Lithium in pregnancy: the need to treat, the duty to ensure safety

INTRODUCTION: Untreated bipolar disorder during pregnancy leads to detrimental repercussions on the mother-infant pair's health. Despite different drugs having been proposed as mood stabilizers, lithium remains the first-choice agent for preventing mood changes. AREAS COVERED: Analyzing up-to-date information on the reproductive safety of lithium and providing practice guidelines to optimize its use during pregnancy. EXPERT OPINION: Findings from prospective and case-control studies confirm an increased, specific risk of Ebstein's anomaly (4.45-7.6/1000 live births), although lower than that previously reported. A potential increase in the risk of neural tube defects should also be taken into consideration. Moreover, several perinatal complications may occur, and even in the presence of relatively low infant serum levels, in the case of drug exposure during late pregnancy. Despite such concerns, lithium should still be considered the first-choice agent for treating bipolar disorder in pregnancy. Indeed, the U.S. FDA recently issued a new warning regarding the reproductive safety of antipsychotics. Moreover, the risk of fetal valproate/carbamazepine syndrome (and the confirmed neurodevelopmental teratogenicity of valproate) contraindicates the use of both medications, whereas the use of lamotrigine is limited by efficacy concerns. However, women who need lithium treatment during pregnancy should be carefully monitored: a strict gynecologic and psychiatric surveillance and, probably, preconception folate supplementation is highly advisable. Moreover, delivery should be programmed in Neonatal Intensive Care Units to ensure optimal management of potential iatrogenic perinatal complications.     

Pharmacotherapy for the peripartum management of bipolar disorder

ABSTRACT

Introduction: The peripartum period in bipolar disorder (BD) patients is associated with high risk of relapse. Relapse during this period may affect fetal and child development. The consequences of psychotropic medication during pregnancy are also a major concern. The extent to which mood stabilizers may potentially affect the embryogenesis or the child development varies from high (e.g. valproate) to less clear and more debated (e.g. lithium).

Areas covered: This review describes the current state of evidence with respect to the impact of recommended pharmacological interventions for BD during the peripartum period. It compares recent international treatment guidelines for the management of BD during the peripartum period. Last, this review presents a summary of key recommendations for BD women of childbearing age, for BD women during pregnancy and postpartum period from the international guidelines.

Expert opinion: Management of the pharmacological treatment for BD patients during the perinatal period is challenging. Although treatment guidelines may be of significant help, high heterogeneity exists across them. Shared decision-making represents a useful patient-centered approach during the perinatal period. Large cohort studies are needed to better identify risk associated to treatment discontinuation or treatment exposure.     

Combination of aripiprazole with mood stabilizers for the treatment of bipolar disorder: from acute mania to long-term maintenance

Introduction: Bipolar disorder is characterized by a complex set of symptoms, including recurrent manic, depressive or mixed episodes. Acute and long-term treatment of patients with bipolar disorder is mandatory to prevent symptom relapse and episode recurrences. Outcomes with monotherapy are often unsatisfactory in clinical practice, hence combinations of mood stabilizers and antipsychotics are widely utilized in patients showing no or partial response to, as well as intolerance to, monotherapies. This may offer a therapeutic advantage, however, the possibility of an increased incidence of side effects should be considered.

Areas covered: This paper reviews the current treatment guidelines for the treatment of bipolar disorder and examines the rationale behind the use of aripiprazole in combination with mood stabilizers for acute and long-term treatment of bipolar disorder.

Expert opinion: The combination of aripiprazole and mood stabilizers seems to offer an effective and relatively well-tolerated option for the treatment of acute mania and for the maintenance treatment of patients with bipolar I disorder. The combination presents a lower risk of metabolic side effects compared with other combination therapies, but increases the risk of extrapyramidal side effects with long-term treatment. The aripiprazole–valproate combination seems to be particularly promising in the treatment of patients with comorbidities such as anxiety and drug abuse, obsessive-compulsive disorder and bipolar disorder, as well as in mixed depressive disorder. Controlled trials are necessary in order to confirm these observations and to provide a useful insight for improving the use of drug combinations in bipolar patients.     

