≥ 4 on the Clinical Global Impression (CGI)-Severity and a score of ≤ 49 on the Functional Assessment for Comprehensive Treatment of Schizophrenia (FACT-Sz) or ≤ 50 on the Global Assessment of Functioning (GAF) scales to define TRS. Once TRS is established, we propose that subsequent treatment response be defined based on a CGI-Change score of ≤ 2, a ≥ 20% decrease on the total PANSS or Brief Psychiatric Rating Scale (BPRS) scores, and an increase of ≥ 20 points on the FACT-Sz or GAF. While these suggestions provide a pragmatic framework for TRS classification, they need to be tested in future trials.

Treatment-Resistant Schizophrenia: Treatment Response and Resistance in Psychosis (TRRIP) Working Group Consensus Guidelines on Diagnosis and Terminology

OBJECTIVE Research and clinical translation in schizophrenia is limited by inconsistent definitions of treatment resistance and response. To address this issue, the authors evaluated current approaches and then developed consensus criteria and guidelines. METHOD A systematic review of randomized antipsychotic clinical trials in treatment-resistant schizophrenia was performed, and definitions of treatment resistance were extracted. Subsequently, consensus operationalized criteria were developed through 1) a multiphase, mixed methods approach, 2) identification of key criteria via an online survey, and 3) meetings to achieve consensus. RESULTS Of 2,808 studies identified, 42 met inclusion criteria. Of these, 21 studies (50%) did not provide operationalized criteria. In the remaining studies, criteria varied considerably, particularly regarding symptom severity, prior treatment duration, and antipsychotic dosage thresholds; only two studies (5%) utilized the same criteria. The consensus group identified minimum and optimal criteria, employing the following principles: 1) current symptoms of a minimum duration and severity determined by a standardized rating scale; 2) moderate or worse functional impairment; 3) prior treatment consisting of at least two different antipsychotic trials, each for a minimum duration and dosage; 4) systematic monitoring of adherence and meeting of minimum adherence criteria; 5) ideally at least one prospective treatment trial; and 6) criteria that clearly separate responsive from treatment-resistant patients. CONCLUSIONS There is considerable variation in current approaches to defining treatment resistance in schizophrenia. The authors present consensus guidelines that operationalize criteria for determining and reporting treatment resistance, adequate treatment, and treatment response, providing a benchmark for research and clinical translation.

Pharmacological Strategies to Counteract Antipsychotic-Induced Weight Gain and Metabolic Adverse Effects in Schizophrenia: A Systematic Review and Meta-analysis

BACKGROUND Antipsychotic-induced metabolic adversities are often difficult to manage. Using concomitant medications to counteract these adversities may be a rational option. OBJECTIVE To systematically determine the effectiveness of medications to counteract antipsychotic-induced metabolic adversities in patients with schizophrenia. DATA SOURCES Published articles until November 2013 were searched using 5 electronic databases. Clinical trial registries were searched for unpublished trials. STUDY SELECTION Double-blind randomized placebo-controlled trials focusing on patients with schizophrenia were included if they evaluated the effects of concomitant medications on antipsychotic-induced metabolic adversities as a primary outcome. DATA EXTRACTION Variables relating to participants, interventions, comparisons, outcomes, and study design were extracted. The primary outcome was change in body weight. Secondary outcomes included clinically relevant weight change, fasting glucose, hemoglobin A1c, fasting insulin, insulin resistance, cholesterol, and triglycerides. DATA SYNTHESIS Forty trials representing 19 unique interventions were included in this meta-analysis. Metformin was the most extensively studied drug in regard to body weight, the mean difference amounting to -3.17 kg (95% CI: -4.44 to -1.90 kg) compared to placebo. Pooled effects for topiramate, sibutramine, aripiprazole, and reboxetine were also different from placebo. Furthermore, metformin and rosiglitazone improved insulin resistance, while aripiprazole, metformin, and sibutramine decreased blood lipids. CONCLUSION When nonpharmacological strategies alone are insufficient, and switching antipsychotics to relatively weight-neutral agents is not feasible, the literature supports the use of concomitant metformin as first choice among pharmacological interventions to counteract antipsychotic-induced weight gain and other metabolic adversities in schizophrenia.

