Dose response relationship between lithium serum levels during pregnancy and birth outcomes.

INTRODUCTION: Lithium use during pregnancy reduces the risk of mood episodes in the perinatal period for women with bipolar disorder. Some previous studies found deleterious effects of intrauterine lithium exposure on birth outcomes, yet little is known about a dose response relationship. The current study investigated the influence of maternal lithium serum levels on birth outcomes. METHODS: This retrospective observational cohort study included women with a bipolar spectrum disorder who were referred to a specialized psychiatric and obstetric outpatient clinic from 2003 to 2019 and used lithium during the entire pregnancy. For 101 pregnancies at least one lithium level during pregnancy was available. A weighted average lithium level was calculated for the entire pregnancy, as well as for each trimester. Detailed information on maternal, obstetric and neonatal outcomes were retrieved from the medical records. Linear and logistic regression models were used to investigate the association between weighted average lithium level and pregnancy duration, birth weight percentiles, preterm birth and large for gestational age births (LGA). In subsequent exploratory analyses, we studied the role of thyroid-stimulating hormone (TSH) and thyroxine (T4) as a mediator in the found associations. RESULTS: The weighted average lithium serum level during pregnancy was negatively associated with pregnancy duration and positively with preterm birth, but not with birth weight percentile or LGA. In exploratory analyses, TSH and T4 did not mediate the association between average lithium serum level and pregnancy duration. CONCLUSION: The results of this cohort study during pregnancy indicate a dose response relationship between maternal lithium serum levels and pregnancy duration.

Brain development after intrauterine exposure to lithium: A magnetic resonance imaging study in school-age children.

OBJECTIVE: Lithium is often continued during pregnancy to reduce the risk of perinatal mood episodes for women with bipolar disorder. However, little is known about the effect of intrauterine lithium exposure on brain development. The aim of this study was to investigate brain structure in children after intrauterine exposure to lithium. METHODS: Participants were offspring, aged 8-14 years, of women with a diagnosis of bipolar spectrum disorder. In total, 63 children participated in the study: 30 with and 33 without intrauterine exposure to lithium. Global brain volume outcomes and white matter integrity were assessed using structural MRI and diffusion tensor imaging, respectively. Primary outcomes were total brain, cortical and subcortical gray matter, cortical white matter, lateral ventricles, cerebellum, hippocampus and amygdala volumes, cortical thickness, cortical surface area and global fractional anisotropy, and mean diffusivity. To assess how our data compared to the general population, global brain volumes were compared to data from the Generation R study (N = 3243). RESULTS: In our primary analyses, we found no statistically significant associations between intrauterine exposure to lithium and structural brain measures. There was a non-significant trend toward reduced subcortical gray matter volume. Compared to the general population, lithium-exposed children showed reduced subcortical gray and cortical white matter volumes. CONCLUSION: We found no differences in brain structure between lithium-exposed and non-lithium-exposed children aged 8-14 years following correction for multiple testing. While a rare population to study, future and likely multi-site studies with larger datasets are required to validate and extend these initial findings.

Neurodevelopment in school-aged children after intrauterine exposure to antipsychotics.

OBJECTIVE: Antipsychotics are increasingly prescribed in pregnancy, yet little is known about potential long-term developmental effects on children. In this study, we investigated the effect of prenatal antipsychotic exposure on neurodevelopmental functioning in school-aged children. METHODS: We performed a cross-sectional neurodevelopmental assessment of 91 children aged 6-14 years whose mothers had severe mental illness and were either exposed or unexposed to antipsychotic medication during pregnancy. Neurodevelopmental outcomes were assessed using validated neurodevelopmental assessment instruments to examine the child's IQ and global cognitive functioning, and the presence of any psychiatric disorders and/or learning problems in the child was assessed by parental report. RESULTS: No statistically significant associations were found between antipsychotic exposure during pregnancy and either adverse neurodevelopmental outcomes (IQ, neuropsychological function), likelihood of psychiatric diagnosis, or learning problems based on parental report. Analyses were likely limited in power to detect subtler differences in neurodevelopmental functioning because of small sample size and heterogeneity of the sample. CONCLUSIONS: In this exploratory cohort study, intrauterine exposure to antipsychotics was not associated with any adverse effect on IQ or neurodevelopmental functioning in a cohort of school-aged children (6-14 years).