Pharmacotherapy of mood disorders and psychosis in pre- and post-natal women

Introduction: Untreated mood and psychotic disorders can have substantial adverse impacts on the patient, the fetus and the family, while treatment can ameliorate such problems. To address concerns by clinicians about the risks of psychotropic medications, this review addresses the risk/benefit analysis of somatic therapies for psychiatric disorders during pregnancy and lactation.

Areas covered: All available research was reviewed on the impact on pregnancy and breastfeeding of mood and psychotic disorders, and of antidepressants, mood stabilizers, antipsychotic drugs, and electroconvulsive therapy. References cited in other reviews, case series, formal studies, pharmacologic discussions, and theoretical pieces were added. Available case control and other studies were critically reviewed and diverse explanations for their findings were considered.

Expert opinion: The potential benefits of treatment of mood and psychotic disorders often outweigh the risks after alternative therapies have been considered. Some medications, particularly paroxetine and valproate, pose greater risks during pregnancy, while the teratogenic risks of lithium have probably been overstated. There is more experience with first than with second generation antipsychotic drugs during pregnancy and lactation. Nursing an infant is possible while taking a number of antidepressants, mood stabilizers or antipsychotic drugs.     

The pharmacology of bipolar disorder during pregnancy and breastfeeding

Treating bipolar disorder in women during reproduction presents a significant challenge to the physician. The pharmaceutical agents most commonly used for treating bipolar disorder have been associated with adverse effects when used during pregnancy and breastfeeding. Of particular concern has been the association of lithium with cardiac malformations, and the association of carbamazepine and valproate with neural tube defects including spina bifida. Toxicity in neonates has also been reported for the most commonly used mood-stabilising agents. Treatment options for mood stabilisation are either associated with risks of adverse events, have been used less frequently and their associated risks are unknown, or may not provide effective prophylaxis against recurrences of bipolar episodes. However, strategies are available that minimise the risk to the fetus and infant whilst still providing effective prophylaxis against bipolar disorder in the mother. Ideally, a treatment regimen tailored to suit the individual should consider both mother and baby and should be planned prior to conception.     

The pharmacology of bipolar disorder during pregnancy and breastfeeding

Treating bipolar disorder in women during reproduction presents a significant challenge to the physician. The pharmaceutical agents most commonly used for treating bipolar disorder have been associated with adverse effects when used during pregnancy and breastfeeding. Of particular concern has been the association of lithium with cardiac malformations, and the association of carbamazepine and valproate with neural tube defects including spina bifida. Toxicity in neonates has also been reported for the most commonly used mood-stabilising agents. Treatment options for mood stabilisation are either associated with risks of adverse advents, have been used less frequently and their associated risks are unknown, or may not provide effective prophylaxis against recurrences of bipolar episodes. However, strategies are available that minimise the risk to the fetus and infant whilst still providing effective prophylaxis against bipolar disorder in the mother. Ideally, a treatment regimen tailored to suit the individual should consider both mother and baby and should be planned prior to conception.     

Use of asenapine as add-on therapy in the treatment of bipolar disorder: a comprehensive review and case series

Introduction: Several randomized controlled trials (RCTs), conducted in schizophrenic and bipolar patients, have documented the efficacy and tolerability of asenapine as monotherapy both for short- and long-term treatment. However, evidence on its augmentative use is more limited and related to the manic/mixed phase of bipolar disorder (BD).

Areas covered: The present article reviews augmentative asenapine efficacy and safety/tolerability in the treatment of BD. It also includes some original cases of bipolar patients treated with add-on asenapine in the short- and long-term.

Expert opinion: To date, only a single RCT with manic/mixed patients with partial response to mood-stabilizer monotherapy supports the efficacy and safety/tolerability of augmentative asenapine to lithium/valproate, both in acute and long-term treatment. Additionally, two case reports confirm the overall effectiveness of augmentative asenapine to clozapine and valproate. Our case series, consisting of 4 bipolar patients treated with adjunctive asenapine to mood stabilizers and atypical antipsychotics – with treatment duration ranging from 1 to 14 months – provided clinical results that are consistent with literature data. Taken as a whole, available evidence seems to support the efficacy and safety of adjunctive asenapine in bipolar patients, though additional studies with active comparators are requested to confirm the current body of evidence.     

