Depressive symptoms in psychotic disorders : Trajectories of depression and antidepressive effectiveness of antipsychotic medication

Postponed access: the file will be accessible after 2023-10-16Background: Depressive symptoms are common in psychotic disorders and contribute to impaired functioning, a poorer quality of life, elevated relapse rate and suicide risk. Depression in schizophrenia may emerge as part of the prodromal phase, preceding and during a psychotic episode and as post-psychotic depression. Early studies indicating dysphoric effects of antipsychotics have been superseded by studies demonstrating antidepressive properties for several atypical antipsychotics. Atypical antipsychotics may exert their antidepressive effects through antagonism at serotonergic 5HT2 receptors, agonism at 5HT1 receptors, antagonism at adrenergic α2 receptors and inhibition of trans-membrane monoamine transporters. Guidelines for the treatment of depression in psychotic disorders remain unclear due to unresolved issues related to among others, the heterogeneity of depression in psychosis, thus more studies are needed. To investigate differences in antidepressive effectiveness, we conducted comparative trials of atypical antipsychotics funded independently of the pharmaceutical industry. Methods: Change in depressive symptom sum score measured by Calgary Depression Scale for Schizophrenia was investigated in two separate randomized clinical trials, analysed by means of Linear Mixed Effects models and Latent Growth Curve modelling. Trajectories of depressive symptom change were identified with Growth Mixture Modelling. Results: In the first paper we found depressive symptom reduction that was not significantly different between the atypical antipsychotics olanzapine, quetiapine, risperidone and ziprasidone in a 24-month, industry-independent, randomized trial of 226 patients acutely admitted with psychosis, although olanzapine had the smallest reduction and risperidone the greatest. There were no significant effectiveness differences in the patients with most pronounced depression neither. A much larger drop-out than assumed reduced statistical power. Still, effectiveness differences were smaller than considered clinically relevant. In the second paper from the same trial we investigated heterogeneity in treatment response and found three depression-trajectories: one depressed and treatment refractory group (14.7%), one group with limited depressive symptoms (69.6%) and a third depressed but early responding group (15.7%). A reduction of positive psychotic symptoms predicted depression improvement. Post-psychotic depression did not emerge in patients that were not depressed in the acute phase and we could not identify differentiating characteristics of the depression trajectories. The third paper investigated the antidepressive effectiveness of the atypical antipsychotics amisulpride, aripiprazole and olanzapine in a second randomized clinical trial. In 144 patients no between-drug differences in depressive symptom reduction were found, although the amisulpride group had the greatest depressive symptom reduction. The majority of depressive symptom reduction occurred within 6 weeks. No antidepressive effectiveness differences between the study drugs were found in the group with most pronounced depression, neither. Statistical power was smaller than power-analyses indicated due to discrepancies between presumed and actual study characteristics. Conclusion: We conclude that the net effectiveness of atypical antipsychotics during and following psychotic episodes on group-level is antidepressive and not depression-inducing. Since no head-to-head antipsychotic antidepressive differences were found, we can make no recommendations concerning choice of any particular atypical antipsychotic for targeting symptoms of depression in patients acutely admitted with psychosis. The treatment-refractory patients are candidates for enhanced anti-depressive treatment, for which current evidence is limited. For a substantial portion of patients treatment as usual of the psychotic episode was sufficient to reduce acute-phase depression

Sexual Dysfunction and Hyperprolactinemia in Male Psychotic Inpatients: A Cross-Sectional Study

Introduction. Sexual dysfunction (SD) and hyperprolactinemia are frequently reported in patients with psychotic disorders and have the potential for severe complications but investigations in males are particularly scarce. The primary aims were to determine the prevalence of SD and hyperprolactinemia in male patients and to investigate whether associations exist between SD and prolactin levels. Methods. Cross-sectional data were obtained at discharge from the hospital or 6 weeks after admittance for patients acutely admitted for psychosis and treated with a second-generation antipsychotic drug. Results. Half the patients reported diminished sexual desire and more than a third reported erectile and ejaculatory dysfunctions with no differences among the drugs. More than half the sample was hyperprolactinemic. No association was found between prolactin levels and SD. Conclusion. High rates of SD and hyperprolactinemia were found in male patients and should be a treatment target. SD and hyperprolactinemia were not correlated

Does drug use affect the efficacy of amisulpride, aripiprazole and olanzapine in patients with schizophrenia spectrum disorders? Results from a pragmatic, randomised study

