A Method for Tapering Antipsychotic Treatment That May Minimize the Risk of Relapse

The process of stopping antipsychotics may be causally related to relapse, potentially linked to neuroadaptations that persist after cessation, including dopaminergic hypersensitivity. Therefore, the risk of relapse on cessation of antipsychotics may be minimized by more gradual tapering. There is converging evidence that suggests that adaptations to antipsychotic exposure can persist for months or years after stopping the medication—from animal studies, observation of tardive dyskinesia in patients, and the clustering of relapses in this time period after the cessation of antipsychotics. Furthermore, PET imaging demonstrates a hyperbolic relationship between doses of antipsychotic and D₂ receptor blockade. We, therefore, suggest that when antipsychotics are reduced, it should be done gradually (over months or years) and in a hyperbolic manner (to reduce D₂ blockade “evenly”): ie, reducing by one quarter (or one half) of the most recent dose of antipsychotic, equivalent approximately to a reduction of 5 (or 10) percentage points of its D₂ blockade, sequentially (so that reductions become smaller and smaller in size as total dose decreases), at intervals of 3–6 months, titrated to individual tolerance. Some patients may prefer to taper at 10% or less of their most recent dose each month. This process might allow underlying adaptations time to resolve, possibly reducing the risk of relapse on discontinuation. Final doses before complete cessation may need to be as small as 1/40th a therapeutic dose to prevent a large decrease in D₂ blockade when stopped. This proposal should be tested in randomized controlled trials.     

Antipsychotic Dose in Acute Schizophrenia: A Meta-analysis

Little is known regarding optimal antipsychotic doses in the acute phase of schizophrenia. The aim of the present study was to employ the concept of minimum effective dose (MED) in examining efficacy and tolerability within this population. MED was identified for each antipsychotic through a previous systematic review. We then identified double-blind placebo-controlled randomized trials that involved fixed-dose antipsychotic monotherapy in acute schizophrenia and compared the identified MED vs higher doses of the same oral antipsychotic. Studies were selected from a recent meta-analysis examining dose–response relationship of second-generation antipsychotics and haloperidol. We extracted the data on study discontinuation, psychopathology, extrapyramidal symptoms, and treatment-emergent adverse events. For each antipsychotic, we conducted a meta-analysis to compare outcomes between MED and 2-fold MED, and MED and 3-fold MED. A total of 26 studies involving 5618 patients were included in the meta-analysis. In terms of study discontinuation, significant differences were found in study discontinuation due to lack of efficacy between MED and higher doses, in favor of 2-fold and 3-fold MEDs. Regarding psychopathology, both 2-fold and 3-fold MEDs were superior to MED for total and positive symptom scores. As for side effects, 2-fold MED proved inferior to MED for parkinsonism scores and diarrhea, whereas 3-fold MED was inferior for akathisia, somnolence, and vomiting. Findings suggest that clinicians can dose an antipsychotic at 2-fold or 3-fold MED for patients with acute schizophrenia but should closely monitor side effects.     

Examining Side Effect Variability of Antipsychotic Treatment in Schizophrenia Spectrum Disorders: A Meta-analysis of Variance

Side effects of antipsychotic drugs play a key role in nonadherence of treatment in schizophrenia spectrum disorders (SSD). While clinical observations suggest that side effect variability between patients may be considerable, statistical evidence is required to confirm this. Here, we hypothesized to find larger side effect variability under treatment compared with control. We included double-blind, placebo-controlled, randomized controlled trials (RCTs) of adults with a diagnosis of SSD treated with 1 out of 14 antipsychotics. Standard deviations of the pre-post treatment differences of weight gain, prolactin levels, and corrected QT (QTc) times were extracted. The outcome measure was the variability ratio of treatment to control for individual antipsychotic drugs and the overall variability ratio of treatment to control across RCTs. Individual variability ratios were weighted by the inverse-variance method and entered into a random-effects model. We included N = 16 578 patients for weight gain, N = 16 633 patients for prolactin levels, and N = 10 384 patients for QTc time. Variability ratios (VR) were significantly increased for weight gain (VR = 1.08; 95% CI: 1.02–1.14; P = .004) and prolactin levels (VR = 1.38; 95% CI: 1.17–1.62; P < .001) but did not reach significance for QTc time (VR = 1.05; 95% CI: 0.98–1.12; P = 0.135). We found marked differences between individual antipsychotics and increased variability in side effects in patients under treatment with antipsychotics suggesting that subgroups of patients or individual patients may benefit from treatment allocation through stratified or personalized medicine.     

