Prophylactic Treatment Of Bipolar Disorder Research Articles

Practices, knowledge, and attitudes about lithium treatment: Results of online surveys completed by clinicians and lithium-treated patients

BackgroundLithium remains the gold-standard medication for acute and prophylactic treatment of bipolar disorder. Understanding clinicians' practices and patients’ experiences, knowledge and attitudes about lithium may improve its clinical use. MethodsOnline anonymous surveys collected information about clinician's practices and level of confidence in managing lithium and patients' experiences with lithium treatment and information received about benefits and side effects. Knowledge and attitudes regarding lithium were assessed with the Lithium Knowledge Test (LKT) and the Lithium Attitudes Questionnaire (LAQ). ResultsAmong 201 clinicians, 64.2% endorsed often treating patients with lithium and reported high levels of confidence in assessing and managing lithium. Practices concerning clinical indications, drug titration, and serum levels were guideline-concordant, but compliance with monitoring recommendations was less frequent. Practitioners were interested in receiving more education about lithium. The patients’ survey recruited 219 participants with 70.3% being current lithium users. Most patients (68%) found lithium helpful and 71% reported experiencing any kind of side effect. Most responders did not receive information about side effects or other benefits of lithium. Patients with higher scores on the LKT were more likely to have positive attitudes about lithium. LimitationsCross-sectional design with predominantly English-speaking participants from Brazil and North America. ConclusionsThere is a discrepancy between guidelines, clinician confidence and knowledge of lithium use and practice. A deeper understanding of how to monitor, prevent and manage long-term side effects and which patients are most likely to benefit from lithium may narrow the gap between knowledge and use.

Effectiveness of mood stabilizers in prophylactic treatment of bipolar disorder

IntroductionProphylactic treatment during bipolar disorder aims to prevent recurrences and to improve the functional level.ObjectivesOur aim was to compare the clinical effectiveness of lithium versus sodium valproate in the prophylactic treatment of bipolar disorder type 1MethodsRetrospective, longitudinal, comparative study conducted among 162 patients followed for bipolar disorder type 1 hospitalized at the Psychiatry A department of Razi Hospital. The Alda scale and time to recurrence were used to compare the clinical effectiveness of the mood stabilizers.ResultsA difference between the two groups of patients was noted for some variables. Lithium prescription was associated with educational level, number of depressive episodes, suicide attempts, previous prescription of other thymoregulators, depressive polarity of the index episode and use of atypical antipsychotics.The prescription of Valproate was associated with educational level, unipolar mania, manic predominant polarity, manic polarity of the index episode, presence of psychotic features, prescription of long acting antipsychotics and higher doses of antipsychotics.The study of response by Alda scale showed no significant difference in the mean score of the scale nor in the rate of responders. We noted a higher rate of recurrence in patients on Valproate considering the whole duration of the study. The recurrence rate after one year was higher in patients on Lithium, the recurrence rate after two years was comparable in both groups. Survival curves showed earlier recurrences in patients on Lithium.ConclusionsThe efficacy of the two mood stabilizers was comparable. The recurrences occured earlier under Lithium.Disclosure of InterestNone Declared

Long-Term Lithium Therapy: Side Effects and Interactions

Lithium remains the drug of first choice for prophylactic treatment of bipolar disorder, preventing the recurrences of manic and depressive episodes. The longitudinal experiences with lithium administration greatly exceed those with other mood stabilizers. Among the adverse side effects of lithium, renal, gastrointestinal, neurological, thyroid, metabolic, cognitive, dermatological, cardiologic, and sexual are listed. Probably, the most important negative effect of lithium, occurring mostly after 10-20 years of its administration, is interstitial nephropathy. Beneficial side-effects of long-term lithium therapy also occur such as anti-suicidal, antiviral, and anti-dementia ones. Pharmacokinetic and pharmacodynamic interactions of lithium, mostly those with other drugs, may have an impact on the success of long-term lithium treatment. This paper makes the narrative updated review of lithium-induced side-effects and interactions that may influence its prophylactic effect in bipolar disorder. Their description, mechanisms, and management strategies are provided. The papers appearing in recent years focused mainly on the long-term lithium treatment are reviewed in detail, including recent research performed at Department of Psychiatry, Poznan University of Medical Sciences, Poland. Their own observations on ultra-long lithium treatment of patients with bipolar disorder are also presented. The review can help psychiatrists to perform a successful lithium prophylaxis in bipolar patients.

