Cannabinoids for the treatment of dementia.

BACKGROUND: Dementia is a common chronic condition, mainly affecting older adults, characterised by a progressive decline in cognitive and functional abilities. Medical treatments for dementia are limited. Cannabinoids are being investigated for the treatment of dementia. OBJECTIVES: To determine the efficacy and safety of cannabinoids for the treatment of dementia. SEARCH METHODS: We searched ALOIS - the Cochrane Dementia and Cognitive Improvement Group's Specialised Register - on 8 July 2021, using the terms cannabis or cannabinoid or endocannabinoid or cannabidiol or THC or CBD or dronabinol or delta-9-tetrahydrocannabinol or marijuana or marihuana or hashish. The register contains records from all major healthcare databases (the Cochrane Library, MEDLINE, Embase, PsycINFO, CINAHL, LILACS), as well as from many clinical trials registries and grey literature sources. SELECTION CRITERIA: We included all randomised controlled trials (RCTs) of cannabinoids for the treatment of dementia. We included participants of any age and of either sex with diagnosed dementia of any subtype, or with unspecified dementia of any severity, from any setting. We considered studies of cannabinoids administered by any route, at any dose, for any duration, compared with placebo, no treatment, or any active control intervention. DATA COLLECTION AND ANALYSIS: Two review authors independently screened and selected studies for inclusion, extracted data, and assessed the risk of bias in included studies. When necessary, other review authors were involved in reaching consensus decisions. We conducted meta-analyses using a generic inverse variance fixed-effect model to derive estimates of effect size. We used GRADE methods to assess our confidence in the effect estimates. MAIN RESULTS: We included four studies (126 participants) in this review. Most participants had Alzheimer's disease; a few had vascular dementia or mixed dementia. Three studies had low risk of bias across all domains; one study had unclear risk of bias for the majority of domains.  The included studies tested natural delta-9-tetrahydrocannabinol (THC) (Namisol) and two types of synthetic THC analogue (dronabinol and nabilone). Three trials had a cross-over design. Interventions were applied over 3 to 14 weeks; one study reported adverse events over 70 weeks of follow-up. One trial was undertaken in the USA, one in Canada, and two in The Netherlands. Two studies reported non-commercial funding, and two studies were conducted with the support of both commercial and non-commercial funding. Primary outcomes in this review were changes in global and specific cognitive function, overall behavioural and psychological symptoms of dementia (BPSD), and adverse events. We found very low-certainty evidence suggesting there may be little or no clinically important effect of a synthetic THC analogue on cognition assessed with the standardised Mini-Mental State Examination (sMMSE) (mean difference (MD) 1.1 points, 95% confidence interval (CI) 0.1 to 2.1; 1 cross-over trial, 28 participants).  We found low-certainty evidence suggesting there may be little or no clinically important effect of cannabinoids on overall behavioural and psychological symptoms of dementia assessed with the Neuropsychiatric Inventory (or its modified nursing home version) (MD -1.97, 95% CI -3.87 to -0.07; 1 parallel group and 2 cross-over studies, 110 participants). All included studies reported data on adverse events. However, the total number of adverse events, the total numbers of mild and moderate adverse events, and the total number of serious adverse events (SAEs) were not reported in a way that permitted meta-analysis.  There were no clear differences between groups in numbers of adverse events, with the exception of sedation (including lethargy), which was more frequent among participants taking nabilone (N = 17) than placebo (N = 6) (odds ratio (OR) 2.83, 95% CI 1.07 to 7.48; 1 cross-over study, 38 participants). We judged the certainty of evidence for adverse event outcomes to be low or very low due to serious concerns regarding imprecision and indirectness. AUTHORS' CONCLUSIONS: Based on data from four small, short, and heterogeneous placebo-controlled trials, we cannot be certain whether cannabinoids have any beneficial or harmful effects on dementia. If there are benefits of cannabinoids for people with dementia, the effects may be too small to be clinically meaningful. Adequately powered, methodologically robust trials with longer follow-up are needed to properly assess the effects of cannabinoids in dementia.

Salivary cortisol response to psychosocial stress in patients with first-episode psychosis.