Objectives Drug use is prevalent in patients with schizophrenia spectrum disorders (SSD) but there is limited knowledge about the influence of drug use on the effectiveness of antipsychotic medication. This secondary explorative study compared the effectiveness of three antipsychotics in patients with SSD, with and without drug use. Methods The BeSt InTro multi-centre, head to head, rater-blinded randomised study compared amisulpride, aripiprazole and olanzapine over a 1-year follow-up period. All patients (n = 144) were aged ≥18 years and met the ICD-10 criteria for SSD (F20–29). Clinical symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS). The primary outcome was reduction of a PANSS positive subscale score. Results At baseline, 38% of all patients reported drug use in the last 6 months before inclusion, with cannabis as the main drug (85%), followed by amphetamine-type stimulants (45%), sedatives (26%), hallucinogens (19%), cocaine (13%), opiates (4%), GHB (4%), solvents (4%), analgesics (4%) and anabolic steroids (2%). The predominant pattern was the use of several drugs. There were no significant overall differences in the PANSS positive subscale score reduction for the three studied antipsychotics among patients either with or without drug use. In the drug use group, older patients treated with amisulpride showed a greater PANSS positive subscale score reduction during the treatment period compared to younger patients. Conclusion The current study showed that drug use does not appear to affect the overall effectiveness of amisulpride, aripiprazole and olanzapine in patients with SSD. However, amisulpride may be a particularly suitable choice for older patients with drug use.publishedVersio

Depression trajectories and cytokines in schizophrenia spectrum disorders - A longitudinal observational study

Depression occurs frequently in all phases of schizophrenia spectrum disorders. Altered activity in the immune system is seen in both depression and schizophrenia. We aimed to uncover depressive trajectories in a sample of 144 adult individuals with schizophrenia spectrum disorders followed for one year, in order to identify possible cytokine profile differences. Patients were assessed longitudinally with the Positive and Negative Syndrome Scale (PANSS) and the Calgary Depression Scale for Schizophrenia (CDSS), where a score above 6 predicts depression. The serum cytokine concentrations for tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma, interleukin (IL)-1beta, IL-2, IL-4, IL-6, IL-10, IL-12p70 and IL-17A were measured using immunoassays. Latent growth curve models, multilevel models and latent class growth analysis (LCGA) were applied. The LCGA model supported three latent classes (trajectories) with differing CDSS profiles during the one-year follow-up: a high CDSS group (40.8 % of participants), a moderate CDSS group (43.9 %) and a low CDSS group (15.3 %). Five single PANSS items predicted affiliation to depressive trajectory: hallucinations, difficulty in abstract thinking, anxiety, guilt feelings and tension. In the high CDSS group, despite diminishing psychotic symptoms, depressive symptoms persisted throughout one year. The pro-inflammatory cytokines IFN-γ, IL-1β and TNF-α were differentially distributed between the depressive trajectories, although levels remained remarkably stable throughout 12 months. Significant changes were found for the anti-inflammatory cytokine IL-10 at baseline with an accompanying difference in change over time. More research is required to optimize future treatment stratification and investigate the contribution of inflammation in depressed patients with schizophrenia spectrum disorders.publishedVersio

Antidepressive Effectiveness of Amisulpride, Aripiprazole, and Olanzapine in Patients with Schizophrenia Spectrum Disorders: A Secondary Outcome Analysis of a Pragmatic, Randomized Trial (BeSt InTro)

Background Depressive symptoms are frequent in schizophrenia and associated with a poorer outcome. Currently, the optimal treatment for depressive symptoms in schizophrenia remains undetermined. Amisulpride, aripiprazole, and olanzapine all have antidepressive pharmacodynamic properties, ranging from serotonergic affinities to limbic dopaminergic selectivity. Consequently, in a 12-month pragmatic, randomized clinical trial, we aimed to investigate differences in antidepressive effectiveness among amisulpride, aripiprazole, and olanzapine as a secondary outcome, measured by change in the Calgary Depression Scale for Schizophrenia sum score in patients within the schizophrenia spectrum. Methods Psychotic patients within the schizophrenia spectrum were included, and effectiveness was analyzed with latent growth curve modeling. Results Of the 144 patients, 51 (35%) were women, the mean age was 31.7 (SD 12.7), and 39% were antipsychotic naive. At inclusion, 68 (47%) participants had a Calgary Depression Scale for Schizophrenia sum score >6, indicating severe depressive symptoms. Across the 12-month follow-up, there was a depressive symptom reduction in all medication groups, but no statistically significant differences between the study drugs. Separate analyses of the subcohort with elevated depressive symptoms at inclusion also failed to find differences in depressive symptom reduction between study drugs. The reduction in depressive symptoms mainly occurred within 6 weeks after randomization. Conclusions There was a reduction in depressive symptoms under treatment with amisulpride, aripiprazole, and olanzapine in acutely psychotic patients with schizophrenia spectrum disorder, but no differences between the drugs.publishedVersio

Association between C-reactive protein levels and antipsychotic treatment during 12 months follow-up period after acute psychosis