Personalized medicine in bipolar disorder: how can we overcome the barriers to clinical translation?

Bipolar disorder (BD) is a complex mood disorder characterized by recurrent episodes of mania and depression, affecting 1–4% of the general population [1]. The phenotypic representation of BD is highly heterogeneous, a characteristic that is reflected in the variability in response to mood-stabilizing drugs observed in bipolar patients. Mood stabilizers are a class of drugs that includes anticonvulsants, second-generation antipsychotics and lithium, with the latter being the mainstay in BD treatment. In 1949, John Cade described, for the first time, lithium’s antimanic effect [2]. In the following years, many trials demonstrated lithium’s efficacy in shortterm and prophylactic treatment of BD [3]. The choice of lithium as the first treatment in BD patients has also been influenced by its welldescribed antisuicidal effect – suicide being one of the leading causes of death in BD patients [4]. For these reasons, the vast majority of studies on response to drugs used in BD have thus far been focused on lithium more than any other mood stabilizer. While a significant proportion of patients chronically treated with lithium show full remission with stabilization of mood alterations, approximately 70% of subjects present partial or complete nonresponse [5]. This significant rate of insufficient response, together with the potentially serious adverse effects of lithium treatment, has stimulated a growing body of research aimed at the identification of predicting factors and new drug targets. The first step for the design of targeted therapies should consist of the identification of predictive markers of response. Nevertheless, with the exception of clinical factors, findings have so far provided weak evidence for specific predictors of lithium response. The main barriers

Tiagabine in the maintenance treatment of bipolar disorder

Tiagabine, an anticonvulsant, has been reported to have efficacy in prophylactic treatment of bipolar disorder in case reports and in case series. To assess the efficacy and acceptability of tiagabine, relative to placebo, and other agents in the prevention or attenuation, or both, of episodes of bipolar disorder in adults. The efficacy and acceptability of tiagabine were considered in terms of mood symptoms, mortality, general health, social functioning, adverse effects and overall acceptability to participants. The Cochrane Collaboration Depression, Anxiety and Neurosis review group's specialised registers (CCDANCTR-Studies and CCDANCTR-References) were searched to 1 October 2011. These registers contains relevant randomised controlled trials from: The Cochrane Library (all years to date), EMBASE, (1974 to date) MEDLINE (1950 to date) and PsycINFO (1967 to date). Reference lists of relevant papers and major textbooks of affective disorder were examined. Authors, other experts in the field and pharmaceutical companies were contacted for knowledge of suitable published or unpublished trials. Specialist journals and conference proceedings were handsearched. Randomised controlled trials of tiagabine versus placebo, alternative mood stabilisers or antipsychotics, for the maintenance treatment of bipolar disorder in adults, male and female, aged 18 to 74 years. Data were to be extracted from the original reports of included studies independently by two authors. The main outcomes to be assessed were:(1) the efficacy of tiagabine treatment in preventing or attenuating further episodes of bipolar disorder, including its efficacy in rapid cycling disorder; (2) the acceptability of tiagabine treatment to participants; (3) the prevalence of side effects; and (4) mortality, if any, on tiagabine treatment.Outcomes concerning relapse or recurrence were to be analysed excluding data from studies using discontinuation protocols, which were to be analysed separately. Subgroup analyses were to be performed to examine the effects of tiagabine treatment in rapid cycling bipolar disorder and previous mood stabiliser non-responders. Data were to be analysed using Review Manager 5. No randomised controlled trials of tiagabine in the maintenance treatment of bipolar disorder were found. There is an insufficient methodologically rigorous evidence base to draw any conclusions regarding the use of tiagabine in the maintenance treatment of bipolar disorder. There is a need for randomised controlled trials examining the therapeutic potential of this agent in bipolar disorder. There have been some reports of syncope or seizures, or both, when tiagabine has been used for the acute treatment of mania. It needs to be established if such adverse effects occur in the maintenance phase as well.

