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.

The effect of prednisolone on symptom severity in schizophrenia: A placebo-controlled, randomized controlled trial.

OBJECTIVE: Immune dysregulation may be involved in the pathophysiology of schizophrenia. Given the need for new treatment options in schizophrenia, anti-inflammatory medication could be a potential treatment in this illness. METHODS: In this double-blind, placebo-controlled clinical trial, patients with schizophrenia, schizoaffective disorder or psychosis NOS were randomized 1:1 to either prednisolone or placebo, in addition to their regular antipsychotic medication. Patients diagnosed with schizophrenia for less than 7 years and on antipsychotics, were treated with prednisolone or placebo, tapered-off within six weeks in the following schedule: 40 mg/day for 3 days and 30 mg/day for 4 days, followed by a decrease of 5 mg/day per week during the remaining 5 weeks. Change in symptom severity relative to baseline was compared between treatment arms, as measured through the Positive and Negative Syndrome Scale total score. RESULTS: In total, 68 patients signed informed consent and were screened on eligibility criteria, of whom 42 patients were randomized to either prednisolone or placebo, with 39 patients completing the treatment and tapering phase. Due to recruitment difficulties, the study was terminated prematurely. Symptom severity decreased significantly in both the prednisone and placebo treatment arm (p < 0.001). The degree of improvement was not significantly different between treatment arms (p = 0.96). No serious adverse events occurred during the treatment phase. DISCUSSION: There is no indication that prednisolone has a beneficial effect on symptom severity, as adjunctive treatment in patients with schizophrenia, as compared to placebo. CONCLUSION: Adjunctive treatment with prednisolone did not improve symptom severity compared to placebo in patients with schizophrenia.

Prednisolone versus placebo addition in the treatment of patients with recent-onset psychotic disorder: a trial design.

BACKGROUND: The symptom severity of a substantial group of schizophrenia patients (30-40%) does not improve through pharmacotherapy with antipsychotic medication, indicating a clear need for new treatment options to improve schizophrenia outcome. Meta-analyses, genetic studies, randomized controlled trials, and post-mortem studies suggest that immune dysregulation plays a role in the pathophysiology of schizophrenia. Some anti-inflammatory drugs have shown beneficial effects on the symptom severity of schizophrenia patients. Corticosteroids are effective in various chronic inflammatory and autoimmune disorders. Prednisolone, a potent glucocorticosteroid, has minor mineral-corticosteroid potencies and can adequately pass the blood-brain barrier and its side effects and safety profile are well known. Therefore, the effect of prednisolone can be studied as a proof of concept for immune modulation as a treatment for schizophrenia. METHODS/DESIGN: In total, 90 subjects aged 18-70 years and diagnosed with schizophrenia, schizoaffective disorder, or schizophreniform disorder (Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV) 295.x) or psychosis not otherwise specified (NOS; 298.9) will be included. The time interval between the onset of psychosis and study entry should not exceed 7 years. Patients will be randomized 1:1 to either prednisolone or placebo daily for a period of 6 weeks in addition to a stable dose of antipsychotic medication. Study medication will be initiated at 40 mg for 3 days, after which it will be tapered down within 6 weeks after initiation, following inflammatory bowel diseases treatment guidelines. Primary outcome is change in symptom severity, expressed as change in total score on the Positive and Negative Symptom Scale (PANSS) from baseline to end of treatment. Cognitive functioning (measured through the Brief Assessment of Cognition in Schizophrenia (BACS)) and change in Global Assessment Functioning (GAF) and depressive symptoms as measured with the Calgary Depression Scale for Schizophrenia (CDS) will be assessed, in addition to various immunological biomarkers. Secondary outcomes are a 4- and 6-month follow-up assessment of PANSS, BACS, and GAF scores and immunological biomarkers. Additionally, a subgroup of patients will be included in the magnetic resonance imaging (MRI) part of the study where MR spectroscopy and structural, functional, and diffusion MRI will be conducted. DISCUSSION: It is expected that prednisolone addition to current antipsychotic medication use will reduce symptom severity and will improve cognition when compared to placebo. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02949232 and NCT03340909. Registered 31 October 2016 and 14 November 2017. EudraCT-number 2014-000520-14 and 2017-000163-32.

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.

Early course of schizophrenia in a representative Dutch incidence cohort.

