Long-term Management Of Bipolar Disorder Research Articles

New Advances in the Pharmacology and Toxicology of Lithium: A Neurobiologically Oriented Overview.

Over the last six decades, lithium has been considered the gold standard treatment for the long-term management of bipolar disorder due to its efficacy in preventing both manic and depressive episodes as well as suicidal behaviors. Nevertheless, despite numerous observed effects on various cellular pathways and biologic systems, the precise mechanism through which lithium stabilizes mood remains elusive. Furthermore, there is recent support for the therapeutic potential of lithium in other brain diseases. This review offers a comprehensive examination of contemporary understanding and predominant theories concerning the diverse mechanisms underlying lithium's effects. These findings are based on investigations utilizing cellular and animal models of neurodegenerative and psychiatric disorders. Recent studies have provided additional support for the significance of glycogen synthase kinase-3 (GSK3) inhibition as a crucial mechanism. Furthermore, research has shed more light on the interconnections between GSK3-mediated neuroprotective, antioxidant, and neuroplasticity processes. Moreover, recent advancements in animal and human models have provided valuable insights into how lithium-induced modifications at the homeostatic synaptic plasticity level may play a pivotal role in its clinical effectiveness. We focused on findings from translational studies suggesting that lithium may interface with microRNA expression. Finally, we are exploring the repurposing potential of lithium beyond bipolar disorder. These recent findings on the therapeutic mechanisms of lithium have provided important clues toward developing predictive models of response to lithium treatment and identifying new biologic targets. SIGNIFICANCE STATEMENT: Lithium is the drug of choice for the treatment of bipolar disorder, but its mechanism of action in stabilizing mood remains elusive. This review presents the latest evidence on lithium's various mechanisms of action. Recent evidence has strengthened glycogen synthase kinase-3 (GSK3) inhibition, changes at the level of homeostatic synaptic plasticity, and regulation of microRNA expression as key mechanisms, providing an intriguing perspective that may help bridge the mechanistic gap between molecular functions and its clinical efficacy as a mood stabilizer.

Optical determination of lithium therapeutic levels in micro-volumes of interstitial fluid.

Long-term management of bipolar disorder (BD), characterized by mood fluctuating between episodes of mania and depression, involves the regular taking of lithium preparations as the most reliable mood stabilizer for bipolar patients. However, despite its effectiveness in preventing and reducing mood swings and suicidality, lithium has a very narrow therapeutic index and it is crucial to carefully monitor lithium plasma levels as concentrations >1.2 mmol/L are potentially toxic and can be fatal. Current methods of lithium therapeutic monitoring involve frequent blood tests, which have several drawbacks related to the invasiveness of the technique, comfort, cost and reliability. Dermal interstitial fluid (ISF) is an accessible and information-rich biofluid, and correlations have been found between blood and ISF levels of lithium medication. In the current study, we sought to investigate the optical determination of lithium therapeutic concentrations in samples of ISF extracted from porcine skin utilizing a microneedle-based approach. Monitoring of lithium levels in porcine ISF was achieved by employing a spectrophotometric method based on the reaction between the chromogenic agent Quinizarin and lithium. The resulting spectra show spectral variations which relate to lithium concentrations of lithium in samples of porcine ISF with a coefficient of determination (R2 ) of 0.9. This study has demonstrated successfully that therapeutic levels of lithium in micro-volumes of porcine ISF can be measured with a high level of accuracy utilizing spectroscopic techniques. The results support the future development of a miniaturized and minimally-invasive device for lithium monitoring in bipolar patients.

Resilience Predicts Self-Stigma and Stigma Resistance in Stabilized Patients With Bipolar I Disorder.

The identification of factors that prevent self-stigma and on the other hand promote stigma resistance are of importance in the long-term management of bipolar disorder. Accordingly, the aim of the current study was to investigate the association of factors deemed relevant in this context, i.e., resilience, premorbid functioning, and residual mood symptoms, with self-stigma/stigma resistance. Sixty patients diagnosed with bipolar I disorder were recruited from a specialized outpatient clinic. Self-stigma and stigma resistance were measured by the Internalized Stigma of Mental Illness (ISMI) Scale. The presence and severity of symptoms were assessed by the Montgomery-Asberg Depression Rating Scale (MADRS) and the Young Mania Rating Scale (YMRS). Resilience and premorbid functioning were measured by the Resilience Scale (RS-25) and the Premorbid Adjustment Scale (PAS), respectively. Resilience correlated negatively with self-stigma and positively with stigma resistance and was a predictor for self-stigma/stigma resistance in multiple linear regression analysis. Residual depressive symptoms correlated positively with self-stigma and negatively with stigma resistance. There were no significant correlations between sociodemographic variables, premorbid functioning as well as residual manic symptoms and self-stigma/stigma resistance. The findings of this study implicate that resilience may be considered as an important component of self-stigma reduction interventions.

Long-term lithium treatment increases intracellular and extracellular brain-derived neurotrophic factor (BDNF) in cortical and hippocampal neurons at subtherapeutic concentrations.

