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.

Psychopathology, cognition and outcome in Dutch and immigrant first-episode psychosis patients.

AIM: The primary aim was to examine differences in baseline symptom expression, neurocognition, social cognition and psychosocial functioning between Dutch, first-generation immigrants and second-generation immigrants with a first-episode psychosis (FEP). The secondary aim was to examine functional and symptomatic change and between-group differences at 12-months follow-up. Associations between migration, baseline characteristics and outcome were explored. METHODS: Forty-six Dutch, 56 second-generation- and 60 first-generation immigrant patients completed baseline measures for 6 symptom dimensions (positive symptoms, negative symptoms, neurocognitive functioning, social cognitive functioning, excitement and emotional distress) and 5 domains of psychosocial functioning (general functioning, work and study, relationships, self-care and disturbing behaviour). Functioning and psychotic symptoms were assessed at baseline and 12-months follow-up. ANCOVA and t tests were used to assess between-group differences. General linear models were used to explore within-group differences. Backward-regression was used to explore predictors of outcome. RESULTS: Levels of positive symptoms, excitement and emotional distress did not differ between groups at baseline or follow-up. Dutch patients had lower levels of negative symptoms than both immigrant groups at follow-up. On neurocognition and social cognition, Dutch performed better than second-generation immigrants, who in turn performed better than first-generation immigrants. Psychosocial functioning across all domains at baseline and at 12-months follow-up was similar across groups. Baseline levels of general psychosocial functioning and income were the strongest predictors of outcome at follow-up. CONCLUSIONS: Psychosocial functioning and symptom profiles are comparable between Dutch, first-generation immigrant and second-generation immigrant FEP patients, excluding neurocognitive and social cognitive deficits. A range of baseline characteristics predicted outcome.

Psychosocial functioning in first-episode psychosis and associations with neurocognition, social cognition, psychotic and affective symptoms.

AIM: Most studies on the determinants of psychosocial functioning in first-episode psychosis used few predictors. This study examines the effects of multiple cognitive domains and multiple symptoms on psychosocial functioning. METHODS: A total of 162 patients with a first-episode psychosis were assessed within 3 months after referral to an early psychosis treatment department. Four psychopathological subdomains (positive and negative symptoms, depression and anxiety) and five subdomains of psychosocial functioning (work/study, relationships, self-care, disturbing behaviour and general psychosocial functioning) were measured. Neurocognitive and social cognitive factors were identified through principal component analyses (PCA) of a 15-measure cognitive battery. Stepwise backward regression models were computed to identify the determinants of psychosocial functioning. RESULTS: The three neurocognitive and four social cognitive factors identified through PCA were largely independent of psychopathology. The strongest associations were between cognitive factors and anxiety. Higher levels of negative symptoms, poor general neurocognition and poor general social cognition showed strongest associations with impaired psychosocial functioning, followed by low verbal processing speed and low emotion processing speed. Together, these factors accounted for 39.4% of the variance in psychosocial functioning. CONCLUSIONS: The results suggest that negative symptoms, impaired neurocognition and poor social cognition are related to psychosocial problems in patients with first-episode psychosis. None of the affective or positive symptoms had a marked impact on psychosocial functioning.

Psychotic symptoms, cognition and affect as predictors of psychosocial problems and functional change in first-episode psychosis.

OBJECTIVE: To enable further understanding of how cognitive deficits and psychopathology impact psychosocial functioning in first-episode psychosis patients, we investigated how psychopathology and cognitive deficits are associated with psychosocial problems at baseline, and how these predict psychosocial functioning at 12 months follow-up. Also, we tested whether the effect of baseline psychopathology on psychosocial functioning decreases between baseline and 12 months and the effect of baseline cognition increases. METHODS: Eight neurocognitive and four social cognitive subdomains and psychopathology (positive and negative symptoms, depression and anxiety) were assessed at baseline in 153 non-affective first-episode psychosis (FEP) patients. Psychosocial functioning (work/study, relationships, self-care, disturbing behavior and general psychosocial functioning) was assessed at baseline and 12 months. Spearman correlations were examined and backward regression models were computed to test our hypotheses. RESULTS: At baseline, psychosocial functioning was associated strongest with positive and negative symptoms of all assessed clinical domains, followed by neurocognition and social cognition. In contrast, psychosocial functioning at 12 months was not predicted by psychotic symptoms, but rather by neurocognition, social cognition and depression. Change in social functioning in the first 12 months after baseline was predicted by positive and negative symptoms, but to a similar degree by neurocognition and social cognition. CONCLUSIONS: Whereas psychotic symptoms show marked impact on psychosocial functioning at illness onset, cognitive deficits appear to be more accurate longitudinal predictors of psychosocial problems and functional recovery in the early course of psychosis.

Cognitive deficits and ethnicity: a cohort study of early psychosis patients in The Netherlands.

PURPOSE: Incidence rates of psychotic disorders are higher in immigrant groups compared to native populations. This increased risk may partly be explained by misdiagnosis. Neurocognitive deficits are a core feature of psychotic disorders, but little is known about the relationship between migration and cognition in psychotic disorders. We examined whether immigrant patients have cognitive deficits similar to non-immigrant patients, in order to investigate the plausibility of misdiagnosis as explanation for increased incidence rates. METHODS: Patients who made first contact for non-affective psychotic disorder were assessed in the cognitive domains sustained attention, immediate recall and delayed recall. Immigrant patients were compared to Dutch patients on cognitive performance. RESULTS: 407 Patients diagnosed with a non-affective psychotic disorder completed cognitive assessment (157 Dutch, 250 immigrants). Both Dutch and immigrant patients showed large cognitive deficits. Between-subgroup comparisons revealed large cognitive deficits for immigrants compared to Dutch, especially for immigrants from Morocco, Turkey and other non-Western countries. CONCLUSIONS: These results indicate that immigrant status is associated with poorer cognitive functioning in early psychosis. The findings argue against diagnostic bias as an explanation for the increased incidence of psychotic disorders in immigrants.