To continue or not to continue? Antipsychotic medication maintenance versus dose-reduction/discontinuation in first episode psychosis: HAMLETT, a pragmatic multicenter single-blind randomized controlled trial

BACKGROUND: Antipsychotic medication is effective for symptomatic treatment in schizophrenia-spectrum disorders. After symptom remission, continuation of antipsychotic treatment is associated with lower relapse rates and lower symptom severity compared to dose reduction/discontinuation. Therefore, most guidelines recommend continuation of treatment with antipsychotic medication for at least 1 year. Recently, however, these guidelines have been questioned as one study has shown that more patients achieved long-term functional remission in an early discontinuation condition-a finding that was not replicated in another recently published long-term study. METHODS/DESIGN: The HAMLETT (Handling Antipsychotic Medication Long-term Evaluation of Targeted Treatment) study is a multicenter pragmatic single-blind randomized controlled trial in two parallel conditions (1:1) investigating the effects of continuation versus dose-reduction/discontinuation of antipsychotic medication after remission of a first episode of psychosis (FEP) on personal and social functioning, psychotic symptom severity, and health-related quality of life. In total 512 participants will be included, aged between 16 and 60 years, in symptomatic remission from a FEP for 3-6 months, and for whom psychosis was not associated with severe or life-threatening self-harm or violence. Recruitment will take place at 24 Dutch sites. Patients are randomized (1:1) to: continuation of antipsychotic medication until at least 1 year after remission (original dose allowing a maximum reduction of 25%, or another antipsychotic drug in similar dose range); or gradual dose reduction till eventual discontinuation of antipsychotics according to a tapering schedule. If signs of relapse occur in this arm, medication dose can be increased again. Measurements are conducted at baseline, at 3, and 6 months post-baseline, and yearly during a follow-up period of 4 years. DISCUSSION: The HAMLETT study will offer evidence to guide patients and clinicians regarding questions concerning optimal treatment duration and when to taper off medication after remission of a FEP. Moreover, it may provide patient characteristics associated with safe dose reduction with a minimal risk of relapse. TRIAL STATUS: Protocol version 1.3, October 2018. The study is active and currently recruiting patients (since September 2017), with the first 200 participants by the end of 2019. We anticipate completing recruitment in 2022 and final assessments (including follow-up 3.5 years after phase one) in 2026. TRIAL REGISTRATION: European Clinical Trials Database, EudraCT number 2017-002406-12. Registered 7 J

Treatment for Negative Symptoms in Schizophrenia: A Comprehensive Review

Negative symptoms (such as amotivation and diminished expression) associated with schizophrenia are a major health concern. Adequate treatment would mean important progress with respect to quality of life and participation in society. Distinguishing primary from secondary negative symptoms may inform treatment options. Primary negative symptoms are part of schizophrenia. Well-known sources of secondary negative symptoms are psychotic symptoms, disorganisation, anxiety, depression, chronic abuse of illicit drugs and alcohol, an overly high dosage of antipsychotic medication, social deprivation, lack of stimulation and hospitalisation. We present an overview of reviews and meta-analyses of double-blind, controlled randomised trials, in which the efficacy of pharmacological and non-pharmacological interventions for negative symptoms was assessed. Unfortunately, there have been very few clinical trials focusing on primary negative symptoms and selecting chronically ill patients with predominant persistent negative symptoms. An important limitation in many of these studies is the failure to adequately control for potential sources of secondary negative symptoms. At present, there is no convincing evidence regarding efficacy for any treatment of predominant persistent primary negative symptoms. However, for several interventions there is short-term evidence of efficacy for negative symptoms. This evidence has mainly been obtained from studies in chronically ill patients with residual symptoms and studies with a heterogeneous study population of patients in both the acute and chronic phase. Unfortunately, reliable information regarding the distinction between primary and secondary negative symptoms is lacking. Currently, early treatment of psychosis, add-on therapy with aripiprazole, antidepressants or topiramate, music therapy and exercise have been found to be useful for unspecified negative symptoms. These interventions can be considered carefully in a shared decision-making process with patients, and are promising enough to be examined in large, well-designed long-term studies focusing on primary negative symptoms. Future research should be aimed at potential therapeutic interventions for primary negative symptoms since there is a lack of research in this fiel

To continue or not to continue? Antipsychotic medication maintenance versus dose-reduction/discontinuation in first episode psychosis:HAMLETT, a pragmatic multicenter single-blind randomized controlled trial