Carbamazepine

Carbamazepine

Treatments in child and adolescent bipolar disorders

The existence of bipolar disorder in adolescents is now clearly established. However, whether bipolarity exists in children is more controversial. We reviewed the literature on acute and prophylactic treatment of bipolar disorder in youths. The guidelines for the treatment of bipolar disorder in children and adolescents are generally similar to those applied in adult practice. But no evidence-based data support the use of mood stabilisers or antipsychotics since we only found two placebo-randomised controlled trials testing the efficacy of lithium in the paediatric literature. Therefore, we support the view that prescriptions should be limited to the most typical cases. In fact, the use of mood stabilisers or antipsychotics in the treatment of bipolar disorder in children and adolescents appears to be of limited use when a comorbid condition, such as attention deficit hyperactivity disorder, occurs unless aggressive behaviour is the target symptom.

Traitements des troubles bipolaires de type I de l'enfant et de l'adolescent

Recognition of bipolar disorder in adolescent is now clearly established. However, whether bipolarity exists in children is more controversial. We reviewed the literature on acute and prophylactic treatment of bipolar disorder in youth. Mainly, guidelines recommended in the treatment of bipolar disorder in children and adolescent are similar to those in adult practice. But no evidence based data support the use of mood stabilizers or atypical neuroleptics since we only found two placebo-randomised controlled trials testing the efficacy of lithium in the paediatric literature. Therefore, we support the view that prescriptions should be limited to the most typical cases. In fact, the use of mood stabilizers or atypical neuroleptics in the treatment of bipolar disorder in children and adolescents appears of limited interest in children when a comorbid condition, such as attention deficit hyperactivity disorder, occurs.

Lithium: Clinical Considerations in Internal Medicine

Bipolar Disorders affect up to 5% of the population. While the pharmacological options for the treatment of bipolar disorder have expanded over the past several years, lithium remains an inexpensive and efficacious treatment for bipolar disorder. Lithium has been demonstrated to be an effective treatment for acute mania, bipolar depression, the prophylactic treatment of bipolar disorder, and as an augmentation agent in the treatment of unipolar major depression. Lithium also is the only mood stabilizer that has been demonstrated to lower the suicide rate in patients with bipolar disorder. Use in special populations, side effects and toxicity, and drug interactions are discussed. Important laboratory monitoring guidelines are included in this review. Lithium remains an important intervention for the treatment of mood disorders.

Prophylactic treatment of bipolar disorder in pregnancy and breastfeeding: focus on emerging mood stabilizers

Bipolar disorders are reported to have a high incidence during childbearing years and the need may arise to start or continue a pharmacological treatment during pregnancy and the postpartum period. In the last few years several investigations have evaluated the efficacy of emerging mood-stabilizing agents in the treatment of bipolar disorders, such as lamotrigine, olanzapine, risperidone, quetiapine, aripiprazole and ziprasidone. A number of studies, which examined the use of oxcarbazepine, point to its potential usefulness in prophylactic treatment. The aim of this review is to compare information from the literature on the safety of lamotrigine, oxcarbazepine, risperidone, olanzapine, and quetiapine to the safety data on classic mood stabilizers during pregnancy and the postpartum period. A computerized search carried out from 1980 to April 5, 2006 led to the summarization of the results. (References were updated after acceptance and prior to publication.) Emerging mood stabilizers show uncertain safety parameters in pregnancy and lactation. Limited information on lamotrigine and oxcarbazepine does not suggest a clear increase in teratogenicity, while olanzapine appears to be associated with a higher risk of metabolic complications in pregnant women. Data about risperidone and quetiapine are still inconclusive. Finally, the literature on the safety of these compounds in breastfeeding is anecdotal. Untreated pregnant bipolar women are at an increased risk of poor obstetrical outcomes and relapse of affective symptoms. On the other hand, classic antiepileptic drugs are well-known human teratogens, whereas data on lithium are partially ambiguous. The safety of emerging mood stabilizers in pregnancy and breastfeeding has not been examined extensively. Therefore, when approaching bipolar disorder, if possible, each episode must be considered separately.

Is the Prophylactic Antidepressant Efficacy of Lithium in Bipolar I Disorder Dependent on Study Design and Lithium Level?

