Overactive, aggressive, disruptive and agitated behavior associated with the use of psychotropic medications in schizophrenia

Background Evidence is limited for the associations between use of psychotropic medications and overactive, aggressive, disruptive or agitated behavior (OADA)1 in clinical practice. Aims To investigate the associations between risk of readmission with OADA and use of antipsychotics, antidepressants, mood stabilizers and benzodiazepines in patients with schizophrenia. Method A consecutive total cohort diagnosed with schizophrenia (N = 663) after admission to the Haukeland University Hospital psychiatric acute unit in Bergen, Norway, was followed from discharge over a 10-year period. At every following readmission, the level of OADA was assessed using the first item of the Health of the Nation Outcome Scale (HoNOS). Periods of use versus non-use of antipsychotics, antidepressants, mood stabilizers and benzodiazepines were recorded as time-dependent variables in each patient and compared using Cox multiple regression analyses. Results A total of 161 (24.3 %) patients were readmitted with OADA, and the mean (SD) and median times in years to readmission with OADA were 2.8 (2.6) and 2.1, respectively. We found that the risk of readmission with OADA was negatively associated with use of antipsychotics (adjusted hazard ratio (AHR) = 0.33, p < 0.01, CI: 0.24–0.46) and antidepressants (AHR = 0.57, p = 0.03, CI: 0.34–0.95), positively associated with use of benzodiazepines (AHR = 1.95, p < 0.01, CI: 1.31–2.90) and not significantly associated with use of mood stabilizers. Conclusions Use of antipsychotics and antidepressants is associated with reduced risk of readmission with OADA whereas benzodiazepines are associated with an increased risk of readmission with OADA in patients with schizophrenia.publishedVersio

Cognitive profile in ultra high risk for psychosis and schizophrenia: A comparison using coordinated norms

Background: Cognitive impairment is not only a core aspect of schizophrenia but also commonly observed in help-seeking youth at ultra high risk for psychosis (UHR), with potential implications for prognosis and individualized treatment. However, there is no consensus on the cognitive profile in the UHR state, partly due to lack of valid comparisons of performance in established schizophrenia and UHR. Objectives: To compare the cognitive functioning and profile of UHR subjects to a sample with schizophrenia, they were split into two groups based on duration of illness. Comparisons were made using coordinated norms based on healthy controls reflecting the younger UHR age spectrum. Methods: Participants for UHR (n = 51) and schizophrenia groups (n = 19 and n = 22) were included from the Prevention of Psychosis and Bergen Psychosis 2 projects. All subjects completed a comprehensive neurocognitive test battery aiming to measure speed of processing, working memory, verbal learning, reasoning, and problem solving, as well as visual problem solving. Cognitive functioning was compared between groups based on coordinated norms using z-scores derived by regression modeling from an age-matched healthy control group (n = 61). Results: UHR subjects showed significantly impaired speed of processing (p 3 years for speed of processing and working memory (both p < 0.001). There were no significant differences in performance between the UHR group and the group with duration of schizophrenia <3 years. Conclusion: Cognitive performance is impaired in UHR subjects as compared to healthy controls and should thus be monitored when a person is deemed at high risk of psychotic illness. Spatial skills, as measured by tests using physical objects, appear less affected than other domains. The pattern of impairment is similar to that of a group with recent onset schizophrenia but is less severe than in a group with duration of illness <3 years.publishedVersio

Akathisia and atypical antipsychotics. Relation to suicidality, agitation and depression in a clinical trial