Evaluating lurasidone as a treatment option for bipolar disorder

ABSTRACT

Introduction: Lurasidone has been approved in the United States as a monotherapy and adjunct for acute bipolar I depression, as well as an antipsychotic for patients with schizophrenia.

Areas covered: Herein, the authors review the pharmacodynamics and pharmacokinetics of lurasidone as well and the major randomized clinical trials. The authors also provide their expert opinion.

Expert opinion: Lurasidone has not been studied in patients with mania or bipolar psychosis. It has been studied, both as a monotherapy and adjunctive treatment to lithium or valproate, in acute depression and in prevention of recurrence of any mood episode in patients with bipolar disorder initially treated for bipolar depression or mania. It is approved in the United States for acute bipolar I depression. It has clinically meaningful treatment effect sizes for improvement in depression compared to placebo (0.51 monotherapy, 0.34 adjunct). The number needed to treat (NNT) for response with monotherapy was 5 (for both lower and higher dose groups), and for remission was 6 and 7 (for lower dose and higher dose groups, respectively); the NNT for adjunctive therapy was 7. It has not demonstrated efficacy in relapse prevention when added to a mood stabilizer but is safe in combination with other medications.     

The safety of medications for the treatment of bipolar disorder during pregnancy and the puerperium

Risks associated with pharmacological treatment of bipolar disorder are heightened during reproductive events. Treatments need to be planned with the mutual agreement of both the treating physician and the patient and tailored to the needs of the individual so as to minimise risk while providing adequate treatment. Conventional treatments have all been associated with teratogeny in first trimester exposure, lithium with cardiac malformation and valproate and carbamazepine with neural tube malformations. There have been an insufficient number of first trimester exposures to the newer anticonvulsant mood stabilisers, lamotrigine and oxcarbazepine, to determine whether there is a safety advantage in switching to these agents. Increasingly, atypical antipsychotics are being suggested as useful agents for the treatment of bipolar disorder. While not known to be teratogenic, there are other reproductive safety concerns associated with these agents. Bipolar disorder patients may be prescribed antidepressants, and many of these agents are associated with a low safety risk during reproductive events, however data regarding use of these agents are currently equivocal. Adverse outcomes from inadequate pharmacological prophylaxis have been documented for both the mother and the baby. Risks and benefits need to be carefully balanced based on an accurate review of the evidence.     

Sleep- and circadian rhythm–associated pathways as therapeutic targets in bipolar disorder

Introduction: Disruptions in sleep and circadian rhythms are observed in individuals with bipolar disorders (BD), both during acute mood episodes and remission. Such abnormalities may relate to dysfunction of the molecular circadian clock and could offer a target for new drugs.

Areas covered: This review focuses on clinical, actigraphic, biochemical and genetic biomarkers of BDs, as well as animal and cellular models, and highlights that sleep and circadian rhythm disturbances are closely linked to the susceptibility to BDs and vulnerability to mood relapses. As lithium is likely to act as a synchronizer and stabilizer of circadian rhythms, we will review pharmacogenetic studies testing circadian gene polymorphisms and prophylactic response to lithium. Interventions such as sleep deprivation, light therapy and psychological therapies may also target sleep and circadian disruptions in BDs efficiently for treatment and prevention of bipolar depression.

Expert opinion: We suggest that future research should clarify the associations between sleep and circadian rhythm disturbances and alterations of the molecular clock in order to identify critical targets within the circadian pathway. The investigation of such targets using human cellular models or animal models combined with ‘omics’ approaches are crucial steps for new drug development.     