Comparative Effectiveness of Risperidone Long-Acting Injectable vs First-Generation Antipsychotic Long-Acting Injectables in Schizophrenia: Results From a Nationwide,Retrospective Inception Cohort Study

Objective: To compare in a generalizable sample/setting objective outcomes in patients receiving first-generation antipsychotic long-acting injectables (FGA-LAIs) or risperidone-LAI (RIS-LAI). Methods: Nationwide, retrospective inception cohort study of adults with International Classification of Diseases-10 schizophrenia using Danish registers from 1995 to 2009 comparing outcomes between clinician’s/patient’s choice treatment with FGA-LAIs or RIS-LAI. Primary outcome was time to psychiatric hospitalization using Cox-regression adjusting for relevant covariates. Secondary outcomes included time to all-cause discontinuation and psychiatric hospitalization in patients without LAI possession gap >28 days, and number of bed-days after psychiatric hospitalization. Results: Among 4532 patients followed for 2700 patient-years, 2078 received RIS-LAI and 2454 received FGA-LAIs (zuclopenthixol decanoate = 52.2%, perphenazine decanoate = 37.2%, haloperidol decanoate = 5.0%, flupenthixol decanoate = 4.4%, fluphenazine decanoate = 1.3%). RIS-LAI was similar to FGA-LAIs regarding time to hospitalization (RIS-LAI = 246.2±323.7 days vs FGA-LAIs = 276.6±383.3 days; HR = 0.95, 95% confidence interval (CI) = 0.87–1.03, P = 0.199) and time to all-cause discontinuation (RIS-LAI = 245.8±324.0 days vs FGA-LAIs = 287.0±390.9 days; HR = 0.93, 95% CI = 0.86–1.02, P = 0.116). Similarly, in patients without LAI discontinuation, RIS-LAI and FGA-LAIs did not differ regarding time to hospitalization (RIS-LAI = 175.0±268.1 days vs FGA-LAIs = 210.7±325.3 days; HR = 0.95, 95% CI = 0.86–1.04, P = 0.254). Finally, duration of hospitalization was also similar (incidence rate ratio = 0.97, 95% CI = 0.78–1.19, P = 0.744). Results were unchanged when analyzing only patients treated after introduction of RIS-LAI. Conclusions: In this nationwide cohort study, RIS-LAI was not superior to FGA-LAIs regarding time to psychiatric hospitalization, all-cause discontinuation, and duration of hospitalization. Given the cost of hospitalization and second-generation antipsychotic (SGA)-LAIs, these findings require consideration when making treatment choices, but also need to be balanced with the individual relevance of adverse effects/patient centered outcomes. In future, head-to-head trials and additional nationwide database studies including other SGA-LAIs is needed.Key words: schizophrenia, long-acting injectable, risperidone, first-generation antipsychotics, hospitalization, all-cause discontinuation, cohort study     

Prior Antipsychotic Drug Treatment Prevents Response to Novel Antipsychotic Agent in the Methylazoxymethanol Acetate Model of Schizophrenia

Trials of novel compounds for the treatment of schizophrenia are typically tested in patients following brief withdrawal of ongoing medication despite known long-term changes in the dopamine (DA) system following chronic antipsychotic drug therapy. The present study explored the impact of withdrawal from repeated haloperidol (HAL) treatment, as well as the response to a novel α5 gamma-aminobutyric acid (GABA_A) receptor positive allosteric modulator (α5PAM), on the activity of the DA system in the methylazoxymethanol acetate (MAM) neurodevelopmental model of schizophrenia. Electrophysiological recordings were conducted from DA neurons in the ventral tegmental area of MAM and saline (SAL) rats following 7-day withdrawal from repeated HAL (21 d, 0.6mg/kg, orally). In separate animals, amphetamine-induced locomotion was measured to assess changes in DA behavioral sensitivity. SAL rats withdrawn from HAL demonstrated reduced spontaneous DA neuron activity along with an enhanced locomotor response to amphetamine, indicative of the development of DA supersensitivity. Both α5PAM treatment and ventral hippocampal (vHPC) inactivation reversed the DA neuron depolarization block following HAL withdrawal in SAL rats. In contrast, MAM rats withdrawn from HAL exhibited reduced spontaneous DA activity and enhanced locomotor response to amphetamine compared with untreated SAL rats; however, this condition was unresponsive to α5PAM treatment or vHPC inactivation. Withdrawal from prior HAL treatment interferes with the therapeutic actions of this novel treatment in the MAM model of schizophrenia. Consequently, testing novel compounds on chronically treated schizophrenia patients may be ineffective.     