The effect of prenatal lithium exposure on the neuropsychological development of the child.

OBJECTIVES: Lithium is an effective treatment for bipolar disorder, also during pregnancy to prevent the recurrence of episodes in the perinatal period. Little is known about the neuropsychological development of lithium-exposed offspring. The current study was designed to investigate neuropsychological functioning in lithium-exposed children with the aim to provide further knowledge on the long-term effects of lithium use during pregnancy. METHODS: Participants were offspring of women with a diagnosis of bipolar spectrum disorder, aged 6-14 years. In total, 99 children participated in the study, 56 were exposed to lithium in utero and 43 were not exposed to lithium. Neuropsychological tests were administered, including the Snijders-Oomen Nonverbal Intelligence Test and the NEPSY-II-NL assessment. Linear and negative binomial regression models were used to investigate the association between prenatal lithium exposure and neuropsychological functioning. In secondary analyses, the association between lithium blood level during pregnancy and neuropsychological functioning was assessed. Additionally, norm scores and percentiles for task outcomes were calculated. RESULTS: Lithium use during pregnancy was associated with the total number of mistakes made on the Auditory Attention task, but not statistically significant after full adjustment for potential confounding factors. No association between prenatal lithium exposure and IQ was found. Also, no relationship between lithium blood level during pregnancy and neuropsychological functioning was found after adjustment for potential confounders. Task outcomes in both groups were comparable to the general population. CONCLUSION: In this study, we found no evidence for significantly altered neuropsychological functioning of lithium-exposed children at the age of 6-14 years, when compared to non-lithium-exposed controls.

Management of lithium dosing around delivery: An observational study.

OBJECTIVES: Recommendations on lithium dosing around delivery vary, with several guidelines suggesting that lithium should be discontinued prior to delivery. We aimed to evaluate the validity of these recommendations by investigating 1) maternal lithium blood level changes following delivery, and 2) the association between neonatal lithium blood levels at delivery and neonatal outcomes. METHODS: In this retrospective observational cohort study, we included women with at least one lithium blood level measurement during the final week of pregnancy and the first postpartum week. For aim 2, we included a subcohort of women with neonates for whom neonatal lithium blood levels (obtained from the umbilical cord or a neonatal vein puncture within 24 hours of delivery) were available. RESULTS: There were a total of 233 maternal lithium blood level measurements; 55 (23.6%) in the week before delivery and 178 (76.4%) in the week after. There was no association between time and lithium blood level/dose ratio (Pearson correlation coefficient -0.03, P = .63). Additionally, we included a total of 29 neonates for whom a lithium measurement was performed within 24 hours postpartum. Maternal and neonatal lithium blood levels were strongly correlated. We observed no associations between neonatal lithium blood levels at delivery and neonatal outcomes. CONCLUSION: Based on our findings, we do not recommend lowering the dosage or discontinuation of lithium prior to delivery. Stable dosing can prevent subtherapeutic lithium serum levels, which is especially important in the postpartum period when relapse risks are highest.

Long-term neurodevelopmental consequences of intrauterine exposure to lithium and antipsychotics: a systematic review and meta-analysis.

