Cannabidiol as an Adjunctive Treatment for Acute Bipolar Depression: A Pilot Study: Le cannabidiol comme traitement d'appoint de la dépression bipolaire aiguë : une étude pilote.

OBJECTIVE: The treatment of bipolar depression remains challenging due to the limited effective and safe therapeutic options available; thus, developing newer treatments that are effective and well tolerable is an urgent unmet need. The objective of the present trial was to test 150 to 300 mg/day of cannabidiol as an adjunctive treatment for bipolar depression. METHOD: A randomized, double-blind, placebo-controlled pilot study to assess the efficacy of adjunctive cannabidiol in bipolar depression was used. Efficacy parameters were changes in the Montgomery-Åsberg Depression Rating Scale (MADRS) from baseline to week 8. Secondary outcomes included response and remission rates, changes in anxiety and psychotic symptoms, and changes in functioning. Patients continued double-blind treatment until week 12 to monitor for adverse effects, laboratory analysis, and manic symptoms. Study registry: NCT03310593. RESULTS: A total of 35 participants were included. MADRS scores significantly decreased from baseline to the endpoint (placebo, -14.56; cannabidiol, -15.38), but there was no significant difference between the groups. Similarly, there were no other significant effects on the secondary outcomes. However, an exploratory analysis showed a significant effect of cannabidiol 300 mg/day in reducing MADRS scores from week 2 to week 8 (placebo, -6.64; cannabidiol, -13.72). There were no significant differences in the development of manic symptoms or any other adverse effects. CONCLUSION: Cannabidiol did not show significantly higher adverse effects than placebo. Despite the negative finding on the primary outcome, an exploratory analysis suggested that cannabidiol should be further studied in bipolar depression in higher doses of at least 300 mg/day and under research designs that could better control for high placebo response.

Inflammatory and oxidative stress markers in post-traumatic stress disorder: a systematic review and meta-analysis.

Post-traumatic stress disorder (PTSD) has been associated with persistent, low-degree inflammation, which could explain the increased prevalence of autoimmune conditions and accelerated aging among patients. The aim of the present study is to assess which inflammatory and oxidative stress markers are associated with PTSD. We carried out a meta-analytic and meta-regression analysis based on a systematic review of studies comparing inflammatory and oxidative stress markers between patients with PTSD and controls. We undertook meta-analyses whenever values of inflammatory and oxidative stress markers were available in two or more studies. Overall, 28,008 abstracts were identified, and 54 studies were included, with a total of 8394 participants. The Newcastle-Ottawa Quality Assessment Scale was used to evaluate the quality of the studies. Concentrations of C-reactive protein (SMD = 0.64; 95% CI: 0.21 to 1.06; p = 0.0031; k = 12), interleukin 6 (SMD = 0.94; 95% CI: 0.36 to 1.52; p = 0.0014; k = 32), and tumor necrosis factor-α (SMD = 0.89; 95% CI: 0.23 to 1.55; p = 0.0080; k = 24) were significantly increased in patients with PTSD in comparison with healthy controls. Interleukin 1ß levels almost reached the threshold for significance (SMD = 1.20; 95% CI: -0.04 to 2.44; p = 0.0569; k = 15). No oxidative stress marker was associated with PTSD. These findings may explain why PTSD is associated with accelerated aging and illnesses in which immune activation has a key role, such as cardiovascular diseases and diabetes. In addition, they pointed to the potential role of inflammatory markers as therapeutic targets.

Cariprazine in the treatment of Bipolar Disorder: A systematic review and meta-analysis.