A Nationwide Cohort Study of Nonrandom Mating in Schizophrenia and Bipolar Disorder

Nonrandom mating in parents with schizophrenia or bipolar disorder increases the population-level genetic variance among the offspring generation and creates familial (risk) environments likely to be shaped by specific conditions. The objective of this study was to investigate the occurrence of mental disorder and levels of cognitive and social functioning in individuals who have children by partners with schizophrenia or bipolar disorder compared to controls. The Danish High Risk and Resilience Study VIA 7 is a population-based cohort study conducted in Denmark between 2013 and 2016. This study focus on parents diagnosed with schizophrenia (n = 150) or bipolar disorder (n = 100) and control parents (n = 182), as well as their partners without schizophrenia or bipolar disorder (n = 440). We used linear mixed-effect models, and main outcomes were mental disorders, intelligence, processing speed, verbal working memory, and social functioning. We found that parents having children by a partner with schizophrenia or bipolar disorder more often fulfilled the criteria for a mental disorder and had poorer social functioning compared to parents having children by a partner without schizophrenia or bipolar disorder. Furthermore, parents having children by a partner with schizophrenia performed poorer on processing speed compared to parents in the control group. The presence of nonrandom mating found in this study has implications for our understanding of familial transmission of these disorders and our findings should be considered in future investigations of potential risk factors for children with a parent with schizophrenia or bipolar disorder.     

Provider Continuity and Outcomes of Care for Persons with Schizophrenia

The study examines the relationship of provider continuity to outcomes of care (quality of life, payments for services) for Medicaid beneficiaries with schizophrenia. Data sources included Maryland Medicaid claims and enrollment data and in-person interviews. Measures of provider continuity over the year preceding the interview, calculated from claims for mental health ambulatory visits, were usual provider continuity (UPC—fraction of visits to the most frequently seen provider), sequential continuity (SECON—fraction of sequential visit pairs to the same provider), and continuity of care (COC—distribution of visits across different providers). Higher provider continuity was found to be related to lower costs and to lower likelihood of mental illness hospitalization. Provider continuity was not significantly related to general life satisfaction or to satisfaction with health. Persons with zero or one visit in a year (and for whom provider continuity could not be measured) had more severe depressive symptoms and were more likely to abuse substances but reported comparable satisfaction with health and overall quality of life while incurring lower Medicaid costs.     

Risk of Schizophrenia Increases After All Child and Adolescent Psychiatric Disorders: A Nationwide Study

Objective: Earlier smaller studies have shown associations between child and adolescent psychiatric disorders and schizophrenia. Particularly, attention-deficit/hyperactivity-disorder and autism have been linked with schizophrenia. However, large-scale prospective studies have been lacking. We, therefore, conducted the first large-scale study on the association between a broad spectrum of child and adolescent psychiatric disorders and the risk of being diagnosed with schizophrenia. Methods: Danish nationwide registers were linked to establish a cohort consisting of all persons born during 1990–2000 and the cohort was followed until December 31, 2012. Data were analyzed using survival analyses and adjusted for calendar year, age, and sex. Results: A total of 25138 individuals with child and adolescent psychiatric disorders were identified, out of which 1232 individuals were subsequently diagnosed with schizophrenia spectrum disorders. The risk of schizophrenia spectrum disorders was highly elevated, particularly within the first year after onset of the child and adolescent psychiatric disorder, and remained significantly elevated >5 years with an incidence rate ratio of 4.93 (95% confidence interval: 4.37–5.54).We utilized the cumulated incidences and found that among persons diagnosed with a child and adolescent psychiatric disorder between the ages 0–13 years and 14–17 years, 1.68% and 8.74 %, respectively, will be diagnosed with a schizophrenia spectrum disorder <8 years after onset of the child and adolescent psychiatric disorder. Conclusions: The risk of being diagnosed with schizophrenia spectrum disorders after a child and adolescent psychiatric disorder was significantly increased particularly in the short term but also in the long-term period.Key words: epidemiology, psychiatry, cohort study     