Lithium and antipsychotics are often prescribed to treat bipolar disorder or psychotic disorders in women of childbearing age. Little is known about the consequences of these medications during pregnancy for the developing child. The objective of this article is to systematically review findings from preclinical and clinical studies that have examined the neurodevelopmental consequences of intrauterine exposure to lithium and antipsychotics. A systematic search was performed in Embase, Medline, Web of Science, PsychINFO, Cochrane, and Google Scholar. Clinical and experimental studies were selected if they investigated neurodevelopment of offspring exposed to lithium or antipsychotics during gestation. Quality of clinical and preclinical studies was assessed by the Newcastle-Ottawa Scale and the SYRCLE's risk of Bias tool, respectively. In total, 73 studies were selected for qualitative synthesis and three studies were selected for quantitative synthesis. Of preclinical studies, 93% found one or more adverse effects of prenatal exposure to antipsychotics or lithium on neurodevelopment or behaviour. Only three clinical cohort studies have investigated the consequences of lithium exposure, all of which reported normal development. In 66% of clinical studies regarding antipsychotic exposure, a transient delay in neurodevelopment was observed. The relative risk for neuromotor deficits after in utero exposure to antipsychotics was estimated to be 1.63 (95% CI 1.22-2.19; I2 = 0%). Preclinical studies suggest long-term adverse neurodevelopmental consequences of intrauterine exposure to either lithium or antipsychotics. However, there is a lack of high-quality clinical studies. Interpretation is difficult, since most studies have compared exposed children with their peers from the unaffected population, which did not allow correction for potential influences regarding genetic predisposition or parental psychiatric illness.

Management of Lithium Dosing Around Delivery: An Observational Study.

Objectives: Recommendations on lithium dosing around delivery vary, with several guidelines suggesting that lithium should be discontinued prior to delivery. We aimed to evaluate the validity of these recommendations by investigating 1) maternal lithium blood level changes following delivery, and 2) the association between neonatal lithium blood levels at delivery and neonatal outcomes. Methods: In this retrospective observational cohort study, we included women with at least one lithium blood level measurement during the final week of pregnancy and the first postpartum week. For aim 2, we included a subcohort of women with neonates for whom neonatal lithium blood levels (obtained from the umbilical cord or a neonatal vein puncture within 24 hours of delivery) were available. Results: There were a total of 233 maternal lithium blood level measurements; 55 (23.6%) in the week before delivery and 178 (76.4%) in the week after. There was no association between time and lithium blood level/dose ratio (Pearson correlation coefficient -0.03, P = .63). Additionally, we included a total of 29 neonates for whom a lithium measurement was performed within 24 hours postpartum. Maternal and neonatal lithium blood levels were strongly correlated. We observed no associations between neonatal lithium blood levels at delivery and neonatal outcomes. Conclusion: Based on our findings, we do not recommend lowering the dosage or discontinuation of lithium prior to delivery. Stable dosing can prevent subtherapeutic lithium serum levels, which is especially important in the postpartum period when relapse risks are highest.Appeared originally in Bipolar Disord 2021; 23:49-54.

Linked patterns of symptoms and cognitive covariation with functional brain controllability in major depressive disorder.

BACKGROUND: Controllability analysis is an approach developed for evaluating the ability of a brain region to modulate function in other regions, which has been found to be altered in major depressive disorder (MDD). Both depressive symptoms and cognitive impairments are prominent features of MDD, but the case-control differences of controllability between MDD and controls can not fully interpret the contribution of both clinical symptoms and cognition to brain controllability and linked patterns among them in MDD. METHODS: Sparse canonical correlation analysis was used to investigate the associations between resting-state functional brain controllability at the network level and clinical symptoms and cognition in 99 first-episode medication-naïve patients with MDD. FINDINGS: Average controllability was significantly correlated with clinical features. The average controllability of the dorsal attention network (DAN) and visual network had the highest correlations with clinical variables. Among clinical variables, depressed mood, suicidal ideation and behaviour, impaired work and activities, and gastrointestinal symptoms were significantly negatively associated with average controllability, and reduced cognitive flexibility was associated with reduced average controllability. INTERPRETATION: These findings highlight the importance of brain regions in modulating activity across brain networks in MDD, given their associations with symptoms and cognitive impairments observed in our study. Disrupted control of brain reconfiguration of DAN and visual network during their state transitions may represent a core brain mechanism for the behavioural impairments observed in MDD. FUNDING: National Natural Science Foundation of China (82001795 and 82027808), National Key R&D Program (2022YFC2009900), and Sichuan Science and Technology Program (2024NSFSC0653).

The impact of pregnancy on the pharmacokinetics of antiseizure medications: A systematic review and meta-analysis of data from 674 pregnancies.