Polytherapy in bipolar disorder

Bipolar disorder is a life-long condition that is associated with frequent recurrence/relapse of symptoms. Although putative mood stabilisers, such as lithium, are considered to improve the natural course of bipolar disorder, complete long-term remission is rarely achieved. In order to effectively control mood symptoms and to reduce relapse, clinicians often use polypharmacy to treat patients with bipolar disorder. In this article, we examine the recent literature on treatment strategies in bipolar disorder to determine if combination treatments provide additional benefit over monotherapy for the management of various phases of bipolar disorder. The evidence suggests that for acute mania a combination of lithium or valproate and an atypical antipsychotic is the most effective approach, with approximately 20% more patients responding to the combination than to monotherapy with any antimanic agent. Few studies have examined the use of combination therapy in comparison to monotherapy for bipolar depression. The limited evidence suggests that lithium plus an antidepressant appears to be more effective than lithium alone in those with lower serum lithium concentrations. Similarly, the combination of olanzapine plus fluoxetine is more effective than olanzapine alone. There is consensus that antidepressant monotherapy is not appropriate because of concerns of a manic switch, but monotherapy with lithium or lamotrigine may be adequate for mild to moderate bipolar depression. For maintenance treatment, commonly used agents, such as lithium, valproate or olanzapine appear to be most effective in preventing manic relapses, whereas lamotrigine is more effective in preventing depressive relapses. As a result of these findings, it makes intuitive sense to combine lamotrigine with lithium, valproate or an atypical antipsychotic to achieve better mood stability. However, the efficacy and safety of such combinations have not been systematically compared with monotherapy. Preliminary studies suggest that lithium plus valproate may be more effective than lithium alone in preventing affective relapses. Similarly, the combination of lithium or valproate plus olanzapine seems to be more effective than monotherapy with a mood stabiliser in preventing manic episodes.     

The effects of lithium, valproic acid, and carbamazepine during pregnancy and lactation

The chronic, complex, and episodic course of bipolar mood disorder presents a particularly formidable challenge to the clinician making a treatment plan for the onset or recurrence of the illness during pregnancy and lactation. Women treated with anti-manic drugs who become pregnant are commonly considered to be at high risk for fetal complications during the pregnancy or during lactation. The risks of antimanic drug use during pregnancy include teratogenic effects, direct neonatal toxicity, and the potential for longer-term neurobehavioral sequela. The use of medications during pregnancy and lactation requires critical attention to the timing of exposure, dosage, duration of use, and fetal susceptibility. The postnatal period is a time of increased onset and relapse of mental illness. No antimanic drug can be proven completely safe. Prescribing antimanic medications with a long safety record, avoiding exposure in the first trimester; avoiding multidrug regimens, and prescribing the lowest dose for the shortest duration will minimize the fetal risk. This review considers treatment with lithium, valproic acid, and carbamazepine. It assesses the risk to the fetus, the perinatal risks for the infant, the risks associated with treatment during the puerperium and breast-feeding, and the risks to the later development of the child.     

Avoiding drug-induced switching in patients with bipolar depression.

Antidepressant-induced switching is a major risk during the treatment of bipolar depression. Despite several clinical studies, questions remain regarding both the definition of these mood switches and the most appropriate therapeutic strategy to avoid this adverse effect.This review will first briefly consider the current guidelines for the acute treatment of bipolar depression. We will then review the mechanisms of action of antidepressant and mood stabilisers, and the switches induced by various types of antidepressant treatments, or triggered by antidepressant withdrawal, as well as by atypical antipsychotics. We then will address the risk of mood switch according to the type of mood stabiliser used. The propensity to mood switches in bipolar patients is subject to individual differences. Therefore we will describe both the clinical and biological characteristics of patients prone to mood switches under antidepressant treatment. However, the clinical characteristics of the depressive syndrome may also be a key determinant for mood switches. Various data help identify the most appropriate drug management strategies for avoiding mood switches during the treatment of bipolar depression. Selective serotonin reuptake inhibitors appear to be the drugs of first-choice because of the low associated risk of mood switching. Antidepressants must be associated with a mood stabiliser and the most effective in the prevention of switches seems to be lithium. Whatever the mood stabiliser used, effective plasma levels must be ensured. The optimal duration of antidepressant treatment for bipolar depression is still an open issue - prolonged treatments after recovery may be unnecessary and may facilitate mood elation. Moreover, some mood episodes with mixed symptoms can be worsened by antidepressants pointing to the need for a better delineation of the categories of symptoms requiring antidepressant treatment. Finally, as a result of this review, we suggest some propositions to define drug-induced switches in bipolar patients, and to try to delineate which strategies should be recommended in clinical practice to reduce as far as possible the risk of mood switch during the treatment of bipolar depression.     

