International Journal of Bipolar Disorders最新文献

Background: Neonatal effects of late intrauterine and early postpartum exposure to lithium through mother's own milk are scarcely studied. It is unclear whether described symptoms in breastfed neonates are caused by placental lithium transfer or postnatal exposure to lithium through breastfeeding. We aimed to investigate lithium clearance and neonatal morbidity in breastfed infants with high versus low serum lithium concentrations at birth.

Methods: This retrospective study focused on breastfed infants to women treated with lithium during and after pregnancy, born between 2006 and 2021 in Stockholm, Sweden. Information on serum lithium concentrations and adverse neonatal outcomes was obtained from medical records. Neonatal symptoms and lithium clearance were compared between a high exposure group (HEG, lithium concentrations ≥ 0.6 meq/l) and a low exposure group (LEG, < 0.6 meq/l).

Results: A total of 25 infant-mother dyads were included. Median lithium serum concentration at birth was 0.90 meq/l in the HEG as compared with 0.40 meq/l in the LEG (p < 0.05). The difference was still significant at follow-up (0.20 meq/l vs 0.06 meq/l, p < 0.05), despite reduction in maternal dose. The rate of neonatal symptoms was 85.7% in HEG and 41.2% in LEG (p = 0.08) at birth and 28.6% vs 11.8% at follow-up (p = 0.55). Furthermore, 28.6% of infants in HEG were admitted to neonatal care, vs 5.9% in LEG (p = 0.19). Two infants in the HEG had therapeutic lithium levels at follow-up. All infants with symptoms at follow-up were either in the HEG or exposed to additional psychotropic medication.

Conclusions: Neonatal symptoms are common after late intrauterine lithium exposure, however transient, treatable and mostly mild. In this study, a high lithium concentration at birth was a risk factor for an increased lithium level at follow-up. Polypharmacy may constitute an additional risk factor. This study suggests that the late intrauterine exposure to lithium might add to the adverse effects in lithium-exposed, breastfed infants. Consequently we recommend breastfed infants with therapeutic lithium concentrations at birth to be followed up promptly to avoid lithium toxicity.

For over half a century, it has been widely known that lithium is the most efficacious maintenance treatment for bipolar disorder. Despite thorough research on the long-term effects of lithium on renal function, a number of important questions relevant to clinical practice remain. The risk of polyuria, reflecting renal tubular dysfunction, is seen in a substantial proportion of patients treated with long term lithium therapy. The duration of lithium may be the most important risk factor for lithium-induced polyuria. Most, but not all, studies find that lithium is associated with higher rates of chronic kidney disease compared to either age matched controls or patients treated with other mood stabilizers. Age, duration of lithium therapy and medical disorders such as hypertension and diabetes mellitus are risk factors for chronic kidney disease in lithium-treated patients. The relationship between polyuria and chronic kidney disease is inconsistent but poorly studied. Although not all studies agree, it is likely that lithium may increase the risk for end stage renal disease but in a very small proportion of treated patients. Patients whose renal function is relatively preserved will show either no progression or improvement of renal function after lithium discontinuation. In contrast, patients with more renal damage frequently show continued deterioration of renal function even after lithium discontinuation. Optimal management of lithium treatment requires obtaining a baseline measure of renal function (typically estimated glomerular filtration rate [eGFR]) and regular monitoring of eGFR during treatment. Should the eGFR fall rapidly or below 60 ml/minute, patients should consider a consultation with a nephrologist. A decision as to whether lithium should be discontinued due to progressive renal insufficiency should be made using a risk/benefit analysis that takes into account other potential etiologies of renal dysfunction, current renal function, and the efficacy of lithium in that individual patient.

Background: The impact of long-term lithium treatment on weight gain has been a controversial topic with conflicting evidence. We aim to assess reporting of weight gain associated with lithium and other mood stabilizers compared to lamotrigine which is considered free of metabolic adverse drug reactions (ADRs).

Methods: We conducted a case/non-case pharmacovigilance study using data from the AMSP project (German: "Arzneimittelsicherheit in der Psychiatrie"; i.e., Drug Safety in Psychiatry), which collects data on ADRs from patients treated in psychiatric hospitals in Germany, Austria, and Switzerland. We performed a disproportionality analysis of reports of weight gain (> 10% of baseline body weight) calculating reporting odds ratio (ROR). We compared aripiprazole, carbamazepine, lithium, olanzapine, quetiapine, risperidone, and valproate to lamotrigine. Additional analyses related to different mood stabilizers as reference medication were performed. We also assessed sex and age distributions of weight-gain reports.