Treatment resistant schizophrenia and response to antipsychotics: A review

BACKGROUND There remains a lack of agreement regarding criteria for treatment-resistant schizophrenia (TRS) and definition of response. METHOD A literature search was conducted to identify clinical studies of antipsychotics in TRS using PubMed, EMBASE and PsycINFO (last search 31 July 2011). Psychopharmacological studies with the number of participants of ≥ 40 were evaluated in terms of definitions for TRS and subsequent treatment response. RESULTS Thirty-three studies of antipsychotics in TRS were reviewed. TRS has been defined mainly by severity in symptoms. Many studies based TRS with at least 2 failed adequate antipsychotic trials (at chlorpromazine equivalent doses of ≥ 1000 mg/day for ≥ 6 weeks), but some studies adopted prospective treatment arm to be certain of sample refractoriness. Treatment response has been defined by a relative change in the representative scales (most commonly ≥ 20% decrease in the Positive and Negative Syndrome Scale), but it sometimes included the absolute criteria such as post-treatment score of ≤ 35 in the Brief Psychiatric Rating Scale or Clinical Global Impression-severity score of ≤ 3 (mild or less severe). Social functioning has not been a primary outcome measure in past pivotal trials, and other important domains of the illness such as cognition and subjective perspectives have not been incorporated into definitions of treatment resistance or response. However, adopting various assessment scales can be time-consuming and complicated, with an additional possibility of disagreement among raters. CONCLUSION Defining outcomes in schizophrenia is a challenging task. It is imperative that the field agrees on how this population is better defined and what constitutes treatment response.

Revising polypharmacy to a single antipsychotic regimen for patients with chronic schizophrenia

Antipsychotic polypharmacy has been empirically used and a recent trend in favour of that mode of therapy has been suggested for the treatment of schizophrenia. The clinical efficacy, however, still remains to be clarified. In order to critically evaluate the usefulness of such kind of psychopharmacotherapy, antipsychotic combination regimen (polypharmacy) was switched to a treatment with the single main antipsychotic (monotherapy) in cross-tapered fashion, while approximately maintaining the total amount, for patients with chronic schizophrenia. Patients had been treated with an average of three antipsychotics and maintained with the same antipsychotic polypharmacy regimen for more than 6 months before the entry. They were followed up with an antipsychotic monopharmacy and evaluated at 24 wk after completion of switching. Forty-seven patients were recruited for this study. Of 44 patients for whom evaluation was possible, 24 (54.5%) remained stable, while 10 (22.7%) showed improvement and the same number of patients ended in a deleterious status. Twenty-two patients were converted to antipsychotic monotherapy, while another 12 needed minimal dosing of low-potency agents. Overall, social functioning, evaluated by the Global Assessment of Functioning and the Clinical Global Impression, remained unchanged. Eighteen of 34 successful patients showed adverse effects of the main antipsychotic medication, which necessitated a significant dose reduction. Nine out of 10 deteriorating patients had been treated with a combination of low- and high-potency antipsychotics. It is suggested that many instances of antipsychotic polypharmacy is avoidable. The result is compatible with the current treatment recommendations, which dictate the use of a single antipsychotic agent.

Effects of Risperidone and Olanzapine Dose Reduction on Cognitive Function in Stable Patients With Schizophrenia: An Open-Label, Randomized, Controlled, Pilot Study

Impact of dose reduction of atypical antipsychotics on cognitive function has not been investigated in stable patients with schizophrenia. In this open-label, 28-week, randomized controlled trial, stable patients with schizophrenia treated with risperidone or olanzapine were randomly assigned to the reduction group (dose reduced by 50% in 4 weeks and then maintained) or maintenance group (dose kept constant). Assessments at baseline and week 28 included the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), Positive and Negative Syndrome Scale (PANSS), and Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS). Sixty-one patients were enrolled; 2 of 31 (6.5%) and 5 of 30 (16.7%) patients prematurely withdrew from the study in the reduction and maintenance groups, respectively. While no significant differences in change in the PANSS total score were observed between the 2 groups, the reduction group showed significantly greater improvements in the RBANS and DIEPSS total scores compared with the maintenance group (mean ± SD, +7.0±7.1 vs -0.1±8.0, P < .001; -0.9±1.7 vs +0.1±1.2, P = .010, respectively). This 6-month pilot study suggests that risperidone or olanzapine dose reduction of 50% can improve cognitive function for stable patients with schizophrenia. Due to the open-label design, small sample size, and short study duration, however, there is a need to confirm the finding through double-blind, larger scale trials with longer follow-up periods. Moreover, potential risks of relapse following antipsychotic dose reduction should be thoroughly investigated in longer term studies.