OBJECTIVES: Cariprazine is a partial agonist at D2/D3 receptors that has been approved for the treatment of mania associated with bipolar disorder (BD). This meta-analysis aimed to assess the efficacy and tolerability of cariprazine in the treatment of BD. METHODS: Randomized controlled trials investigating the efficacy of cariprazine in BD were included. Of the 391 studies yielded by search, 7 were included. The PRISMA protocol was followed and a set of analyses involving random-effects model with restricted maximum-likelihood estimator were used to synthesize effect sizes. RESULTS: Cariprazine was associated with a moderate and significant reduction of manic symptoms based on YMRS change scores (SMD: -0.52; 95%CI: -0.82 to -0.21; P = .018). Cariprazine resulted in significantly higher remission (OR: 2.05; 95%CI: 1.61-2.61; P = .006) and response rates (OR: 2.31; 95%CI: 1.35-3.95; P = .021) for manic and mixed episodes compared with placebo. Both cariprazine 1.5 mg and 3 mg doses were associated with small but significant reduction in depressive symptoms assessed with MADRS scores (SMD: -0.26, 95%CI: -0.49 to -0.02; P = .040) (SMD: -0.21, 95%CI: -0.41 to -0.01; P = .045), respectively. Cariprazine was significantly associated with the development of adverse effects but not with dropouts due to these adverse effects, when compared to placebo. CONCLUSION: Cariprazine appears to be safe and efficacious in the treatment of acute mania and mixed episodes associated with BD. Cariprazine at doses of 1.5-3 mg/day is efficacious in acute bipolar depression but the effect sizes were smaller. Controlled studies evaluating its efficacy for prophylaxis are needed.

Cannabidiol as a Treatment for Mood Disorders: A Systematic Review.

OBJECTIVE: To review the current evidence for efficacy of cannabidiol in the treatment of mood disorders. METHODS: We systematically searched PubMed, Embase, Web of Science, PsychInfo, Scielo, ClinicalTrials.gov , and The Cochrane Central Register of Controlled Trials for studies published up to July 31, 2019. The inclusion criteria were clinical trials, observational studies, or case reports evaluating the effect of pure cannabidiol or cannabidiol mixed with other cannabinoids on mood symptoms related to either mood disorders or other health conditions. The review was reported in accordance with guidelines from Preferred Reporting Items for Systematic reviews and Meta-Analyses protocol. RESULTS: Of the 924 records initially yielded by the search, 16 were included in the final sample. Among them, six were clinical studies that used cannabidiol to treat other health conditions but assessed mood symptoms as an additional outcome. Similarly, four tested cannabidiol blended with Δ-9-tetrahydrocannabinol in the treatment of general health conditions and assessed affective symptoms as secondary outcomes. Two were case reports testing cannabidiol. Four studies were observational studies that evaluated the cannabidiol use and its clinical correlates. However, there were no clinical trials investigating the efficacy of cannabidiol, specifically in mood disorders or assessing affective symptoms as the primary outcome. Although some articles point in the direction of benefits of cannabidiol to treat depressive symptoms, the methodology varied in several aspects and the level of evidence is not enough to support its indication as a treatment for mood disorders. CONCLUSIONS: There is a lack of evidence to recommend cannabidiol as a treatment for mood disorders. However, considering the preclinical and clinical evidence related to other diseases, cannabidiol might have a role as a treatment for mood disorders. Therefore, there is an urgent need for well-designed clinical trials investigating the efficacy of cannabidiol in mood disorders.

Early growth response 1 (EGR1) is downregulated in peripheral blood from patients with major psychiatric disorders.

OBJECTIVES: To evaluate relative expression of genes with the potential to translate environmental stimuli into long-term alterations in the brain - namely Early Growth Response (EGR)1, EGR3, and Cryptochrome Circadian Regulator 2 (CRY2) - in peripheral blood from patients with Bipolar Disorder (BD), Schizophrenia (SZ), Major Depressive Disorder (MDD) and healthy controls (HC). METHODS: Thirty individuals ranging from 18 to 60 years were recruited for each group (BD, SZ, MDD or HC) from a Brazilian public hospital. Therefore, individuals' peripheral blood was collected and EGR1, EGR3 and CRY2 gene expression analyzed by PCR Real Time. RESULTS: EGR1 mRNA levels are significantly lower in psychiatric patients when compared to HC, but there is no difference for EGR3 and CRY2. Exploring the findings for each diagnosis, there is a significant difference between each diagnosis group only for EGR1, which was lower in BD, MDD and SZ as compared to HC. No significant correlations were found between gene expression and clinical features. CONCLUSIONS: EGR1 is downregulated in psychiatric patients, regardless of the diagnosis and may be a potential common target in major psychiatric disorders. EGR1, as a transcription factor, modulates many other genes and participates in crucial neuronal and synaptic processes, such as plasticity, neurotransmitters metabolism, vesicular transport and signaling pathways. The study of EGR1 and its upstream regulators in psychiatry might lead to potential new therapeutic targets.