Objective: Akathisia is among the most unpleasant side effects related to antipsychotic drug (AP) use, and possible associations between akathisia and agitation, depression and suicidal behaviour, respectively, have been described in previous literature. New generation antipsychotics are however regarded less prone to induce this particular adverse effect compared to older drugs, but evidence is incomplete and in need of confirmation from clinically relevant samples and settings. We, therefore, aim to investigate akathisia at hospital discharge for patients consecutively admitted with acute-phase psychosis and treated with atypical antipsychotics according to guideline-concordant clinical practice. Methods: This exploratory study is part of a naturalistic randomised controlled study in patients admitted with acute phase psychosis (N = 109). We report cross-sectional data at discharge/first follow-up after acute psychiatric hospital admission for patients with schizophrenia and related psychotic disorders. Results: There were statistically significant positive associations between akathisia and the following; suicidality in men (Beta 0.306, p = 0.048), but not in women; agitation in those previously unexposed to antipsychotics (Beta 0.288, p = 0.047) and depression in those exposed to antipsychotics before hospital admittance (Beta 0.375, p = 0.031). Conclusion: Main findings were that akathisia is still a prevalent side effect in a clinically relevant sample of patients treated with atypical antipsychotics. Our results suggest that akathisia is significantly associated with depression, suicidality and agitation in different subgroups of patients receiving APs. Akathisia can be detrimental and the relations between akathisia and depression, suicidality and agitation should be investigated further in prospective, hypothesis-testing studies with larger samples.publishedVersio

Dynamic Functional Connectivity Patterns in Schizophrenia and the Relationship With Hallucinations

There is a wealth of evidence showing aberrant functional connectivity (FC) in schizophrenia but with considerable variability in findings across studies. Dynamic FC is an extension of traditional static FC, in that such analyses allow for explorations of temporal changes in connectivity. Thereby they also provide more detailed information on connectivity abnormalities in psychiatric disorders such as schizophrenia. The current study investigated dynamic FC in a sample of 80 schizophrenia patients and 80 matched healthy control subjects, replicating previous findings of aberrant dwell times in specific FC states, and further supporting a role for default mode network (DMN) dysfunction. Furthermore, relationships with hallucinations, a core symptom of schizophrenia, were explored. Two measures of hallucinations were used, one measure of current hallucination severity assessed on the day of scanning, and one trait-measure where hallucinations were assessed repeatedly over the course of 1 year. Current hallucination severity did not show a significant relationship with dynamic FC. However, the trait-measure of hallucination proneness over 1 year showed a significant relationship with dynamic FC. Patients with high hallucination proneness spent less time in connectivity states characterized by strong anti-correlation between the DMN and task-positive networks. The findings support theoretical models of hallucinations which have proposed an instability of the DMN and impaired cognitive control in patients with hallucinations. Furthermore, the results point to hallucination proneness as a potential marker for identifying distinct subgroups of schizophrenia patients.publishedVersio

Trajectories of response in schizophrenia-spectrum disorders: A one-year prospective cohort study of antipsychotic effectiveness

Background: Antipsychotic drugs remain the mainstay of schizophrenia treatment; however, their effectiveness has been questioned, and it is not possible to predict the response to a specific antipsychotic drug in an individual patient. Thus, it is important to compare the effectiveness of the various antipsychotics and search for possible response predictors. Aim: To investigate the effectiveness of antipsychotic drugs, we examined response trajectories and predictors for belonging to different trajectory groups. Methods: The Bergen-Stavanger-Innsbruck-Trondheim (BeSt InTro) trial compared the effectiveness of three atypical antipsychotics-amisulpride, aripiprazole, and olanzapine-in a prospective, semirandomized, rater-blind, head-to-head design. Adult participants with a schizophrenia spectrum disorder diagnosis, according to international classification of diseases, Tenth Revision (ICD-10) F20–29, were included. Participants were followed for a period of 12 mo, with assessments at baseline; after one, three and six weeks; and after three, six, nine and 12 mo. A latent class mixed model was fitted to our data. The three-trajectory model based on the Positive and Negative Syndrome Scale (PANSS) total score reduction was found to have adequate fit, and the study drugs, as well as various demographic and clinical parameters, were tested as predictors for belonging to the different trajectory groups. Results: Overall, 144 participants were included, and 41% completed the 12-mo study period. The largest trajectory group, consisting of 74% of participants, showed a PANSS total score reduction of 59% from baseline to 12 mo (Good response group). A trajectory group comprising 13% of participants had their PANSS total score reduced by 82.5% at 12 mo (Strong response group), while the last response trajectory group comprising 13% of the participants had a PANSS total score reduction of 13.6% (Slight response group). The largest part of the total reduction for the Good and Strong response groups occurred at six weeks of treatment, amounting to 45% and 48% reductions from baseline, respectively. The use of amisulpride predicted belonging to the Strong response group, while unemployment, depression, and negative psychotic symptoms at baseline increased the chance of belonging to the Slight response group, indicating a poor response to antipsychotic drug treatment. Conclusion: Most of the participants (87%) had a good outcome after one year. Amisulpride users, more often than aripiprazole and olanzapine users, belonged to the response trajectory group with a strong response.publishedVersio