Accelerating response to antidepressant treatment in depression: A review and clinical suggestions

OBJECTIVE The primary objective of this article is to review the literature regarding the speed of response to antidepressant drugs and potential strategies to accelerate the antidepressant response in new antidepressant-free patients with depression. Based on these data, we try to propose both an effective and safe antidepressant treatment strategy to alleviate depressive symptoms at the earliest opportunity. DATA SOURCES Data were identified by searches of Medline (1966 to September 2009) and references from relevant articles and books. Search terms included depression, antidepressant, predictor, response, onset, acceleration, and augmentation. As our focus was on the acute phase treatment of depression, articles relevant to treatment-resistant depression were excluded. Only articles written in English or Japanese were consulted. DATA SELECTION Studies, reviews, and books pertaining to the treatment of depression with a special regard to accelerating therapeutic effects were selected. DATA SYNTHESIS Most of the available treatment guidelines for major depressive disorders recommend the continuous use of antidepressants for 4 to 8 weeks based on the idea of a delayed onset of response to these drugs. Contrary to this conventional belief, the recent data indicate that antidepressants start to exert their effects within 2 weeks and early non-response could predict a subsequent unfavorable outcome. CONCLUSIONS These findings suggest the need of revisiting the timing of an antidepressant switch for early non-responders, whereby switching could be commenced in as early as 2 weeks.

Antipsychotic treatment for schizophrenia in the maintenance phase: A systematic review of the guidelines and algorithms

OBJECTIVE Antipsychotic treatment strategy for the maintenance phase of schizophrenia has been inconsistent in the literature. The purpose of this systematic review is to overview recommendations in various guidelines and algorithms. METHODS The guidelines and algorithms for schizophrenia that were published or updated in English after 2000 were searched, using Medline, PubMed, EMBASE, and PsycINFO with the following key words: guideline, algorithm, schizophrenia, and psychosis (last search: July 2011). The reference lists of the relevant reports were also examined. RESULTS Fourteen guidelines and algorithms were identified; only five of them clearly defined terms about the maintenance phase and treatment. Ten of 11 guidelines and algorithms did not recommend discontinuation of antipsychotics within five years; six of them partially recommended antipsychotic discontinuation for patients with first-episode schizophrenia exclusive. All nine guidelines and algorithms that referred to intermittent or targeted antipsychotic strategy endorsed against this strategy. Although being a hot topic of controversy, dose reduction of antipsychotics or lower dose therapy in the maintenance phase compared to the acute dosage is not recommended on the whole concerning atypical antipsychotics, whereas dose reduction appears sometimes considered acceptable for typical antipsychotics. CONCLUSION What constitutes maintenance phase and its treatment in schizophrenia has not yet been established in the literature. While discontinuation and intermittent or targeted strategies are not generally recommended, there is controversy regarding dose reduction or lower dose therapy, especially with regards to atypical antipsychotics. Further evidence is needed in order to derive treatment recommendations on antipsychotics in this critical treatment phase of schizophrenia.

Effectiveness of antipsychotic polypharmacy for patients with treatment refractory schizophrenia: an open-label trial of olanzapine plus risperidone for those who failed to respond to a sequential treatment with olanzapine, quetiapine and risperidone.

To evaluate the effectiveness of antipsychotic polypharmacy in a methodologically sound manner.

Low Dose vs Standard Dose of Antipsychotics for Relapse Prevention in Schizophrenia: Meta-analysis

BACKGROUND It remains unknown as to whether the antipsychotic dose needed for the acute-phase treatment of schizophrenia is also necessary for relapse prevention. AIM To compare the efficacy between standard dose [(World Health Organization daily defined dose (DDD)] vs low dose (≥50% to <1 DDD) or very low dose (<50% DDD) for relapse prevention in schizophrenia. DATA SOURCE Double-blind, randomized, controlled trials with a follow-up duration of ≥24 weeks, including ≥2 dosage groups of the same antipsychotic drug for relapse prevention in schizophrenia, were searched using MEDLINE, the Cochrane Central Register of Controlled Trials, and EMBASE (last search: August 2009). DATA EXTRACTION Data on overall treatment failure, hospitalization, relapse, and dropouts due to side effects were extracted and combined in a meta-analysis. DATA SYNTHESIS Thirteen studies with 1395 subjects were included in this meta-analysis. Compared with the standard-dose treatment, the low-dose therapy did not show any statistically significant difference in overall treatment failure or hospitalization, while the standard dose showed a trend-level (P = .05) superiority in risk of relapse. The very low-dose group was inferior to the standard-dose group in all efficacy parameters. No significant difference was found in the rate of dropouts due to side effects between either standard dose vs low dose or very low dose. CONCLUSIONS Although antipsychotic treatment with ≥50% to <1 DDD may be as effective as standard-dose therapy, there are insufficient clinical trial data to draw firm conclusions on standard- vs low-dose maintenance antipsychotic therapy for schizophrenia.