Ketamine study: Protocol for naturalistic prospective multicenter study on subcutaneous ketamine infusion in depressed patients with active suicidal ideation.

Background: Psychiatric disorders are associated with more than 90% of reported suicide attempts worldwide, but few treatments have demonstrated a direct effect in reducing suicide risk. Ketamine, originally an anesthetic, has been shown anti-suicide effects in clinical trials designed to treat depression. However, changes at the biochemical level were assessed only in protocols of ketamine with very limited sample sizes, particularly when the subcutaneous route was considered. In addition, the inflammatory changes associated with ketamine effects and their correlation with response to treatment, dose-effect, and suicide risk warrant further investigation. Therefore, we aimed to assess whether ketamine results in better control of suicidal ideation and/or behavior in patients with depressive episodes and whether ketamine affects psychopathology and inflammatory biomarkers. Materials and methods: We report here the design of a naturalistic prospective multicenter study protocol of ketamine in depressive episodes carried out at Hospital de Clínicas de Porto Alegre (HCPA) and Hospital Moinhos de Vento (HMV). The study was planned to recruit adult patients with Major depressive disorder (MDD) or Bipolar disorder (BD) types 1 or 2, who are currently in a depressive episode and show symptoms of suicidal ideation and/or behavior according to the Columbia-Suicide Severity Rating Scale (C-SSRS) and have been prescribed ketamine by their assistant psychiatrist. Patients receive ketamine subcutaneously (SC) twice a week for 1 month, but the frequency can be changed or the dose decreased according to the assistant physician's decision. After the last ketamine session, patients are followed-up via telephone once a month for up to 6 months. The data will be analyzed using repeated measures statistics to evaluate the reduction in suicide risk as a primary outcome, as per C-SSRS. Discussion: We discuss the need for studies with longer follow-ups designed to measure a direct impact on suicide risk and that additional information about the safety and tolerability of ketamine in particular subset of patients such as those with depression and ideation suicide. In line, the mechanism behind the immunomodulatory effects of ketamine is still poorly understood. Trial registration: https://clinicaltrials.gov/, identifier NCT05249309.

Early intervention for people at high risk of developing bipolar disorder: a systematic review of clinical trials.

Early intervention approaches are built on the premise of preventing disability, burden, and cognitive sequelae caused by bipolar disorder. The objective of this systematic review was to characterise the effectiveness of all the available psychological and pharmacological treatments for early intervention in people at high risk of developing bipolar disorder. The study was registered with PROSPERO (CRD42019133420). We did a systematic search to identify studies published in ten databases up to March 27, 2020. Randomised controlled trials and cohort studies that assessed the effect of pharmacological or psychological interventions in people at high risk of developing bipolar disorder were included. Studies of first episodes of mania were excluded. Eligible papers were assessed for quality and data were extracted. The primary outcomes were change in manic and depressive symptoms from baseline to endpoint. Of the 2856 citations retrieved by our search, 16 studies were included; five evaluated pharmacotherapeutic strategies (three randomised controlled trials and two open-label studies), ten assessed psychotherapeutic strategies (four randomised controlled trials and six open-label studies), and one randomised controlled trial assessed combination therapy; these 16 trials included a total of 755 participants at high risk of developing bipolar disorder. Quality assessment indicated fair to good quality for open-label studies, and a high risk of bias in four randomised controlled trials. Among the pharmacotherapeutic interventions, there is preliminary support for the efficacy of aripiprazole in reducing mood symptoms in people at high risk of developing bipolar disorder. Psychological interventions were effective for various outcomes. There was substantial methodological heterogeneity across studies. This systematic review underscores the need for multicentre, prospective, methodologically homogeneous studies evaluating conversion to bipolar disorder as an outcome measure.

Dopamine release during psychological stress in euthymic bipolar I disorder: a Positron Emission Tomography study with [11C]raclopride.