In the 1970s, several randomized controlled trials demonstrated significant antimanic and antidepressant properties of lithium in the prophylactic treatment of bipolar disorder. However, a recent meta-analysis of randomized, placebo-controlled trials of lithium in bipolar disorder found that its protective effect against depressive relapse/recurrence was equivocal. By examining potentially relevant parameters of recent randomized controlled trials with regard to lithium's prophylactic antidepressant efficacy, we try to identify factors which might help to explain these discrepant results across the different trials. Lithium's efficacy against manic relapse/recurrence appears rather robust at plasma levels between 0.8 and 1.2 mmol/L, whereas lithium's efficacy against depressive relapse/recurrence may be more modest and dependent on whether a response during the preceding acute episode was achieved by lithium treatment. Furthermore, it might be advisable to continue lithium without interruption at the same dose/plasma level, which yielded the initial response. A lithium level between 0.5 and 0.8 mmol/L may be equally efficacious against overall relapse and associated with equal or even superior efficacy regarding depressive relapse/recurrence. To provide evidence-based guidelines on this issue, large prospective, randomized, double-blind, placebo-controlled trials are needed comparing the efficacy of lithium at different plasma levels against manic and depressive relapse/recurrence. In these trials, factors previously associated with predicting response to lithium should also be assessed.

Pharmacokinetics of lithium in rat brain regions by spectroscopic imaging

Lithium (Li) and its salts have been demonstrated to be the most effective drug in both acute and prophylactic treatment of bipolar disorder. The exact molecular mechanisms and particular target regions accounting for its mood-stabilizing effect remain unknown. Knowledge of Li distribution and its regional pharmacokinetic properties in the living brain is of value in localizing its action in the brain. Pharmacokinetic measurements in different anatomical regions of the human brain are not yet available. Limited pharmacokinetic measurements in rat brain subvolumes have been performed using atomic absorption technique. However, a noninvasive way of estimating the pharmacokinetics in different regions of the brain where the drug exerts its beneficial effects would allow such methods to be used in the study of patients undergoing Li therapy. Earlier (7)Li MR studies on rat brain regions have provided preliminary pharmacokinetic information from the whole brain. Using (7)Li MR spectroscopic imaging (SI) technology, Li distribution in brain regions of the rat at therapeutic dosages has been recently demonstrated by us. Here we report feasibility of local pharmacokinetic measurements on brain regions obtained by magnetic resonance SI technology. Our results suggest that Li is most active in a region stretching from the anterior cingulate cortex and striatum to the caudal midbrain, with greatest activity including the preoptic area and hypothalamic region. Some activity was seen in prefrontal cortex, but only minimal amounts in the region of the cerebellum and metencephalic brainstem.

Epidemiology of Bipolar Disorders

Bipolar, or manic-depressive, disorders are frequent and severe mental illnesses associated with considerable morbidity and mortality. Epilepsy and bipolar disorder could probably share some aspects of pathophysiology because manic as well as depressive symptoms are seen in patients with seizures, and a number of antiepileptic drugs are effectively used in the acute and prophylactic treatment of bipolar disorder. Epidemiologic research suggests a dimensional composition of bipolar illness at the population level. Apart from the DSM-IV diagnostic features of bipolar I (mania and depression) and bipolar II (hypomania and depression), the concept of bipolar spectrum disorders comprises a range of bipolar conditions with less obvious manifestations with estimated lifetime prevalence rates ranging from 2.8 to 6.5%. Expanding the definition of bipolar II disorders shows that half of the patients currently diagnosed with a unipolar depressive episode could suffer from unrecognized bipolar II disorder, and about the same number of mild depressive patients could be minor bipolars. Research efforts to refine the diagnostic criteria of bipolar disorder aim at an earlier and complete recognition of the disease to provide appropriate pharmacological and nonpharmacological treatment early in the course of the illness to anticipate individual suffering, suicidal behavior, and increased socioeconomic costs for society. This article also discusses risk factors, comorbid conditions, course of illness, as well as the individual and socioeconomic impact of bipolar disorders. The findings suggest reconceptualizing bipolar illnesses as highly recurrent, malignant disorders that occur far more frequently than previously thought. Interdisciplinary knowledge transfer could help to increase our understanding of the pathophysiology of these disorders as well as provide grounds for better recognition and treatment of patients with manic and/or depressive symptoms.

