Longitudinal clinical and functional outcome in distinct cognitive subgroups of first-episode psychosis: a cluster analysis.

BACKGROUND: Cognitive deficits may be characteristic for only a subgroup of first-episode psychosis (FEP) and the link with clinical and functional outcomes is less profound than previously thought. This study aimed to identify cognitive subgroups in a large sample of FEP using a clustering approach with healthy controls as a reference group, subsequently linking cognitive subgroups to clinical and functional outcomes. METHODS: 204 FEP patients were included. Hierarchical cluster analysis was performed using baseline brief assessment of cognition in schizophrenia (BACS). Cognitive subgroups were compared to 40 controls and linked to longitudinal clinical and functional outcomes (PANSS, GAF, self-reported WHODAS 2.0) up to 12-month follow-up. RESULTS: Three distinct cognitive clusters emerged: relative to controls, we found one cluster with preserved cognition (n = 76), one moderately impaired cluster (n = 74) and one severely impaired cluster (n = 54). Patients with severely impaired cognition had more severe clinical symptoms at baseline, 6- and 12-month follow-up as compared to patients with preserved cognition. General functioning (GAF) in the severely impaired cluster was significantly lower than in those with preserved cognition at baseline and showed trend-level effects at 6- and 12-month follow-up. No significant differences in self-reported functional outcome (WHODAS 2.0) were present. CONCLUSIONS: Current results demonstrate the existence of three distinct cognitive subgroups, corresponding with clinical outcome at baseline, 6- and 12-month follow-up. Importantly, the cognitively preserved subgroup was larger than the severely impaired group. Early identification of discrete cognitive profiles can offer valuable information about the clinical outcome but may not be relevant in predicting self-reported functional outcomes.

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.

Repetitive transcranial magnetic stimulation for negative symptoms of schizophrenia: review and meta-analysis.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) has been proposed as a treatment for the negative symptoms of schizophrenia. During the past decade, several trials have reported on the efficacy of rTMS treatment; however, the results were inconsistent. OBJECTIVE: To assess the efficacy of prefrontal rTMS for treating negative symptoms of schizophrenia. DATA SOURCES: A literature search was performed in PubMed, ISI Web of Science, and EMBASE for the years 1985 through July 2008. The search terms used (language not specified) were "transcranial magnetic stimulation," "negative symptoms," and "schizophrenia." A cross-reference search of eligible articles was performed to identify studies not found in the computerized search. STUDY SELECTION: Studies selected were randomized controlled trials assessing the therapeutic efficacy of prefrontal rTMS for negative symptoms in schizophrenia. DATA EXTRACTION: Effect sizes (Cohen d) of each study were calculated. The overall standardized mean difference was calculated under a random effects model with 95% confidence intervals. DATA SYNTHESIS: Nine trials, involving 213 patients, were included in the meta-analysis. The overall mean weighted effect size for rTMS versus sham was in the small-to-medium range and statistically significant (d = 0.43; 95% CI, 0.05-0.80). When including only the studies using a frequency of stimulation of 10 Hz, the mean effect size increased to 0.63 (95% CI, 0.11-1.15). When including only the studies requiring participants to be on a stable drug regimen before and during the study, the mean weighted effect size decreased to 0.34 (95% CI, 0.01-0.67). Studies with a longer duration of treatment (> or =3 weeks) had a larger mean effect size when compared to studies with a shorter treatment duration: d = 0.58 (95% CI, 0.19-0.97) and d = 0.32 (95% CI, -0.3 to 0.95), respectively. CONCLUSIONS: The results of this meta-analysis warrant further study of rTMS as a potential treatment of negative symptoms of schizophrenia.

Guided discontinuation versus maintenance treatment in remitted first-episode psychosis: relapse rates and functional outcome.

OBJECTIVE: To compare the consequences of a guided discontinuation strategy and maintenance treatment in remitted first-episode psychosis in terms of relapse rates and functional outcome. METHOD: The study was conducted in 7 mental health care organizations and the Department of Psychiatry of the University Medical Center Groningen in The Netherlands, covering a catchment area of 3.1 million inhabitants. A sample of 131 remitted first-episode patients, aged 18 to 45 years, with a DSM-IV diagnosis of schizophrenia or related psychotic disorder was included (i.e., all patients with a first psychotic episode from October 2001 through December 2002 who were willing to participate). After 6 months of positive symptom remission, they were randomly and openly assigned to the discontinuation strategy or maintenance treatment. Maintenance treatment was carried out according to American Psychiatric Association guidelines, preferably using low-dose atypical antipsychotics. The discontinuation strategy was carried out by gradual symptom-guided tapering of dosage and discontinuation if feasible. Follow-up was 18 months. Main outcome measures were relapse rates and social and vocational functioning. RESULTS: Twice as many relapses occurred with the discontinuation strategy (43% vs. 21%, p = .011). Of patients who received the strategy, approximately 20% were successfully discontinued. Recurrent symptoms caused another approximately 30% to restart antipsychotic treatment, while in the remaining patients discontinuation was not feasible at all. There were no advantages of the discontinuation strategy regarding functional outcome. CONCLUSIONS: Only a limited number of patients can be successfully discontinued. High relapse rates do not allow a discontinuation strategy to be universal practice. However, if relapse risk can be carefully managed by close monitoring, in some remitted first-episode patients a guided discontinuation strategy may offer a feasible alternative to maintenance treatment. Further research is needed to find predictors of successful discontinuation.