Genetic Variants Within Molecular Targets of Antipsychotic Treatment: Effects on Treatment Response,Schizophrenia Risk,and Psychopathological Features

Schizophrenia (SCZ) is a common and severe mental disorder. Genetic factors likely play a role in its pathophysiology as well as in treatment response. In the present study, we investigated the effects of several single nucleotide polymorphisms (SNPs) within 9 genes involved with antipsychotic (AP) mechanisms of action. Two independent samples were recruited. The Korean sample included 176 subjects diagnosed with SCZ and 326 healthy controls, while the Italian sample included 83 subjects and 194 controls. AP response as measured by the positive and negative syndrome scale (PANSS) was the primary outcome, while the secondary outcome was the SCZ risk. Exploratory analyses were performed on (1) symptom clusters response (as measured by PANSS subscales); (2) age of onset; (3) family history; and (4) suicide history. Associations evidenced in the primary analyses did not survive to the FDR correction. Concerning SCZ risk, we partially confirmed the associations among COMT and MAPK1 genetic variants and SCZ. Finally, our exploratory analysis suggested that CHRNA7 and HTR2A genes may modulate both positive and negative symptoms responses, while PLA2G4A and SIGMAR1 may modulate respectively positive and negative symptoms responses. Moreover, GSK3B, HTR2A, PLA2G4A, and S100B variants may determine an anticipation of SCZ age of onset. Our results did not support a primary role for the genes investigated in AP response as a whole. However, our exploratory findings suggested that these genes may be involved in symptom clusters response.     

七种抗精神病药对精神分裂症患者维持治疗一年的有效性及安全性研究

目的 比较氯丙嗪、舒必利、氯氮平、利培酮、奥氮平、奎硫平、阿立哌唑7种抗精神病药对精神分裂症患者1年维持治疗的有效性及安全性.方法 对服用7种药物之一、病程≤5年稳定期的1227例精神分裂症患者给予1年的维持治疗,以治疗中断率、中断前治疗时间并结合临床疗效评价抗精神病药的总体有效性,采用不良事件和实验室检查评价安全性,每间隔3个月评估1次.结果 随访1年,1227例患者中共有541例(44.1%)患者中断治疗.7个药物组间治疗中断率(P=0.283)及中断前治疗时间(P=0.400)的差异均无统计学意义(P>0.05);495例(40.3%)患者完成1年随访并达到临床痊愈标准,临床痊愈率在7个药物组间的差异无统计学意义(χ2=3.211,P>0.05).7个药物组总的不良反应发生率(88.3%～95.6%)的差异无统计学意义(χ2=8.345,P>0.05),但镇静作用(χ2=100.836)、锥体外系不良反应(χ2=68.074)、月经紊乱(χ2=71.295)及体质量增加(χ2=13.527)等不良反应在不同药物间的差别有统计学意义(P<0.01和0.05).结论 7种抗精神病药治疗精神分裂症患者1年的临床疗效相当,但药物的不良反应各异.     

Family Interventions for Schizophrenia: A Review of Long-term Benefits of International Studies

Abstract

Clinical, social, family and economic benefits are achieved by adding psychosocial family interventions, based on the vulnerability/stress model of mental disorders, to pharmacotherapy and case management for schizophrenic disorders. Twenty-two controlled studies with treatment extending for at least 6 months (including 14 randomized, controlled comparisons with good quality methodology) have documented the benefits of structured types of family approaches. A re-analysis of the effectiveness of these approaches, with outcome variables that included all major psychotic and affective episodes, deaths, hospital admissions, and serious non-compliance or withdrawal from drug or psychosocial interventions as indices of poor outcome, showed significantly better results for the addition of family-based stress management to medication and case management alone. Although fewer studies examined social and family benefits, the trends supported the family-based approaches. Further delays in implementing these methods in clinical practice can no longer be justified.