P.3.20 Arrythmic markers affected by clozapine treatment in patients with schizophrenia: heart rate variability, late potentials and QT dispersion

Background: The literature on the use of quetiapine for the treatment of bipolar disorder (BD) is limited to case reports, and there are no systematic studies on the efficacy of quetiapine in the prophylactic treatment of BD. The aim of the present study was to compare the efficacy of flexible doses of quetiapine and well established mood stabilizers in the maintenance treatment of BD. Methods: Twenty-eight DSM-IV BD outpatients were consecutively recruited into the study and were randomized to receive one of two open-label treatments, with quetiapine or classical mood stabilizers at flexible doses for 12 months. Clinical assessment was carried out using BPRS, CGI, YMRS and the 21-item HAM-D at baseline (T0) and every 2 months until the end of the study. ANOVAs with repeated measures were applied to the rating scale scores considering the time and the treatment group as main factors. Results: All patients experienced a significant improvement on the BPRS, CGI and HAM-D scores, with no significant side-effects and a good compliance. Limitations: This study should be considered preliminary given the small sample size investigated and the open-label design. Conclusions: If these results will be replicated on larger samples and in controlled studies, there could be relevant implications for the use of quetiapine as an alternative maintenance treatment for BD.

Lithium augmentation in treatment-resistant depression: clinical evidence, serotonergic and endocrine mechanisms.

For now more than 50 years, lithium has been the gold standard for the pharmacologic treatment of bipolar disorder. However, its utility is not restricted to acute mania and prophylactic treatment of bipolar disorder. A relatively new indication for its use is the addition to an antidepressant in the acute treatment phase of unipolar major depression. To date, this treatment approach called lithium augmentation is the best-documented approach in the treatment of refractory depression. In international treatment guidelines and algorithms, lithium augmentation is considered a first-line treatment strategy for patients with a major depressive episode who do not adequately respond to standard antidepressant treatment. In a recent double-blind, placebo-controlled trial, lithium augmentation has demonstrated to also be effective in the continuation treatment phase to prevent early relapses. From animal studies there is robust evidence that lithium augmentation increases serotonin (5-HT) neurotransmission, possibly by a synergistic action of lithium and the antidepressant on brain 5-HT pathways. In contrast to the established decline of HPA system activity during treatment with tricyclic antidepressants, neuroendocrine studies on the effects of lithium augmentation on the HPA system showed an unexpected and marked increase in the ACTH and cortisol response in the combined DEX/CRH test. Here we review new data on the efficacy and mechanism of action of lithium augmentation.

Efficacy and tolerability of quetiapine in the treatment of bipolar disorder: preliminary evidence from a 12-month open-label study

Background: The literature on the use of quetiapine for the treatment of bipolar disorder (BD) is limited to case reports, and there are no systematic studies on the efficacy of quetiapine in the prophylactic treatment of BD. The aim of the present study was to compare the efficacy of flexible doses of quetiapine and well established mood stabilizers in the maintenance treatment of BD. Methods: Twenty-eight DSM-IV BD outpatients were consecutively recruited into the study and were randomized to receive one of two open-label treatments, with quetiapine or classical mood stabilizers at flexible doses for 12 months. Clinical assessment was carried out using BPRS, CGI, YMRS and the 21-item HAM-D at baseline (T0) and every 2 months until the end of the study. ANOVAs with repeated measures were applied to the rating scale scores considering the time and the treatment group as main factors. Results: All patients experienced a significant improvement on the BPRS, CGI and HAM-D scores, with no significant side-effects and a good compliance. Limitations: This study should be considered preliminary given the small sample size investigated and the open-label design. Conclusions: If these results will be replicated on larger samples and in controlled studies, there could be relevant implications for the use of quetiapine as an alternative maintenance treatment for BD.

Lithium in bipolar disorder: can drug concentrations predict therapeutic effect?