Niacin skin flushing in schizophrenic and depressed patients and healthy controls.

This study compares the skin reactions to the niacin flushing test of 16 schizophrenic patients with those of 17 depressed patients and 16 healthy controls. Methyl nicotinate (niacin) in a concentration of 0.1 M was applied to the forearm for 5 min. Significant differences could be observed between the group of schizophrenic patients (less flushing) in comparison to the other groups. There were no statistical differences in niacin flushing between patients with depression and healthy controls. Gender, age and the use of antipsychotic agents did not appear to be confounders. The differences in flushing within the group of schizophrenic patients were striking, however. Most patients showed little or no flushing, but some patients reacted strongly. Although the three groups could be differentiated by the niacin flushing test, to develop a reliable clinical application of this test, further research is necessary.

Evaluation of the subjects' response to antipsychotics questionnaire.

The present study reports on the development of a new self-administered instrument to assess patients' responses to antipsychotic medication. The Subjects' Response to Antipsychotics (SRA) Questionnaire is a 74-item instrument with eight scales (Recovery, Weight Gain, Sexual Anhedonia, Sedation, Affective Flattening, Extrapyramidal Side-Effects, Diminished Sociability and Increased Sleep), and a total adverse responses score including additional items. Psychometric aspects were examined in a study of 320 inpatients and outpatients showing good internal consistency, reproducibility and external validity. Concordance with other instruments claiming to measure the subjective response is low, suggesting that the instruments measure different concepts. The SRA Questionnaire appears to be a reliable and efficient way of measuring patients' subjective responses to antipsychotic medication.

Predominant role of the 9-hydroxy metabolite of risperidone in elevating blood prolactin levels.

OBJECTIVE: The atypical antipsychotic risperidone significantly raises plasma prolactin levels in patients, but clozapine, olanzapine, and quetiapine do not. The differences in neuroendocrine response may be connected with the metabolism of the medications. The authors examined the contributory role of risperidone's active metabolite 9-hydroxy-risperidone by measuring plasma concentrations of risperidone, 9-hydroxy-risperidone, and prolactin. METHOD: Blood samples taken from 25 patients with psychotic disorders following 6 weeks of treatment with risperidone (mean dose=3 mg/day) were examined. Mean plasma concentrations of risperidone, 9-hydroxy-risperidone, and prolactin were 4.6, 19.4, and 49.3 ng/ml, respectively. RESULTS: The oral dose of risperidone correlated significantly with plasma concentrations of risperidone, 9-hydroxy-risperidone, active moiety, and prolactin. The plasma concentration of 9-hydroxy-risperidone, but not of risperidone, correlated significantly with increases in plasma prolactin. CONCLUSIONS: These data suggest that the 9-hydroxy metabolite plays a predominant role in risperidone's effect on prolactin release.

A randomized open-label study of the impact of quetiapine versus risperidone on sexual functioning.

OBJECTIVE: To compare sexual functioning in patients treated with quetiapine or risperidone. METHODS: This open-label study included patients with schizophrenia or a related psychotic illness who were randomized to quetiapine (200-1200 mg/d) or risperidone (1-6 mg/d) for 6 weeks. Sexual dysfunction was assessed by a semistructured interview, the Antipsychotics and Sexual Functioning Questionnaire (ASFQ), based upon the Utvalg for Kliniske Undersogelser (UKU). RESULTS: Four of 25 quetiapine-treated patients (16%) and 12 of 24 risperidone-treated patients (50%) reported sexual dysfunction (chi 2 = 6.4; df = 1; P = 0.006) on the ASFQ. Six patients (11.7%; 4 on risperidone, 2 on quetiapine) spontaneously reported sexual dysfunction. The mean+/-SD dose was 580+/-224 mg/d for quetiapine and 3.2 +/- 1.3 mg/d for risperidone. Mean +/- SD prolactin levels in quetiapine- and risperidone-treated patients were 13.8 +/- 17.9 and 57.7 +/- 39.7 ng/mL, respectively. CONCLUSION: Sexual dysfunction was less common in patients treated with quetiapine than with risperidone. Direct questioning about sexual functioning is necessary to avoid underestimating the frequency of sexual side effects in patients with schizophrenia and related psychotic disorders.

Influence of antipsychotic agents on neurological soft signs and dyskinesia in first episode psychosis.

First episode psychosis patients treated with atypical antipsychotics had significantly fewer signs of dyskinesia than patients treated with classical antipsychotics, but there were no significant differences regarding the total number of neurological soft signs (NSS). This suggests that the type of antipsychotic medication does not influence NSS, but that atypical antipsychotics are associated with less dyskinesia in the early stages of treatment.

The spectrum of subjective effects of antipsychotic medication.

BACKGROUND: This study examined the spectrum of subjective experiences which patients attribute to the use of antipsychotic medication. METHODS: We collected interview data and answers to structured questions based on a comprehensive checklist in 77 patients using various types of classical or atypical antipsychotic drugs. RESULTS: The responses of the patients could be categorized into psychological and somatic domains. The psychological domain could be subdivided into emotional, cognitive and sociability domains. The somatic set could be subdivided into activation and physiological domains. CONCLUSIONS: Our data reveal that the same effects may be experienced in either a positive or a negative way by different patients. We conclude that existing scales for measuring subjective effects of antipsychotic medication are incomplete.