AIM: To analyze the difference in the salivary cortisol response to psychosocial stress between the patients with the first episode of psychosis (FEP) and the control group. METHODS: We performed a cross-sectional analysis of the baseline measurements of a prospective cohort study conducted from 2015 to 2018 at two Croatian psychiatric hospitals. The study consecutively enrolled 53 patients diagnosed with FEP and 63 healthy controls. The primary outcome was the difference in the changes of salivary cortisol concentration during the stress test. The secondary outcome was the difference in the baseline levels of salivary cortisol between patients with FEP and controls. The tertiary outcome were the correlations of salivary cortisol levels with the results of the Positive and Negative Syndrome Scale for Schizophrenia, Rosenberg Self-Esteem Scale, and the International Personality Item Pool. RESULTS: Patients with FEP had significantly higher baseline salivary cortisol than controls, but their salivary cortisol increased significantly less during the stress test. CONCLUSION: Patients with FEP respond differently to stressful stimuli than controls, as shown by the increased baseline salivary cortisol and blunted cortisol response, possibly indicating a greater vulnerability to psychosocial stress.

Association of HSPA1B genotypes with psychopathology and neurocognition in patients with the first episode of psychosis: a longitudinal 18-month follow-up study.

Our aim was to analyze the association of HSPA1B genotypes and treatment response measured by the changes of psychopathology and neurocognitive symptoms in patients with first-episode psychosis (FEP) after 18 months of treatment. A sample of 159 patients with FEP admitted at two Croatian psychiatric hospitals in the period between year 2014 and year 2017 was assessed at baseline and after 18 months of follow-up with Positive and Negative Syndrome Scale (PANSS), Calgary Depression Scale for Schizophrenia (CDSS) and a battery of neurocognitive tests. Associations of scale and test results with HSPA1B polymorphic locus rs1061581 were analyzed using the general linear model. The carriers of the AA genotype showed the highest improvement in CDSS and RAVLT A test after the 18-month follow-up. Concordantly, we found significantly higher improvement assessed with the CDSS, RAVLT A, RAVLT A 30' and positive PANSS scales in the not-GG (AA/AG) group compared with the GG group. Our study suggests that HSPA1B rs1061581variants may moderate treatment response in FEP measured with changes of psychopathology and neurocognitive test results.

General Functioning in Patients With First-Episode Psychosis After the First 18 Months of Treatment.

BACKGROUND: One of the main goals in the treatment of first-episode psychosis (FEP) is achieving functional remission. This study aims to analyze whether initial neurocognitive status and the use of specific pharmacological and psychosocial treatment options in FEP can predict general functioning after 18 months of treatment. METHODS: We conducted a longitudinal naturalistic study with a sample of 129 patients with FEP treated at 2 Croatian psychiatric clinics from 2016until 2018. Ordinal regression was used to predict the global level of functioning assessed with the Global Assessment of Functioning scale (GAF) at the 18th month of treatment from the baseline symptoms (assessed with a set of neurocognitive tests) and different treatment options. RESULTS: Higher score on GAF at the 18th month was significantly predicted by female sex, better baseline verbal memory and GAF scores, and the type of treatment. Group multimodal psychosocial treatment, antipsychotic polytherapy, and not being treated with sedatives at baseline predicted better GAF scores at follow-up. In the exploratory analysis, taking sedatives in the final assessment and being rehospitalized due to relapse predicted worse GAF scores at the end of follow-up. CONCLUSIONS: Although baseline neurocognitive features and baseline general functioning seem to influence the overall long-term functioning of persons with FEP, addition of a multimodal group psychosocial treatment program and appropriate medication seem to be equally important for improving the patients' level of functioning after the FEP.

Differences in Facial Emotional Recognition Between Patients With the First-Episode Psychosis, Multi-episode Schizophrenia, and Healthy Controls.