Results: We identified a total of 527 cases of severe drug-induced weight gain representing 7.4% of all severe ADRs. The ROR for lithium was 2.1 (95%CI 0.9-5.1, p > 0.05), which did not reach statistical significance. Statistically significant disproportionate reporting of weight gain was reported for olanzapine (ROR: 11.5, 95%CI 4.7-28.3, p < 0.001), quetiapine (ROR: 3.4, 95%CI 1.3-8.4, p < 0.01), and valproate (ROR: 2.4, 95%CI 1.1-5.0, p = 0.03) compared to lamotrigine. Severe weight gain was more prevalent in non-elderly (< 65 years) than in elderly patients, with an ROR of 7.6 (p < 0.01) in those treated with lithium, and an ROR of 14.7 (p < 0.01) in those not treated with lithium.

Conclusions: Our findings suggest that lithium is associated with more reports of severe weight gain than lamotrigine, although this difference did not reach statistical significance. However, lithium use led to fewer reports of severe weight gain than some alternative drugs for long-term medication (olanzapine, quetiapine, and valproate), which is consistent with recent studies. Monitoring of weight gain and metabolic parameters remains essential with lithium and its alternatives.

Background: The differential diagnosis of patients presenting for the first time with a depressive episode into unipolar disorder versus bipolar disorder is crucial to establish the correct pharmacological therapy (antidepressants vs mood stabilizers), but no biological markers are currently available. Several lines of evidence indicate an involvement of Glycogen Synthase Kinase-3 (GSK3) in the pathophysiology of depression. However, previous reports about GSK3 in peripheral blood were incomplete or inconsistent, so a specific marker is not yet available. The aim was to search for consistent differences in GSK3α and GSK3β or of their phosphorylated forms in samples of peripheral blood from patients with unipolar and bipolar depression.

Methods: Mononucleate peripheral blood cells (PBMCs) of samples from patients presenting with a depressive episode were analyzed with the western blot technique.

Results: The total amount of GSK3β in PBMCs was significantly lower in patients with bipolar disorder than in patients with unipolar depression. The sensitivity based on GSK3β was 85%. GSK3α was not significantly different but allowed a correct detection of 57% of BD patients. The combination in series of GSK3β and GSK3α yields a sensitivity of about 100%, but with 26.7% false negatives.

Conclusions: Our results suggest that PBMC GSK3β could be a candidate biomarker for the differential diagnosis of bipolar disorder versus unipolar depression. This finding may help in implementing the still limited panel of peripheral biomarkers for differential diagnosis between unipolar and bipolar disorder in patients presenting with a depressive episode.

Background: Widely reported by bipolar disorder (BD) patients, cognitive symptoms, including deficits in executive function, memory, attention, and timing are under-studied. Work suggests that individuals with BD show impairments in interval timing tasks, including supra-second, sub-second, and implicit motor timing compared to the neuronormative population. However, how time perception differs within individuals with BD based on disorder sub-type (BDI vs II), depressed mood, or antipsychotic medication-use has not been thoroughly investigated. The present work administered a supra-second interval timing task concurrent with electroencephalography (EEG) to patients with BD and a neuronormative comparison group. As this task is known to elicit frontal theta oscillations, signal from the frontal (Fz) lead was analyzed at rest and during the task.

Results: Results suggest that individuals with BD show impairments in supra-second interval timing and reduced frontal theta power during the task compared to neuronormative controls. However, within BD sub-groups, neither time perception nor frontal theta differed in accordance with BD sub-type, depressed mood, or antipsychotic medication use.

Conclusions: This work suggests that BD sub-type, depressed mood status or antipsychotic medication use does not alter timing profile or frontal theta activity. Together with previous work, these findings point to timing impairments in BD patients across a wide range of modalities and durations indicating that an altered ability to assess the passage of time may be a fundamental cognitive abnormality in BD.

Background: Childhood trauma (CT) are frequently reported by patients with bipolar disorder (BD), but it is unclear whether and how CT contribute to patients' cognitive and psychosocial impairments. We aimed to examine the impact of CT on cognition and psychosocial functioning in a large sample of 345 patients with BD and 183 healthy control participants (HC) using the Childhood Trauma Questionnaire, neurocognitive tests and ratings of mood symptoms and functioning.

Results: Patients showed broad cognitive impairments across memory, attention and executive function and functional disability despite being in partial or full remission and had higher levels of CT than HC. Higher levels of CT correlated with impairments across almost all cognitive domains and lower psychosocial functioning across BD patients and HC. Of these, the associations between CT and poorer working memory and lower psychosocial functioning, respectively, prevailed after adjusting for clinical and demographical variables. Diagnosis of BD and estimated verbal intelligence did not moderate these associations. Analysis of CT sub-categories showed that working memory impairments were related particularly to childhood physical and emotional abuse, while psychosocial difficulties were related to physical and emotional neglect.

Conclusions: CT may have negative implications for working memory and psychosocial functioning across both BD and healthy populations. If the findings are replicated, this would suggest that early interventions that reduce the frequency of CT in vulnerable families may aid children's cognitive and psychosocial development.