PURPOSE: To describe the early course of psychotic disorders in general and to examine whether certain variables can predict the early course of schizophrenic disorders (DSM-IV: schizophrenia, schizophreniform or schizoaffective disorder). SUBJECTS AND METHOD: Follow-up and re-diagnosis of a highly representative Dutch incidence cohort (N=181), thirty months after first contact with a physician for a psychotic disorder. Poor course was defined as a continuous psychotic illness or a score of less than 39 on the Global Assessment of Functioning scale. RESULTS: The follow-up rate was 92%. 125 Subjects were diagnosed with a schizophrenic disorder. Poor course was present in 70 of these subjects (56%). Univariable analysis showed that male sex, heavy cannabis use during the follow-up period (sometimes or often more than one joint a day) and long duration of dysfunctioning before psychosis onset (>1 month) were predictors of poor course, while age at onset, ethnicity, socioeconomic status and duration of untreated psychosis (trend, p=0.08) were not. The effect of cannabis was confounded by sex. Multivariable analysis showed that male sex was the sole significant and independent predictor of poor course and explained 13% of the variation. The odds ratio for males, adjusted for duration of pre-psychotic dysfunctioning and cannabis use during the follow-up period, was 3.0 (95% CI, 1.0-8.9). STRENGTHS AND LIMITATIONS: This is the first study to examine the influence of cannabis in an epidemiological, highly representative sample. A limitation was the sample size. CONCLUSION: Male sex is an independent risk factor for an unfavorable early course in schizophrenia.

Incidence of schizophrenia among ethnic minorities in the Netherlands: a four-year first-contact study.

There is only one previous report on the first-contact incidence of schizophrenia among immigrants in the Netherlands, which was based on a small number of cases, particularly for second generation immigrants. We conducted another two-year first-contact incidence study in the same geographical area, combined the data of both studies and compared risks over all four years. The incidence of schizophrenia was increased for all first generation non-Western immigrants. The risk was particularly high for second generation immigrants: the age- and gender-adjusted incidence rate ratio was 5.8 (95% CI, 2.9-11.4) for Moroccans, 2.9 (1.6-5.0) for Surinamese, 2.3 (1.0-5.4) for Turks, and 3.5 (1.8-6.8) for immigrants from other non-Western countries.

Diagnostic stability in a Dutch psychosis incidence cohort.

BACKGROUND: No study outside the UK has examined the diagnostic stability of psychotic disorders in a population-based sample. AIMS: To determine diagnostic stability in a Dutch population-based psychosis incidence cohort, to examine the frequencies of diagnostic shifts to and from schizophrenic disorders and to report the revised relative risks of schizophrenic disorders for immigrants. METHOD: A 30-month follow-up study assessed the cohort (n=181) by means of face-to-face diagnostic interviews. RESULTS: Diagnostic stability of schizophrenic disorders was high (91%), but lower for other psychotic disorders. At follow-up, the initial diagnosis was adjusted to schizophrenic disorder more often than that the reverse occurred. Almost half (49%) of the patients who were not initially diagnosed as having a schizophrenic disorder received this diagnosis at follow-up. The relative risks for most immigrant groups were stable. CONCLUSIONS: Schizophrenic disorders are underdiagnosed, rather than overdiagnosed, at first presentation.

Cannabis use and age at onset of schizophrenia.

OBJECTIVE: The purpose of the study was to assess the independent influences of gender and cannabis use on milestones of early course in schizophrenia. METHOD: In this population-based, first-contact incidence study conducted in The Hague, the Netherlands, patients (N=133) were interviewed with the Comprehensive Assessment of Symptoms and History, and key informants were interviewed with the Instrument for the Retrospective Assessment of the Onset of Schizophrenia. Milestones of early course were 1) first social and/or occupational dysfunction, 2) first psychotic episode, and 3) first negative symptoms. RESULTS: Male patients were significantly younger than female patients at first social and/or occupational dysfunction, first psychotic episode, and first negative symptoms. Cannabis-using patients were significantly younger at these milestones than were patients who did not use cannabis. Multivariate analyses showed that cannabis use, but not gender, made an independent contribution to the prediction of age at first psychotic episode: male cannabis users were a mean of 6.9 years younger at illness onset than male nonusers. In contrast, age at first social and/or occupational dysfunction and the risk of developing negative symptoms before the first contact with a physician for treatment of possible psychotic disorder were predicted by gender, but not by cannabis use. CONCLUSIONS: The results indicate a strong association between use of cannabis and earlier age at first psychotic episode in male schizophrenia patients. Additional studies examining this possibly causal relationship are needed.

Hair analysis for cannabinoids and amphetamines in a psychosis incidence study.

It remains often uncertain whether the use of illicit substances has contributed to the aetiology of psychosis. Gas chromatography-mass spectrometry can be used to detect them in hair of the head. Given a monthly growth rate between 1.0 and 1.5 cm, one can examine hair segments that originated during the pre-psychotic period. We examined the usefulness of hair analysis to detect the use of cannabinoids or amphetamines during this period. One hundred patients participated in a psychosis incidence study and 64 yielded hair. Refusal was associated with non-Dutch ethnicity, not with a clinical diagnosis of use. A monthly growth rate of 1.5 cm was assumed and 33 specimens were found to be long enough. Cannabinoids or amphetamines were detected in nine specimens. In seven they were not detected, whereas the patients had reported their use. It is likely that their hair grew at a slower rate and that the examined segments belonged to an earlier period of time, during which the substances were not used. Lack of knowledge about the individual hair growth rate is an important limitation to the usefulness of this method.