White matter microstructural differences between hallucinating and non-hallucinating schizophrenia spectrum patients

The relation between auditory verbal hallucinations (AVH) and white matter has been studied, but results are still inconsistent. This inconsistency may be related to having only a single time-point of AVH assessment in many studies, not capturing that AVH severity fluctuates over time. In the current study, AVH fluctuations were captured by utilizing a longitudinal design and using repeated (Positive and Negative Symptoms Scale) PANSS questionnaire interviews over a 12 month period. We used a Magnetic Resonance Diffusion Tensor Imaging (MR DTI) sequence and tract-based spatial statistics (TBSS) to explore white matter differences between two subtypes of schizophrenia patients; 44 hallucinating (AVH+) and 13 non-hallucinating (AVH-), compared to 13 AVH- matched controls and 44 AVH+ matched controls. Additionally, we tested for hemispheric fractional anisotropy (FA) asymmetry between the groups. Significant widespread FA-value reduction was found in the AVH+ group in comparison to the AVH- group. Although not significant, the extracted FA-values for the control group were in between the two patient groups, for all clusters. We also found a significant difference in FA-asymmetry between the AVH+ and AVH- groups in two clusters, with significantly higher leftward asymmetry in the AVH- group. The current findings suggest a possible qualitative difference in white matter integrity between AVH+ and AVH- patients. Strengths and limitations of the study are discussed.publishedVersio

Illicit substances detected through high-resolution MS analysis in urine samples are associated with greater symptom burden in patients with psychosis

Background The prevalence of new psychoactive substances (NPS) in acute psychotic patients has not been investigated systematically. We applied a highly sensitive and specific mass spectrometry method for detection of NPS as well as traditional drugs of abuse (including illicit or prescription substances) in order to assess their prevalence and associations with symptom severity. Identification of these substances is useful in both the diagnostic process and evaluation of treatment effects. Methods Demographic data, results from the Positive and Negative Syndrome Score (PANSS) and Calgary Depression Scale for Schizophrenia (CDSS) and urine samples from admission were collected from 53 patients recruited into a clinical study of psychosis during 2014-2017. Urine samples were analysed with liquid chromatography high resolution mass spectrometry (LC-QTOF-MS), through both highly specific detection of 191 substances using internal standards and untargeted screening by means of pre-defined libraries. PANSS and CDSS scores in patients with or without drugs of abuse were compared. Results Potential drugs of abuse, i.e. drugs that could be used in a controlled therapeutic or a non-prescribed manner, were detected in samples from 20 of the 53 patients. Seven samples contained illicit drugs, but no NPS were detected. In this small patient subgroup, PANSS total score and CDSS score were significantly higher than in patients with negative urine sample results. Conclusion Drug screening could play an important role in the differential diagnostic evaluation of patients admitted with psychotic symptoms. Although no NPS were detected in the study population, we found other substances that were associated with psychotic and depressive symptoms.publishedVersio

Use of Benzodiazepines and Antipsychotic Drugs Are Inversely Associated with Acute Readmission Risk in Schizophrenia