Background: Antipsychotic medication is effective for symptomatic treatment in schizophrenia-spectrum disorders. After symptom remission, continuation of antipsychotic treatment is associated with lower relapse rates and lower symptom severity compared to dose reduction/discontinuation. Therefore, most guidelines recommend continuation of treatment with antipsychotic medication for at least 1 year. Recently, however, these guidelines have been questioned as one study has shown that more patients achieved long-term functional remission in an early discontinuation condition - a finding that was not replicated in another recently published long-term study. Methods/design: The HAMLETT (Handling Antipsychotic Medication Long-term Evaluation of Targeted Treatment) study is a multicenter pragmatic single-blind randomized controlled trial in two parallel conditions (1:1) investigating the effects of continuation versus dose-reduction/discontinuation of antipsychotic medication after remission of a first episode of psychosis (FEP) on personal and social functioning, psychotic symptom severity, and health-related quality of life. In total 512 participants will be included, aged between 16 and 60 years, in symptomatic remission from a FEP for 3-6 months, and for whom psychosis was not associated with severe or life-threatening self-harm or violence. Recruitment will take place at 24 Dutch sites. Patients are randomized (1:1) to: continuation of antipsychotic medication until at least 1 year after remission (original dose allowing a maximum reduction of 25%, or another antipsychotic drug in similar dose range); or gradual dose reduction till eventual discontinuation of antipsychotics according to a tapering schedule. If signs of relapse occur in this arm, medication dose can be increased again. Measurements are conducted at baseline, at 3, and 6 months post-baseline, and yearly during a follow-up period of 4 years. Discussion: The HAMLETT study will offer evidence to guide patients and clinicians regarding questions concerning optimal treatment duration and when to taper off medication after remission of a FEP. Moreover, it may provide patient characteristics associated with safe dose reduction with a minimal risk of relapse. Trial status: Protocol version 1.3, October 2018. The study is active and currently recruiting patients (since September 2017), with the first 200 participants by the end of 2019. We anticipate completing recruitment in 2022 and final assessments (including follow-up 3.5 years after phase one) in 2026. Trial registration: European Clinical Trials Database, EudraCT number 2017-002406-12. Registered 7 June 2017

Associations between polygenic risk score loading, psychosis liability, and clozapine use among individuals with schizophrenia

Importance: Predictors consistently associated with psychosis liability and course of illness in schizophrenia (SCZ) spectrum disorders (SSD), including the need for clozapine treatment, are lacking. Longitudinally ascertained medication use may empower studies examining associations between polygenic risk scores (PRSs) and pharmacotherapy choices. Objective: To examine associations between PRS-SCZ loading and groups with different liabilities to SSD (individuals with SSD taking clozapine, individuals with SSD taking other antipsychotics, their parents and siblings, and unrelated healthy controls) and between PRS-SCZ and the likelihood of receiving a prescription of clozapine relative to other antipsychotics. Design, Setting, and Participants: This genetic association study was a multicenter, observational cohort study with 6 years of follow-up. Included were individuals diagnosed with SSD who were taking clozapine or other antipsychotics, their parents and siblings, and unrelated healthy controls. Data were collected from 2004 until 2021 and analyzed between October 2021 and September 2022. Exposures: Polygenic risk scores for SCZ. Main Outcomes and Measures: Multinomial logistic regression was used to examine possible differences between groups by computing risk ratios (RRs), ie, ratios of the probability of pertaining to a particular group divided by the probability of healthy control status. We also computed PRS-informed odd ratios (ORs) for clozapine use relative to other antipsychotics. Results: Polygenic risk scores for SCZ were generated for 2344 participants (mean [SD] age, 36.95 years [14.38]; 994 female individuals [42.4%]) who remained after quality control screening (557 individuals with SSD taking clozapine, 350 individuals with SSD taking other antipsychotics during the 6-year follow-up, 542 parents and 574 siblings of individuals with SSD, and 321 unrelated healthy controls). All RRs were significantly different from 1; RRs were highest for individuals with SSD taking clozapine (RR, 3.24; 95% CI, 2.76-3.81; P = 2.47 × 10−46), followed by individuals with SSD taking other antipsychotics (RR, 2.30; 95% CI, 1.95-2.72; P = 3.77 × 10−22), parents (RR, 1.44; 95% CI, 1.25-1.68; P = 1.76 × 10−6), and siblings (RR, 1.40; 95% CI, 1.21-1.63; P = 8.22 × 10−6). Polygenic risk scores for SCZ were positively associated with clozapine vs other antipsychotic use (OR, 1.41; 95% CI, 1.22-1.63; P = 2.98 × 10−6), suggesting a higher likelihood of clozapine prescriptions among individuals with higher PRS-SCZ. Conclusions and Relevance: In this study, PRS-SCZ loading differed between groups of individuals with SSD, their relatives, and unrelated healthy controls, with patients taking clozapine at the far end of PRS-SCZ loading. Additionally, PRS-SCZ was associated with a higher likelihood of clozapine prescribing. Our findings may inform early intervention and prognostic studies of the value of using PRS-SCZ to personalize antipsychotic treatment

Additional file 1 of To continue or not to continue? Antipsychotic medication maintenance versus dose-reduction/discontinuation in first episode psychosis: HAMLETT, a pragmatic multicenter single-blind randomized controlled trial

Additional file 1: Table S1. Tapering off schedules