Lithium,but not Valproate,Reduces Impulsive Choice in the Delay-Discounting Task in Mice

Both lithium and valproate are well-established treatments for bipolar disorder. Studies have also found that lithium is effective at reducing suicidal behaviors in patients with mood disorders. Impulsivity is a validated endophenotype of both bipolar disorder and suicidal behavior. We assessed effects of treatment with lithium or valproate on cognitive impulsivity in selectively bred mice previously shown to manifest relatively high levels of cognitive impulsivity. Mice were trained in the delay-discounting paradigm, a measure of cognitive impulsivity reflecting a behavioral bias towards immediacy, and then treated with lithium, valproate, or control chow. After 3 weeks of drug treatment, mice were tested at various delays to a large, delayed reward. Drug treatment continued during this time. Lithium reduced impulsivity, whereas valproate had no effect on choice behavior. Both drugs increased the number of choice trials and reinforcer intake, but effects on choice behavior did not depend on these motivational changes. To our knowledge, this is the first study demonstrating lithium''s effects to reduce cognitive impulsivity. Future studies may focus on the ability of putative pharmacotherapies for patients at risk for bipolar disorder or suicide to modify the impulsive choice dimension of this diseases.     

Adjunctive topiramate in the maintenance treatment of bipolar disorders: an open-label study

SUMMARY

Objective: A considerable number of patients with bipolar disorder fail to respond completely to mood stabilizers. The anti-epileptic topiramate shares some pharmacological actions with carbamazepine and valproate. We therefore explored the efficacy and tolerability of topiramate in the prophylaxis of bipolar disorder.

Methods: Fifty-six patients receiving outpatient treatment for bipolar affective disorder who had been on mood stabilizers, and had relapsed at least once in the past 12?months, were treated with topiramate in an add-on design and were evaluated for 1?year. Patients were assessed biweekly for the first 3?months and every month thereafter.

Results: Fifty out of 56 patients completed the 1-year study, which indicated that adjunctive topiramate was associated with a significant reduction of new manic and depressive episodes compared to the past 12?months. The most common adverse effects were reduced appetite, fatigue and somnolence.

Conclusions: This was an open-label, uncontrolled study involving retrospective evaluation of episodes prior to the initiation of treatment, and the use of more than one mood stabilizer in a few patients. However, these preliminary observations of adjunctive topiramate as a maintenance treatment encourage further investigations, especially with controlled trials, for its long-term effect.     

The effect of adjunctive mood stabilizers on antipsychotic utilization pattern and health resource utilization for Medicaid enrollees with schizophrenia

ABSTRACT

Background: Prescribing adjunctive mood stabilizers to manage schizophrenia is prevalent, despite the lack of substantial evidence to support the long-term use of this treatment regimen.

Objective: The objective of this study was to assess the impact of using adjunctive mood stabilizers on antipsychotic utilization, total health expenditures, inpatient hospital­izations, long-term care stays, and emergency room (ER) visits for patients with schizophrenia.

Methods: Georgia Medicaid claims from 1999 through 2001 were analyzed to identify recipients diagnosed with schizophrenia (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD?9?CM]: 295.XX). The treatment groups consisted of subjects who received combination therapy of mood stabilizers and anti­psychotics (including both atypical and typical medica­tions), while the comparison group consisted of subjects who were on antipsychotic medications without exposure to the mood stabilizers under investigation. Four treatment groups (valproate, lithium, carbamazepine, and combina­tion mood stabilizer therapy) were formed based on the mood stabilizers patient received. Differences in annual health care use and expenditures were estimated between propensity score matched treatment and comparison groups controlling for comorbidity, prior utilization, demographic, and health provider specialty.

Results: During the 1?year observation period, subjects in treatment groups filled an average of 200-days supply of adjunctive mood stabilizers. These adjunctive mood stabilizer recipients had significantly longer antipsychotic treatment durations than the subjects who did not have exposure to mood stabilizers (valproate + antipsychotic vs. antipsychotic only, net difference: 56.47 days, p < 0.0001; lithium + antipsychotic vs. antipsychotic only, net difference: 90.25 days, p < 0.0001; carbamazepine + antipsychotic vs. antipsychotic only, net difference: 41.27 days, p = 0.0439; multiple mood stabilizers + anti­psychotic vs. antipsychotic only, net difference: 83.14 days, p < 0.0001). The intensive pharmacotherapy associated with treatment groups resulted in $900–$1300 higher pharmacy costs than the comparison groups (valproate + antipsychotic vs. antipsychotic only, net difference: $1218.43, p < 0.0001; lithium + antipsychotic vs. antipsychotic only, net difference: $985.79, p = 0.0015; carbamazepine + antipsychotic vs. anti­psychotic only, net difference: $911.63, p = 0.0497; multiple mood stabilizers + antipsychotic vs. antipsychotic only, net difference: $1281.91, p < 0.0047). However, there were no statistically significant differences for total health expenditures, hospitalizations, emergency room visits, and nursing home admissions between propensity-matched treatment and control groups.