BACKGROUND: Neurochemical mechanisms underlying stress induced relapse of mood episodes in Bipolar I Disorder (BD) remain unknown. This study investigated whether euthymic BD patients have a greater dopamine release in ventral striatum, caudate and putamen in response to psychological stress using Positron Emission Tomography (PET) scanning with the radiotracer [11C]raclopride. METHODS: Euthymic patients with BD (n = 10) and 10 matched healthy controls underwent two [11C]raclopride PET scans, one during a "stress" and the other in a "no stress" condition separated by at least 24 h. Montreal Imaging Stress Test (MIST) was used to induce stress during stress condition. Participants received an injection of [11C]raclopride over one minute followed by PET scan for 60 min. Participants were assessed for mood symptom severity at baseline, and before and after each scan. The reduction in [11C]raclopride binding in stress condition compared with non-stress rest condition for each subject provided an estimate of dopamine release due to stress. RESULTS: There was a significant effect of stress in reducing the [11C]raclopride binding in the ventral striatum, caudate and putamen; however, no significant effects of group or condition x group interaction were found. LIMITATIONS: Small sample size and recruitment of euthymic patients who may be less vulnerable to stress may limit the generalizability of findings. CONCLUSIONS: Our findings showed that psychological stress led to dopamine release in the basal ganglia for all participants but the magnitude of dopamine release during a stress task was not different between euthymic BD patients and healthy controls.

Remission and recurrence in bipolar disorder: The data from health outcomes and patient evaluations in bipolar disorder (HOPE-BD) study.

BACKGROUND: The HOPE-BD was a naturalistic study established to follow individuals in Canada seeking treatment for bipolar disorder (BD). The study aimed to examine the course of BD and describe how clinical and sociodemographic factors are associated with outcomes. METHODS: Individuals with BD had their clinical data recorded at enrolment and were naturalistically treated. Participant were followed for up to four years, and visits occurred at least once every three months. We investigated the longitudinal outcomes with logistic, Cox, and quantile regressions. RESULTS: Among the 354 participants, 57.3% had BD type I. Depression as first episode, younger ages at onset and older ages of the first professional help predicted longer delays in correct diagnosis. Among the symptomatic patients at baseline, the median time to remission was 10.9 months. Comorbid alcohol use disorder and the severity of baseline depressive symptoms predicted longer times to remission. Among the euthymic participants, the median time to recurrence was 14.5 months. History of anxiety disorder and younger ages at onset predicted shorter times to recurrence. Baseline depression scores predicted recurrence in euthymic patients. LIMITATIONS: We did not investigate the predictors of each polarity. Our findings may not apply to individuals followed in non-specialised outpatient services. CONCLUSION: Our study reinforces the necessity of early diagnosis and interventions, as well as the importance of treating depressive symptoms and comorbidities.

Efficacy and safety of cariprazine in the treatment of bipolar disorder.

Introduction: Cariprazine, a D3-preferring, dopamine D2/D3 partial agonist, has efficacy in treating both acute phases of bipolar I disorder (BD-I). It has been approved by the FDA for treatment of acute manic, mixed and depressive episodes associated with BD-I.Areas covered: In this review, the authors discuss the unique pharmacological properties and clinical efficacy profile of cariprazine, and their relevance in the context of routine clinical decision-making for BD-I. For the purpose of this review, the authors searched for clinical trials in BD published in the PubMed, Web of Science, Embase and PsychInfo databases as well as for studies registered in the ClinicalTrials.gov database.Expert opinion: Based on evidence from RCTs in manic and mixed episodes, cariprazine in a dose-range of 3-12 mg is effective for treating acute mania and mixed states associated with BD-I. Importantly, evidence from placebo-controlled trials in bipolar depression suggests that cariprazine is also effective as a monotherapy in treating acute bipolar depression in doses of 1.5-3 mg/day. It is overall well tolerated; however, clinicians need to monitor patients for akathisia.

The prevalence and clinical correlates of cannabis use and cannabis use disorder among patients with bipolar disorder: A systematic review with meta-analysis and meta-regression.