OBJECTIVES: The aim of our study was to assess the differences in facial emotional recognition (FER) between patients with first-episode psychosis (FEP), patients with multi-episode schizophrenia (SCH), and healthy controls (HC) and to find possible correlations of FER with psychopathology in the two patient groups. METHODS: We performed a cross-sectional study enrolling 160 patients from two psychiatric hospitals in Croatia (80 FEP and 80 SCH) and 80 HC during the period from October 2015 until October 2017. Patients were assessed once during their hospital treatment, using the Penn Emotion Recognition Task for assessment of FER, rating scales for psychopathology and depression and self-reporting questionnaires for impulsiveness, aggression, and quality of life. RESULTS: The number of correctly identified emotions significantly decreased from HC to FEP [Δ -7%; 95% confidence interval (CI) [-12% to -3%], effect size r = 0.30] and more markedly in SCH (Δ -15%; 95% CI [-25% to -10%], effect size r = 0.59) after the adjustment for age and gender and correction for multiple testing. Correct FER for negative emotions, but not for happiness and neutral emotions, had a statistically significant negative correlation with some features on the scales of psychopathology, impulsivity and aggression in both patient groups. CONCLUSIONS: Impairment of FER is present from the first episode of schizophrenia and increases further with multiple psychotic episodes, but it may depend on or contribute to clinical symptoms. Therefore, assessment of FER should be included in the clinical assessment and integrated in the plan of treatment from the beginning of the illness. (JINS, 2019, 25, 165-173).

Interventions for prodromal stage of psychosis.

BACKGROUND: Psychosis is a serious mental condition characterised by a loss of contact with reality. There may be a prodromal period or stage of psychosis, where early signs of symptoms indicating onset of first episode psychosis (FEP) occur. A number of services, incorporating multimodal treatment approaches (pharmacotherapy, psychotherapy and psychosocial interventions), developed worldwide, now focus on this prodromal period with the aim of preventing psychosis in people at risk of developing FEP. OBJECTIVES: The primary objective is to assess the safety and efficacy of early interventions for people in the prodromal stage of psychosis. The secondary objective is, if possible, to compare the effectiveness of the various different interventions. SEARCH METHODS: We searched Cochrane Schizophrenia's study-based Register of studies (including trials registers) on 8 June 2016 and 4 August 2017. SELECTION CRITERIA: All randomised controlled trials (RCTs) evaluating interventions for participants older than 12 years, who had developed a prodromal stage of psychosis. DATA COLLECTION AND ANALYSIS: Review authors independently inspected citations, selected studies, extracted data, and assessed study quality. MAIN RESULTS: We included 20 studies with 2151 participants. The studies analysed 13 different comparisons. Group A comparisons explored the absolute effects of the experimental intervention. Group B were comparisons within which we could not be clear whether differential interactive effects were also ongoing. Group C comparisons explored differential effects between clearly distinct treatments. A key outcome for this review was 'transition to psychosis'. For details of other main outcomes please see 'Summary of findings' tables. In Group A (comparisons of absolute effects) we found no clear difference between amino acids and placebo (risk ratio (RR) 0.48 95% confidence interval (CI) 0.08 to 2.98; 2 RCTs, 52 participants; very low-quality evidence). When omega-3 fatty acids were compared to placebo, fewer participants given the omega-3 (10%) transitioned to psychosis compared to the placebo group (33%) during long-term follow-up of seven years (RR 0.24 95% CI 0.09 to 0.67; 1 RCT, 81 participants; low-quality evidence). In Group B (comparisons where complex interactions are probable) and in the subgroup focusing on antipsychotic drugs added to specific care packages, the amisulpiride + needs-focused intervention (NFI) compared to NFI comparison (no reporting of transition to psychosis; 1 RCT, 102 participants; very low-quality evidence) and the olanzapine + supportive intervention compared to supportive intervention alone comparison (RR 0.58 95% CI 0.28 to 1.18; 1 RCT, 60 participants; very low-quality evidence) showed no clear differences between groups. In the second Group B subgroup (cognitive behavioural therapies (CBT)), when CBT + supportive therapy was compared with supportive therapy alone around 8% of participants allocated to the combination of CBT and supportive therapy group transitioned to psychosis during follow-up by 18 months, compared with double that percentage in the supportive therapy alone group (RR 0.45 95% CI 0.23 to 0.89; 2 RCTs, 252 participants; very low-quality evidence). The CBT + risperidone versus CBT + placebo comparison identified no clear difference between treatments (RR 1.02 95% CI 0.39 to 2.67; 1 RCT, 87 participants; very low-quality evidence) and this also applies to the CBT + needs-based intervention (NBI) + risperidone versus NBI comparison (RR 0.75 95% CI 0.39 to 1.46; 1 RCT, 59 participants; very low-quality evidence). Group C (differential effects) also involved six comparisons. The first compared CBT with supportive therapy. No clear difference was found for the 'transition to psychosis' outcome (RR 0.74 95% CI 0.28 to 1.98; 1 RCT, 72 participants; very low-quality evidence). The second subgroup compared CBT + supportive intervention was compared with a NBI + supportive intervention, again, data were equivocal, few and of very low quality (RR 6.32 95% CI 0.34 to 117.09; 1 RCT, 57 participants). In the CBT + risperidone versus supportive therapy comparison, again there was no clear difference between groups (RR 0.76 95% CI 0.28 to 2.03; 1 RCT, 71 participants; very low-quality evidence). The three other comparisons in Group C demonstrated no clear differences between treatment groups. When cognitive training was compared to active control (tablet games) (no reporting of transition to psychosis; 1 RCT, 62 participants; very low quality data), family treatment compared with enhanced care comparison (RR 0.54 95% CI 0.18 to 1.59; 2 RCTs, 229 participants; very low-quality evidence) and integrated treatment compared to standard treatment comparison (RR 0.57 95% CI 0.28 to 1.15; 1 RCT, 79 participants; very low-quality evidence) no effects of any of these approaches was evident. AUTHORS' CONCLUSIONS: There has been considerable research effort in this area and several interventions have been trialled. The evidence available suggests that omega-3 fatty acids may prevent transition to psychosis but this evidence is low quality and more research is needed to confirm this finding. Other comparisons did not show any clear differences in effect for preventing transition to psychosis but again, the quality of this evidence is very low or low and not strong enough to make firm conclusions.