OBJECTIVE: Increasing evidence suggests that the physiological changes of pregnancy may impact pharmacokinetics of antiseizure medications (ASM), and this may affect treatment outcomes. The aim of this study was to quantify the pregnancy impact on the ASM pharmacokinetics. METHODS: A systematic literature search was conducted in PubMed/EMBASE in November 2022 and updated in August 2023 for studies comparing levels of ASM in the same individuals during pregnancy and in the preconception/postpartum period. Alteration ratios between the 3rd trimester and baseline were estimated. We also performed a random-effects meta-analysis calculating between-timepoint differences in mean differences (MDs) and 95% confidence intervals (95%CIs) for dose-adjusted plasma concentrations (C/D ratios). Study quality was assessed using the ClinPK guidelines. RESULTS: A total of 65 studies investigating 15 ASMs in 674 pregnancies were included. The largest differences were reported for lamotrigine, oxcarbazepine and levetiracetam (alteration ratio 0.42, range 0.07-2.45, 0.42, range 0.08-0.82 and 0.52, range 0.04-2.77 respectively): accordingly, C/D levels were lower in the 3rd trimester for lamotrigine, levetiracetam and the main oxcarbazepine metabolite monohydroxycarbazepine (MD = -12.33 × 10-3, 95%CI = -16.08 to -8.58 × 10-3 (µg/mL)/(mg/day), p < 0.001, MD = -7.16 (µg/mL)/(mg/day), 95%CI = -9.96 to -4.36, p < 0.001, and MD = -4.87 (µg/mL)/(mg/day), 95%CI = -9.39 to -0.35, p = 0.035, respectively), but not for oxcarbazepine (MD = 1.16 × 10-3 (µg/mL)/(mg/day), 95%CI = -2.55 to 0.24 × 10-3, p = 0.10). The quality of studies was acceptable with an average rating score of 11.5. CONCLUSIONS: Data for lamotrigine, oxcarbazepine (and monohydroxycarbazepine) and levetiracetam demonstrate major changes in pharmacokinetics during pregnancy, suggesting the importance of therapeutic drug monitoring to assist clinicians in optimizing treatment outcomes.

Bipolar episodes after reproductive events in women with bipolar I disorder, A study of 919 pregnancies.

BACKGROUND: Women with bipolar I disorder are at high risk for severe episodes after childbirth, but there is no study that provides an overview on bipolar episode risk both during pregnancy and after childbirth, miscarriage and induced abortion. The aim of this study was to determine the episode risk during all pregnancy outcomes subdivided by first and subsequent pregnancies. METHODS: Participants were 436 women with bipolar I disorder from the Dutch Bipolar Cohort, having 919 pregnancies of which 762 resulted in a live childbirth, 118 ended in a miscarriage and 39 ended in induced abortion. Women reported on the occurrence of manic or depressed episodes during the perinatal period. Information about medication use was obtained by questionnaires. RESULTS: Episode risk was 5.2% during pregnancy, and 30.1% in the postpartum period, with a peak in the early postpartum period. Risk of an episode was highest after live birth (34.4%), and lower after miscarriage (15.2%) and induced abortion (27.8%). Women with an episode during pregnancy or postpartum were less likely to have a second child compared to women with an uneventful first pregnancy (cOR=0.34; 95%CI: 0.22-0.51; p<0.001); if they had a second child their risk of an episode was significantly elevated with a subsequent pregnancy (cOR=6.17; 95%CI: 3.64-10.45; p<0.001). LIMITATIONS: Retrospective cross-sectional design with assessment (partial) through self-report in a homogeneous population. CONCLUSIONS: Women with bipolar I disorder have a six times higher risk of an episode after delivery compared to during pregnancy, therefore preventive strategies are particularly important immediately after delivery.

Lithium Use during Pregnancy and the Risk of Miscarriage.