The evidence is reviewed for effective serum lithium concentrations for the acute and prophylactic treatment of mania and depression in patients with bipolar disorder. The efficacy of lithium in the treatment of acute manic episodes has been recognised for several decades, primarily using concentrations in the range of 0.8 to 2 mmol/L. The number of patients responding increases as the serum lithium concentration increases, although individual patients may respond at lower concentrations (<0.8 mmol/L). Lithium doses and serum concentrations similar to those used to treat acute mania have been studied in bipolar depression, with no evaluation of a relationship between concentration and clinical response. Several prospective controlled trials have evaluated this relationship in the prophylactic treatment of bipolar disorder. Maintaining higher serum lithium concentrations (0.8 to 1 mmol/L) improves the likelihood of good effect in prophylactic treatment, although individual patients may do well on lower concentrations. Despite the paucity of evidence to specifically support the efficacy of lithium at lower serum lithium concentrations in the elderly, lower target ranges (0.5 to 0.8 mmol/L) are commonly recommended due to an increased sensitivity to adverse effects, particularly neurotoxicity. The serum lithium concentrations recommended in adults have been applied to children; however, this has not been studied. Overall, the evidence suggests a relationship between serum lithium concentration and therapeutic effect, although the exact nature of this relationship is not clear. For example, it is not known why some people respond to lower concentrations and others do not. There are many factors that influence studies trying to elucidate this relationship. Many of these factors are related to the interpretation of the serum lithium concentration. In summary, patients have an increased chance of responding to lithium if 12-hour serum lithium concentrations at steady state are above 0.8 mmol/L. Many patients will respond to lower concentrations (0.4 to 0.7 mmol/L), but we are unable to identify these patients a priori. The relationship between serum lithium concentrations and adverse effects is also very important in determining appropriate target lithium concentrations. The current best advice is to individualise the target serum lithium concentrations based on efficacy and tolerability and to optimise the interpretation of these concentrations by ensuring within-patient consistency with respect to dosage schedule, lithium preparation and the timing of blood sampling.

Therapeutic strategies in refractory bipolar disorder

Lithium is still regarded as the first choice substance in the prophylactic treatment of bipolar disorder. However, approximately one third of patients with a "classic" course of bipolar affective disorder do not adequately respond to lithium prophylaxis. The introduction of carbamazepine and valproic acid allowed a more differential syndrome- and course-orientated approach to the prophylactic treatment of bipolar disorder for the first time. However, about 10 to 20 percent of patients still remain refractory to standard regimes. Therefore, criteria for resistance to prophylactic treatment have to be further established. It has been suggested that at least two adequate trials of more than 12 months duration with sufficient drug blood levels have to be performed before refractoriness should be assumed. A severe subtype of affective disorder with poor response to lithium and other treatment approaches is a rapid cycling course which is characterised by at least four affective episodes per year. Here we present an overview of the currently available alternatives for prophylactic treatment, i.e. anticonvulsants, combination treatment, adjunctive thyroxine, calcium channel blockers, and more experimental approaches for treating refractory bipolar disorder patients. Suggestions for optimizing the prophylactic treatment of bipolar disorder are summarized in an algorithm.

New Concepts in Mood Stabilization: Evidence for the Effectiveness of Valproate and Lamotrigine

Recognition of limited overall benefits from lithium in bipolar disorder, with even greater disadvantages in more severe forms of the disease, has spurred interest in alternative therapies. A long history of development of evidence for the utility of valproate has culminated in well-designed, placebo-controlled studies that establish the efficacy of the divalproex form of valproate in acute mania. Generally positive, but as yet not conclusive, studies indicate continued benefits in prophylactic treatment of bipolar disorder. The spectrum of efficacy of valproate is somewhat broader than that of lithium, extending to patients with certain more severe forms of the illness; e.g., mixed manics. Pretreatment plasma GABA activity was positively correlated with magnitude of improvement in manic symptomatology with divalproex. The evidence of comparable clinical benefits for lithium and valproate has stimulated studies that indicate overlapping effects on specific G protein-linked signal transduction for lithium and valproate, but not for carbamazepine. The possibility that additional antiepileptic drugs might have efficacy in bipolar disorder has encouraged early clinical studies with several newer antiepileptic drugs. Preliminary evidence for the efficacy of one of these, lamotrigine, has been presented.

The increasing use of anticonvulsants in prophylactic treatment of bipolar disorder.

The medical records of patents with bipolar disorders who received prophylactic drug treatments during three time periods from January 1983 to December 1984, January 1988 to December 1989, and from January 1993 to December 1994, were reviewed retrospectively. The percentage of lithium monotherapy sharply decreased from 96% (51/53) in the first study period to 51.9% (83/160) in the third study period. Carbamazepine monotherapy and combination of lithium and carbamazepine increased from 3.8% in the first study period to 45.6% in the third study period. These results suggest that anticonvulsants may become one of the major drug treatment strategies for bipolar disorder in the future.