Background A potential role of inflammatory pathways in the pathology of schizophrenia has been suggested for at least a subgroup of patients. Elevated levels of the inflammatory marker C-reactive protein (CRP) have been observed, with associations to pathogenesis and symptoms. The current evidence regarding effects of antipsychotics on CRP levels is ambiguous. Objectives To examine and compare the influence on CRP levels of three pharmacologically diverse new generation antipsychotics during a one-year follow-up in schizophrenia spectrum disorder. Methods In a multicenter, pragmatic and rater-blinded randomized trial, the effects of amisulpride, aripiprazole and olanzapine were compared in 128 patients with schizophrenia spectrum disorder. All had positive symptoms of psychosis at study entry. Clinical and laboratory assessments including the measurement of CRP levels were conducted at baseline, and 1, 3, 6, 12, 26, 39, and 52 weeks thereafter. Results For all antipsychotic drugs analysed together, there was an increase in CRP levels during the one-year follow-up. Aripiprazole, as opposed to amisulpride and olanzapine, was associated with a reduced CRP level after one week, after which the CRP level caught up with the other drugs. Compared to those previously exposed to antipsychotic drugs, antipsychotic-naïve patients had lower CRP levels at all follow-up time points, but with the same temporal patterns of change. Conclusion Treatment with amisulpride, aripiprazole and olanzapine showed different effects on CRP levels in patients with schizophrenia spectrum disorders, modified by previous antipsychotics exposure status. This finding suggests that antipsychotic drugs may vary with respect to their influence on pro-inflammatory pathways.publishedVersio

Anti-depressive effectiveness of olanzapine, quetiapine, risperidone and ziprasidone: a pragmatic, randomized trial

<p>Abstract</p> <p>Background</p> <p>Efficacy studies indicate anti-depressive effects of at least some second generation antipsychotics (SGAs). The Bergen Psychosis Project (BPP) is a 24-month, pragmatic, industry-independent, randomized, head-to-head comparison of olanzapine, quetiapine, risperidone and ziprasidone in patients acutely admitted with psychosis. The aim of the study is to investigate whether differential anti-depressive effectiveness exists among SGAs in a clinically relevant sample of patients acutely admitted with psychosis.</p> <p>Methods</p> <p>Adult patients acutely admitted to an emergency ward for psychosis were randomized to olanzapine, quetiapine, risperidone or ziprasidone and followed for up to 2 years. Participants were assessed repeatedly using the Positive and Negative Syndrome Scale - Depression factor (PANSS-D) and the Calgary Depression Scale for Schizophrenia (CDSS).</p> <p>Results</p> <p>A total of 226 patients were included. A significant time-effect showing a steady decline in depressive symptoms in all medication groups was demonstrated. There were no substantial differences among the SGAs in reducing the PANSS-D score or the CDSS sum score. Separate analyses of groups with CDSS sum scores > 6 or ≤6, respectively, reflecting degree of depressive morbidity, revealed essentially identical results to the primary analyses. There was a high correlation between the PANSS-D and the CDSS sum score (r = 0.77; p < 0.01).</p> <p>Conclusions</p> <p>There was no substantial difference in anti-depressive effectiveness among olanzapine, quetiapine, risperidone or ziprasidone in this clinically relevant sample of patients acutely admitted to hospital for symptoms of psychosis. Based on our findings we can make no recommendations concerning choice of any particular SGA for targeting symptoms of depression in a patient acutely admitted with psychosis.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov ID; URL: <url>http://www.clinicaltrials.gov/</url>: <a href="http://www.clinicaltrials.gov/ct2/show/NCT00932529">NCT00932529</a></p

Elderly Patients With No Previous Psychiatric History: Suicidality and Other Factors Relating to Psychiatric Acute Admissions

Background: The common recommendation that adults with onset of mental illness after the age of 65 should receive specialised psychogeriatric treatment is based on limited evidence. Aims: To compare factors related to psychiatric acute admission in older adults who have no previous psychiatric history (NPH) with that of those who have a previous psychiatric history (PPH). Method: Cross-sectional cohort study of 918 patients aged ≥65 years consecutively admitted to a general adult psychiatric acute unit from 2005 to 2014. Results: Patients in the NPH group (n = 526) were significantly older than those in the PPH group (n = 391) (77.6 v. 70.9 years P 65 years, the subgroup with NPH were characterised by more physical frailty, somatic comorbidity and functional and cognitive impairment as well as higher rates of preadmission suicide attempts. Admitting facilities should be appropriately suited to manage their needs

Mapping psychotic-like experiences: Results from an online survey.

Suggestions have been made that psychotic-like experiences (PLEs), such as hallucinatory and delusional experiences, exist on a continuum from healthy individuals to patients with a diagnosis of schizophrenia. We used the screening questions of the Questionnaire for Psychotic Experiences (QPE), an interview that captures the presence and phenomenology of various psychotic experiences separately, to assess PLEs in Norway. Based on data from an online survey in a sample of more than 1,400 participants, we demonstrated that the QPE screening questions show satisfactory psychometric properties. Participants with mental disorders reported more frequent lifetime and current hallucinatory experiences than participants without mental disorders. Childhood experiences were rather low and ranged from 0.7% to 5.2%. We further replicated findings that young age, illegal drug use, lower level of education, and having parents with a mental disorder are associated with higher endorsement rates of PLEs. Finally, a binomial regression revealed that the mere presence of PLEs does not discriminate between individuals with and without a mental disorder. Taken together, the findings of the present study support existing models that both hallucinations and delusions exist on a structural and phenomenological continuum. Moreover, we demonstrated that the QPE screening questions can be used by themselves as a complementary tool to the full QPE interview