Recent studies have provided new data on the teratogenicity of lithium. Less is known about the risk of miscarriage after lithium use during pregnancy. The aim of this study was to investigate the association between lithium use during pregnancy and miscarriage. Participants were women with bipolar I disorder and one or more pregnancies, of which information on medication use and pregnancy outcome was available (n = 443). The unadjusted odds ratios for miscarriage after lithium use during pregnancy was calculated. Multilevel logistic regression was used to calculate the odds ratio, adjusted for the age at conception and the clustering of pregnancies per woman. Miscarriages occurred in 20.8% of the lithium-exposed pregnancies (16/77), compared with 10.9% of the unexposed pregnancies (40/366) (OR = 2.14; 95% CI: 1.13-4.06). The adjusted odds ratio of miscarriage after lithium use during pregnancy was 2.94 (95% CI: 1.39-6.22). Lithium use during pregnancy may increase the risk of miscarriage.

Lithium during pregnancy and after delivery: a review.

Lithium is an effective treatment in pregnancy and postpartum for the prevention of relapse in bipolar disorder. However, lithium has also been associated with risks during pregnancy for both the mother and the unborn child. Recent large studies have confirmed the association between first trimester lithium exposure and an increased risk of congenital malformations. Importantly, the risk estimates from these studies are lower than previously reported. Tapering of lithium during the first trimester could be considered but should be weighed against the risks of relapse. There seems to be no association between lithium use and pregnancy or delivery related outcomes, but more research is needed to be more conclusive. When lithium is prescribed during pregnancy, lithium blood levels should be monitored more frequently than outside of pregnancy and preferably weekly in the third trimester. We recommend a high-resolution ultrasound with fetal anomaly scanning at 20 weeks. Ideally, delivery should take place in a specialised hospital where psychiatric and obstetric care for the mother is provided and neonatal evaluation and monitoring of the child can take place immediately after birth. When lithium is discontinued during pregnancy, lithium could be restarted immediately after delivery as strategy for relapse prevention postpartum. Given the very high risk of relapse in the postpartum period, a high target therapeutic lithium level is recommended. Most clinical guidelines discourage breastfeeding in women treated with lithium. It is highly important that clinicians inform and advise women about the risks and benefits of remaining on lithium in pregnancy, if possible preconceptionally. In this narrative review we provide an up-to-date overview of the literature on lithium use during pregnancy and after delivery leading to clinical recommendations.

Glutamatergic abnormalities in schizophrenia: a review of proton MRS findings.

The last fifteen years have seen a great increase in our understanding of the role of glutamate in schizophrenia (SCZ). The glutamate hypothesis focuses on disturbances in brain glutamatergic pathways and impairment in signaling at glutamate receptors. Proton Magnetic Resonance Spectroscopy ((1)H-MRS) is an MR-based technique that affords investigators the ability to study glutamate function by measuring in vivo glutamatergic indices in the brains of individuals with SCZ. (1)H-MRS studies have been performed comparing glutamatergic levels of individuals with SCZ and healthy control subjects or studying the effect of antipsychotic medications on glutamatergic levels. In this article we summarize the results of these studies by brain region. We will review the contribution of (1)H-MRS studies to our knowledge about glutamatergic abnormalities in the brains of individuals with SCZ and discuss the implications for future research and clinical care.

In vivo binding of the dopamine-1 receptor PET tracers [¹¹C]NNC112 and [¹¹C]SCH23390: a comparison study in individuals with schizophrenia.

RATIONALE: A deficit in dopamine-1 (D1) receptor function in the prefrontal cortex is suggested to play a role in the cognitive dysfunction observed in patients with schizophrenia. However, the results from positron emission tomography imaging studies of D1 receptor levels in individuals with schizophrenia are mixed. OBJECTIVES: The aim of this investigation was to determine whether the in vivo characteristics of the different D1 receptor tracers used in previous reports, [(11)C]SCH23390 and [(11)C]NNC112, may have contributed to these discrepancies reported in the literature. METHODS: Eight patients with schizophrenia and 12 healthy control subjects were scanned with both [(11)C]SCH23390 and [(11)C]NNC112. RESULTS: [(11)C]SCH23390 and [(11)C]NNC112 binding potentials in both patients and control subjects were compared and no tracer by diagnosis interactions were observed. CONCLUSIONS: The results of this study suggest that differences in the binding of [(11)C]SCH23390 and [(11)C]NNC112 observed in previous studies are not due to differences in the in vivo behavior of these tracers.