Neurocognitive Profiles of Patients with the First Episode of Psychosis and Schizophrenia Do not Differ Qualitatively: a Nested Cross-Sectional Study.

BACKGROUND: The aim of study was to analyze neurocognitive profiles in patients with first-episode psychosis (FEP) and patients with schizophrenia (SCH), and their correlations with other clinical features. SUBJECTS AND METHODS: We performed a multicentric cross sectional study including 100 FEP and 100 SCH recruited from three Croatian hospitals during 2015-2017. Assessment included a set of neurocognitive tests, psychiatric scales and self-reporting questionnaires. The main analysis was done by multigroup latent profile analysis. RESULTS: Multigroup latent profile analysis resulted in three structurally equivalent neurocognitive profiles ("Best", "Medium", "Worst"), with differences in the severity of neurocognitive deficits measured with successfulness in solving domain specific tasks. The "Best" profile was statistically significantly more prevalent in FEP and "Worst" profile in the SCH. Negative symptom score was the highest in patients with the "Worst" profile and the lowest among those with the "Best" profiles. CONCLUSIONS: Differences in neurocognitive profiles between FEP and SCH appear to be quantitative rather than qualitative nature, possibly reflecting a specific trait of illness that may progress over time. Defining neurocognitive profiles from the first episode of psychosis could help in tailoring individualized treatment options with focus on neurocognitive and negative symptoms and possible influence on patients' overall clinical outcome.

Integration of complementary biomarkers in patients with first episode psychosis: research protocol of a prospective follow up study.

In this project, we recruited a sample of 150 patients with first episode of psychosis with schizophrenia features (FEP) and 100 healthy controls. We assessed the differences between these two groups, as well as the changes between the acute phase of illness and subsequent remission among patients over 18-month longitudinal follow-up. The assessments were divided into four work packages (WP): WP1- psychopathological status, neurocognitive functioning and emotional recognition; WP2- stress response measured by saliva cortisol during a stress paradigm; cerebral blood perfusion in the resting state (with single photon emission computed tomography (SPECT) and during activation paradigm (with Transcranial Ultrasonography Doppler (TCD); WP3-post mortem analysis in histologically prepared human cortical tissue of post mortem samples of subjects with schizophrenia in the region that synaptic alteration was suggested by WP1 and WP2; WP4- pharmacogenetic analysis (single gene polymorphisms and genome wide association study (GWAS). We expect that the analysis of these data will identify a set of markers that differentiate healthy controls from patients with FEP, and serve as an additional diagnostic tool in the first episode of psychosis, and prediction tool which can be then used to help tailoring individualized treatment options. In this paper, we describe the project protocol including aims and methods and provide a brief description of planned post mortem studies and pharmacogenetic analysis.