For over half a century, it has been widely known that lithium is the most efficacious treatment for bipolar disorder. Yet, despite this, its prescription has consistently declined over this same period of time. A number of reasons for this apparent disparity between evidence and clinical practice have been proposed, including a lack of confidence amongst clinicians possibly because of an absence of training and lack of familiarity with the molecule. Simultaneously, competition has grown within the pharmacological armamentarium for bipolar disorder with newer treatments promoting an image of being safer and easier to prescribe primarily because of not necessitating plasma monitoring, which understandably is appealing to patients who then exercise their preferences accordingly. However, these somewhat incipient agents are yet to reach the standard lithium has attained in terms of its efficacy in providing prophylaxis against the seemingly inevitable recrudescence of acute episodes that punctuates the course of bipolar disorder. In addition, none of these mimics have the additional benefits of preventing suicide and perhaps providing neuroprotection. Thus, a change in strategy is urgently required, wherein myths regarding the supposed difficulties in prescribing lithium and the gravity of its side-effects are resolutely dispelled. It is this cause to which we have pledged our allegiance and it is to this end that we have penned this article.

Background: We tested the hypothesis that, after initial improvement with intravenous ketamine in patients with bipolar disorder (BD) with severe depression and acute suicidal thinking or behavior, a fixed-dose combination of oral D-cycloserine (DCS) and lurasidone (NRX-101) can maintain improvement more effectively than lurasidone alone.

Methods: This was a multi-center, double-blind, twostage, parallel randomized trial. Adult BD patients with depression and suicidal ideation or behavior were infused with ketamine or saline (Stage 1); those who improved were randomized to a fixed-dose combination of DCS and lurasidone vs. lurasidone alone (Stage 2) to maintain the improvement achieved in Stage 1. Depression was measured by the Montgomery Åsberg Depression Rating Scale (MADRS), and suicidal thinking and behavior was measured by the Columbia Suicide Severity Rating Scale (C-SSRS); global improvement was measured by the clinical global severity scale (CGI-S).

Clinicaltrials: gov NCT02974010; Registered: November 22, 2016.

Results: Thirty-seven patients were screened and 22 were enrolled, randomized, and treated. All 22 patients treated in Stage 1 (17 with ketamine and 5 with saline) were enrolled into Stage 2, and 11 completed the study. The fixed-dose combination of DCS and lurasidone was significantly more effective than lurasidone alone in maintaining improvement in depression (MADRS LMS Δ-7.7; p = 0.03) and reducing suicidal ideation, as measured by C-SSRS (Δ-1.5; p = 0.02) and by CGI-SS (Δ-2.9; p = 0.03), and with a non-statistically significant decrease in depressive relapse (0% vs. 40%; p = 0.07). This sequential treatment regimen did not cause any significant safety events and demonstrated improvements in patient-reported side effects.

Conclusions: Sequential treatment of a single infusion of ketamine followed by NRX-101 maintenance is a promising therapeutic approach for reducing depression and suicidal ideation in patients with bipolar depression who require hospitalization due to acute suicidal ideation and behavior. On the basis of these findings, Breakthrough Therapy Designation was awarded, and a Special Protocol Agreement was granted by the FDA for a registrational trial.

Background: Intrusive mental imagery is associated with anxiety and mood instability within bipolar disorder and therefore represents a novel treatment target. Imagery Based Emotion Regulation (IBER) is a brief structured psychological intervention developed to enable people to use the skills required to regulate the emotional impact of these images.

Methods: Participants aged 18 and over with a diagnosis of bipolar disorder and at least a mild level of anxiety were randomly assigned (1:1) to receive IBER plus treatment as usual (IBER + TAU) or treatment as usual alone (TAU). IBER was delivered in up to 12 sessions overs 16 weeks. Clinical and health economic data were collected at baseline, end of treatment and 16-weeks follow-up. Objectives were to inform the recruitment process, timeline and sample size estimate for a definitive trial and to refine trial procedures. We also explored the impact on participant outcomes of anxiety, depression, mania, and mood stability at 16-weeks and 32-weeks follow-up.

Results: Fifty-seven (28: IBER + TAU, 27: TAU) participants from two sites were randomised, with 50 being recruited within the first 12 months. Forty-seven (82%) participants provided outcome data at 16 and 32-weeks follow-up. Thirty-five participants engaged in daily mood monitoring at the 32-week follow-up stage. Retention in IBER treatment was high with 27 (96%) attending ≥ 7 sessions. No study participants experienced a serious adverse event.

Discussion: The feasibility criteria of recruitment, outcome completion, and intervention retention were broadly achieved, indicating that imagery-focused interventions for bipolar disorder are worthy of further investigation.