Conclusions: There were no differences in health care costs or utilization of ER, long-term care, and inpatient services between schizophrenia patients who did and did not receive adjunctive mood stabilizer; however, longer anti­psychotic treatment durations were observed in patients receiving adjunctive mood stabilizers. Interpretation of these results is limited by the unknown selection bias between the treatment and the comparison groups and the relatively small number of patients in some treatment groups. The development of a better-controlled study to further evaluate this treatment regimen is warranted.     

Resistance to lithium: What alternatives exist?

Lithium is highly valued for the treatment of mania and depression. Resistance may occur to one of its two main indications: firstly for the treatment of acute episodes of mania, and secondly for the prevention of relapse either of bipolar affective disorder (manic depression) or of unipolar affective disorder (recurrent depression). For the management of manic episodes, alternative possibilities include neuroleptics, carbamazepine, electroconvulsive therapy (ECT) and sodium valproate. Neuroleptics are effective, but may precipitate depression. Carbamazepine is effective either alone or as a supplement to the lithium. ECT is an impressively powerful treatment for mania. Valproate appears to be effective but more studies are desirable. Alternatives to lithium in the prevention of relapse of recurrent affective disorders include antidepressants, carbamazepine and ECT. For the prevention of relapses of bipolar affective disorder antidepressants have the disadvantage of increasing the frequency of manic episodes. In unipolar disorder they are a valid alternative to lithium but with some disadvantages. Carbamazepine is effective in the prophylaxis of bipolar affective disorder and should be considered especially in patients with rapid cycling or those with psychotic features. Only open studies are available on ECT and valproate as prophylactic agents. Preliminary work has been carried out on verapamil, flupenthixol, clonazepam, methylene blue, clorgyline, clonidine, tryptophan and 5-hydroxy tryptamine.     

Assessment of safety,tolerability and effectiveness of adjunctive aripiprazole to lithium/valproate in bipolar mania: a 46-week,open-label extension following a 6-week double-blind study

Abstract

Objective:

This study evaluated the long-term tolerability and effectiveness of aripiprazole adjunctive to lithium or valproate in partial responders with bipolar mania.     

Should expectant mothers be vaccinated against flu? A safety review

Introduction: Pregnant women have a higher risk of serious complications from influenza than non-pregnant women of reproductive age. This increased risk has been noted both during pandemic and inter-pandemic influenza seasons. However, although vaccination against flu is recommended at any trimesters by international and national policies, vaccine coverage remains low in pregnant women, possibly due to patient and healthcare providers’ concern about the safety of the vaccine.

Areas covered: This review addresses the effectiveness and safety of seasonal and adjuvanted and non-adjuvanted pandemic 2009 A/H1N1 influenza vaccine.

Expert opinion: Available data suggest no evidence of an increased risk for any adverse event for both mothers and fetuses after vaccination against flu during pregnancy. These results are important when considering the potential of maternal immunization against flu as a public health intervention to protect both the mother and her infant against serious infectious disease.     

丙戊酸盐治疗双相情感障碍的研究进展

作为心境稳定剂,丙戊酸盐治疗各型双相情感障碍均有一定的疗效。近年来对各型双相情感障碍患者进行的临床研究证实：丙戊酸盐能改善躁狂症状;联合镇静药物治疗可有效改善抑郁症状;联合抗抑郁药物预防抑郁发作的疗效优于锂盐。丙戊酸盐与其他心境稳定剂联合治疗快速循环型双相情感障碍患者时可能更有益,也更适用于非快速循环型双相情感障碍患者的长程治疗。