Changes of neurocognitive status in patients with the first-episode psychosis after 18 months of treatment-A prospective cohort study.

Neurocognitive symptoms exert the most influence on treatment outcomes over the course of schizophrenia, starting from the first-episode of psychosis (FEP) onwards. Our aim was to analyze the neurocognitive status of FEP compared to healthy controls (HC), and its change after 18 months of treatment. We performed a study in a sample of 159 patients with FEP and 100 HC. We followed the patients up for 18 months after initial assessment with a battery of neurocognitive tests. We observed statistically significant improvement in the majority of neurocognitive tests after 18 months, but several tests of specific neurocognitive domains (verbal memory, language functions, executive functions) did not show significant differences between the two assessments. The results for the majority of tests obtained from patients with FEP after 18 months of treatment showed significant deterioration compared with HC. Although our study showed significant improvement of baseline neurocognitive deficits in FEP with treatment, this varied across domains and overall performance remained below that of HC. Thus, while it seems that treatment of FEP may help to delay or restore neurocognitive deterioration, it is unclear whether specific areas of neurocognitive deterioration (e.g. verbal domain) would benefit from more time or specific treatment approaches.

Association of CNR1 genotypes with changes in neurocognitive performance after eighteen-month treatment in patients with first-episode psychosis.

INTRODUCTION: We analyzed the association of cannabinoid receptor CNR1 genotypes with changes in neurocognitive performance in patients with first-episode psychosis (FEP) after 18 months of treatment. Our secondary aim was to analyze the association of CNR1 genotypes with changes of perceived levels of stress. METHODS: We enrolled a sample of 159 patients with FEP from two Croatian psychiatric hospitals between 2014 and 2017. Patients were assessed at baseline and after 18 months. We analyzed the associations of changes in neurocognitive test results and the perceived levels of stress with CNR1 polymorphic loci (rs7766029 and rs12720071) in 121 patients. RESULTS: In the analysis adjusted only for baseline neurocognitive test scores, carriers of rs7766029 CC genotype had significantly (with false discovery rate, FDR < 15%) higher improvement in verbal memory (Wechsler, Wechsler 30') and attention (Digit span F) compared with other participants. In such analysis, rs12720071 carriers of AG genotype had significantly (FDR < 15%) higher improvement in executive functions (Block design), but lower improvement in language functions than AA carriers. In the fully adjusted analysis for age, sex, cannabis use and negative symptoms, only the association of rs7766029 genotypes with the change in the Weschler 30' score was significant (FDR < 15%). In the analysis adjusted only for the baseline neurocognitive tests' scores, both rs7766029 and rs12720071 genotypes were significantly associated with the change in perceived levels of stress (FDR < 15%). In the fully adjusted analysis, only the association with rs7766029 genotype remained significant. CONCLUSIONS: The rs7766029 CNR1 variants may moderate changes in neurocognitive performance as well as in perceived levels of stress of patients with FEP over time.

Effects of Long-Term Multimodal Psychosocial Treatment on Antipsychotic-Induced Metabolic Changes in Patients With First Episode Psychosis.

Background: Antipsychotic-induced weight gain and metabolic abnormalities are one of the major challenges in the treatment of psychosis, contributing to the morbidity, mortality and treatment non-adherence. Different approaches were used to counteract these side effects but showed only limited or short-term effects. This study aims to analyse the effects of a long-term multimodal treatment program for first episode psychosis on antipsychotic-induced metabolic changes. Methods: We enrolled 71 patients with first episode psychosis treated at the Zagreb University Hospital Centre from 2016 until 2018. Participants were assigned to one of the two groups: day hospital program vs. treatment as usual (TAU). Outcomes were: body weight, blood glucose, lipids and cholesterol, psychopathology and global level of functioning during the 18-months follow-up. Results: Although the TAU group gained more weight and had higher increase of blood glucose, while the day hospital group had a higher increase in total cholesterol at 18th month follow-up, after the adjustment for age, gender and baseline measures, the type of treatment was not significantly associated with any of the primary outcome measures. Patients' psychopathology measures significantly decreased and their functional level significantly increased at month 18th in both groups. Conclusion: While both types of treatment were effective in reducing psychopathology and restoring the patients' level of functioning, both were relatively ineffective in counteracting antipsychotic-induced metabolic abnormalities and antipsychotic-induced weight gain.