Purpose: Little is known about the impact of different psychotropic drugs on acute readmission risk, when used concomitantly in a real-life setting. We aimed to investigate the association between acute readmission risk and use of antipsychotic drugs, antidepressants, mood stabilizers, and benzodiazepines in patients with schizophrenia. Methods: A cohort study included all patients diagnosed with schizophrenia admitted to a psychiatric acute unit at Haukeland University Hospital in Bergen, Norway, during a 10-year period (N = 663). Patients were followed from discharge until first readmission or censoring. Cox multiple regression analyses were conducted using antipsychotic drugs, antidepressants, mood stabilizers, and benzodiazepines as time-dependent variables, and periods of use and nonuse were compared within individual patients. Adjustments were made for sex, age at index admission, and excessive use of alcohol and illicit substances. Results: A total of 410 patients (61.8%) were readmitted during follow-up, and the mean and median times in days to readmission were 709 and 575, respectively. Compared with nonuse, the use of antipsychotic drugs was associated with reduced risk of readmission (adjusted hazards ratio, 0.20; P < 0.01; confidence interval, 0.16–0.24), and the use of benzodiazepines was associated with increased risk of readmission (adjusted hazards ratio, 1.51; P < 0.01; confidence interval, 1.13–2.02). However, no relation to readmission risk was found for the use of antidepressants and mood stabilizers. Conclusions: We found that use of benzodiazepines and antipsychotic drugs are inversely associated with acute readmission risk in schizophrenia.publishedVersio

Glutamate- and GABA-Modulated Connectivity in Auditory Hallucinations—A Combined Resting State fMRI and MR Spectroscopy Study

Background: Auditory verbal hallucinations (AVH) have been linked to aberrant interhemispheric connectivity between the left and the right superior temporal gyrus (STG), labeled the interhemispheric miscommunication theory. The present study investigated if interhemispheric miscommunication is modulated at the neurochemical level by glutamate (Glu) and gamma-aminobutyric acid (GABA) concentrations in temporal and prefrontal lobe areas, as proposed by the theory. Methods: We combined resting-state fMRI connectivity with MR spectroscopy (MRS) in a sample of 81 psychosis patients, comparing patients with high hallucination severity (high-AVH) and low hallucination severity (low-AVH) groups. Glu and GABA concentrations were acquired from the left STG and the anterior cingulate cortex (ACC), an area of cognitive control that has been proposed to modulate STG functioning in AVH. Results: Functional connectivity showed significant interaction effects between AVH Group and ACC-recorded Glu and GABA metabolites. Follow-up tests showed that there was a significant positive association for Glu concentration and interhemispheric STG connectivity in the high-AVH group, while there was a significant negative association for GABA concentration and interhemispheric STG connectivity in the low-AVH group. Conclusion: The results show neurochemical modulation of STG interhemispheric connectivity, as predicted by the interhemispheric miscommunication hypothesis. Furthermore, the findings are in line with an excitatory/inhibitory imbalance model for AVH. By combining different neuroimaging modalities, the current results provide a more comprehensive insight into the neural correlates of AVH.publishedVersio

Impact of childhood trauma on antipsychotic effectiveness in schizophrenia spectrum disorders: A prospective, pragmatic, semi-randomized trial

Antipsychotic medications are generally effective in ameliorating psychotic symptoms in schizophrenia spectrum disorders (SSDs). Identifying predictors associated with poor treatment response is important for a personalized treatment approach. Childhood trauma (CT) may have a general and differential effect on the effectiveness of different types of antipsychotics in SSDs. The Bergen-Stavanger-Trondheim-Innsbruck (BeSt InTro) study is a pragmatic, researcher-initiated, semi-randomized trial. The present study aimed to investigate symptom change (the Positive and Negative Syndrome Scale) from baseline to 1, 3, 6, 12, 26, 39 and 52 weeks of antipsychotic treatment (amisulpride, aripiprazole and olanzapine) by group (CT/no CT). Participants (n = 98) with diagnoses within the schizophrenia spectrum (F20–29 in the International Classification of Diseases — 10th Revision) were randomized to receive amisulpride, aripiprazole or olanzapine, and for this study categorized into groups of none and low CT, and moderate to severe CT according to thresholds defined by the Childhood Trauma Questionnaire Short-Form manual. CT in SSDs predicted an overall slower treatment response and less antipsychotic effectiveness after 26 weeks of treatment, which was statistically nonsignificant at 52 weeks. Secondary analyses showed a differential effect of CT related to type of antipsychotic medication: patients with SSDs and CT who received olanzapine showed less antipsychotic effectiveness throughout 52 weeks of treatment. The intention-to-treat and per-protocol analyses were convergent. Our findings indicate that in patients with SSD and CT, delayed response to antipsychotics could be expected, and a longer evaluation period before considering change of medication may be recommended.publishedVersio