Bipolar disorder (BD) is commonly associated with comorbidities, especially substance use disorders. In light of this, the present review aimed to investigate the prevalence and clinical correlates of cannabis use in BD. Studies evaluating the prevalence of cannabis use among patients with BD and studies reporting a dichotomous sample of patients with cannabis use compared to those without the use were included. Meta-analyses using random-effects models were performed, and sources of heterogeneity were explored using meta-regression. The search resulted in 2918 publications, of which 53 were included. The prevalence of cannabis use was 24% (95%CI:18-29; k = 35; n = 51,756). Cannabis use was significantly associated with being younger, male, and single; having fewer years of education and an earlier onset of affective symptoms; and lifetime psychotic symptoms, suicide attempts, and use of tobacco, alcohol, and other substances. In conclusion, cannabis use present in almost one-quarter of patients with BD and is associated with factors that are highly relevant for both clinical practice and public health.

Neuron-glia Interaction as a Possible Pathophysiological Mechanism of Bipolar Disorder.

Accumulating evidence has shown the importance of glial cells in the neurobiology of bipolar disorder. Activated microglia and inflammatory cytokines have been pointed out as potential biomarkers of bipolar disorder. Indeed, recent studies have shown that bipolar disorder involves microglial activation in the hippocampus and alterations in peripheral cytokines, suggesting a potential link between neuroinflammation and peripheral toxicity. These abnormalities may also be the biological underpinnings of outcomes related to neuroprogression, such as cognitive impairment and brain changes. Additionally, astrocytes may have a role in the progression of bipolar disorder, as these cells amplify inflammatory response and maintain glutamate homeostasis, preventing excitotoxicity. The present review aims to discuss neuron-glia interactions and their role in the pathophysiology and treatment of bipolar disorder.

On the transdiagnostic nature of peripheral biomarkers in major psychiatric disorders: A systematic review.

The search for biomarkers has been a leading endeavor in biological psychiatry. To analyze its evolution over the years, we performed a systematic review to evaluate (a) the most studied peripheral molecular markers in major psychiatric disorders, (b) the main features of studies proposing them as biomarkers and (c) whether their patterns of variation are similar across disorders. Of the six molecules most commonly studied as plasmatic markers of schizophrenia, major depressive disorder or bipolar disorder, five (BDNF, TNF-alpha, IL-6, C-reactive protein and cortisol) were the same across diagnoses. An analysis of this literature showed that, while 66% of studies compared patients and controls, only 34% were longitudinal, and only 10% presented a measure of diagnostic or prognostic efficacy. Meta-analyses showed variation in the levels of these molecules to be robust across studies, but similar among disorders, suggesting them to reflect transdiagnostic systemic consequences of psychiatric illness. Based on this, we discuss how current publication practices have led to research fragmentation across diagnoses, and suggest approaches to face this issue.

Positive effects of transcranial direct current stimulation in adult patients with attention-deficit/hyperactivity disorder - A pilot randomized controlled study.

Almost 30% of adult patients with attention-deficit/hyperactivity disorder (ADHD) do not respond or tolerate standard pharmacological interventions. Few clinical investigations addressed the efficacy and tolerability of transcranial direct current stimulation (tDCS), a non-invasive neuromodulatory technique, in the disorder. We performed a double-blind, sham-controlled randomized clinical trial in 17 patients with ADHD. The set up for tDCS was the following: 2mA/20min/day for 5 days with the anode over the right dorsolateral prefrontal cortex and cathode over the left dorsolateral prefrontal cortex. ADHD symptoms were measured by the Adult ADHD Self-Report Scale (ASRS) and impairment with the Sheehan Disability Scale (SDS) in four different time points after stimulation. Participants achieved significant lower ASRS inattention and SDS scores after active tDCS in comparison with sham stimulation group. In addition, we detected a trend for a lower ASRS total score in the active tDCS group. Follow up data analysis revealed a positive interaction between time and treatment in both ASRS inattention, SDS and ASRS total scores. Short-term application of tDCS in adult patients with ADHD improved their symptoms, and this improvement persisted after the end of the stimulation. Future studies with larger sample sizes are needed.