The putative neuroprotective effects of lithium treatment rely on the fact that it modulates several homeostatic mechanisms involved in the neurotrophic response, autophagy, oxidative stress, inflammation, and mitochondrial function. Lithium is a well-established therapeutic option for the acute and long-term management of bipolar disorder and major depression. The aim of this study was to evaluate the effects of subtherapeutic and therapeutic concentrations of chronic lithium treatment on brain-derived neurotrophic factor (BDNF) synthesis and secretion. Primary cultures of cortical and hippocampal neurons were treated with different subtherapeutic (0.02 and 0.2mM) and therapeutic (2mM) concentrations of chronic lithium treatmentin cortical and hippocampal cell culture. Lithium treatment increased the intracellular protein expression of cortical neurons (10% at 0.02mM) and hippocampal neurons (28% and 14% at 0.02mM and 0.2mM, respectively). Extracellular BDNF of cortical neurons increased 30% and 428% at 0.02 and 0.2 mM, respectively and in hippocampal neurons increased 44% at 0.02 mM. The present study indicates that chronic, low-dose lithium treatment up-regulates BDNF production in primary neuronal cell culture.

Engaging Patients in Long-Term Management of Bipolar Disorder

Engaging Patients in Long-Term Management of Bipolar Disorder

The association between biological rhythms, depression, and functioning in bipolar disorder: a large multi-center study.

We examined the relationship between biological rhythms and severity of depressive symptoms in subjects with bipolar disorder and the effects of biological rhythms alterations on functional impairment. Bipolar patients (n=260) and healthy controls (n=191) were recruited from mood disorders programs in three sites (Spain, Brazil, and Canada). Parameters of biological rhythms were measured using the Biological Rhythms Assessment in Neuropsychiatry (BRIAN), an interviewer administered questionnaire that assesses disruptions in sleep, eating patterns, social rhythms, and general activity. Multivariate analyses of covariance showed significant intergroup differences after controlling for potential confounders (Pillai's F=49.367; df=2, P<0.001). Depressed patients had the greatest biological rhythms disturbance, followed by patients with subsyndromal symptoms, euthymic patients, and healthy controls. Biological rhythms and HAMD scores were independent predictors of poor functioning (F=12.841, df=6, P<0.001, R2 =0.443). Our study shows a dose-dependent association between the severity of depressive symptoms and degree of biological rhythms disturbance. Biological rhythms disturbance was also an independent predictor of functional impairment. Although the directionality of this relationship remains unknown, our results suggest that stability of biological rhythms should be an important target of acute and long-term management of bipolar disorder and may aid in the improvement of functioning.

The diagnosis and treatment of bipolar disorder: decision-making in primary care.

Bipolar disorder is a chronic episodic illness, characterized by recurrent episodes of manic or depressive symptoms. Patients with bipolar disorder frequently present first to primary care, but the diversity of the potential symptoms and a low index of suspicion among physicians can lead to misdiagnosis in many patients. Frequently, co-occurring psychiatric and medical conditions further complicate the differential diagnosis. A thorough diagnostic evaluation at clinical interview, combined with supportive case-finding tools, is essential to reach an accurate diagnosis. When treating bipolar patients, the primary care physician has an integral role in coordinating the multidisciplinary network. Pharmacologic treatment underpins both short- and long-term management of bipolar disorder. Maintenance treatment to prevent relapse is frequently founded on the same pharmacologic approaches that were effective in treating the acute symptoms. Regardless of the treatment approach that is selected, monitoring over the long term is essential to ensure continued symptom relief, functioning, safety, adherence, and general medical health. This article describes key decision-making steps in the management of bipolar disorder from the primary care perspective: from initial clinical suspicion to confirmation of the diagnosis to decision-making in acute and longer-term management and the importance of patient monitoring.

Neuroprotective effects of lithium: implications for the treatment of Alzheimer's disease and related neurodegenerative disorders.

Lithium is a well-established therapeutic option for the acute and long-term management of bipolar disorder and major depression. More recently, based on findings from translational research, lithium has also been regarded as a neuroprotective agent and a candidate drug for disease-modification in certain neurodegenerative disorders, namely, Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and, more recently, Parkinson's disease (PD). The putative neuroprotective effects of lithium rely on the fact that it modulates several homeostatic mechanisms involved in neurotrophic response, autophagy, oxidative stress, inflammation, and mitochondrial function. Such a wide range of intracellular responses may be secondary to two key effects, that is, the inhibition of glycogen synthase kinase-3 beta (GSK-3β) and inositol monophosphatase (IMP) by lithium. In the present review, we revisit the neurobiological properties of lithium in light of the available evidence of its neurotrophic and neuroprotective properties, and discuss the rationale for its use in the treatment and prevention of neurodegenerative diseases.

Acute and long-term management of bipolar disorder

Acute and long-term management of bipolar disorder

Beating Bipolar: exploratory trial of a novel internet‐based psychoeducational treatment for bipolar disorder

Psychoeducational approaches are promising interventions for the long-term management of bipolar disorder. In consultation with professionals, patients, and their families we have developed a novel web-based psychoeducational intervention for bipolar disorder called Beating Bipolar. We undertook a preliminary exploratory randomized trial to examine efficacy, feasibility and acceptability. This was an exploratory randomized controlled trial of Beating Bipolar (current controlled trials registration number: ISRCTN81375447). The control arm was treatment-as-usual and the a priori primary outcome measure was quality of life [measured by the brief World Health Organization Quality of Life (WHOQOL-BREF) scale]. Secondary outcomes included psychosocial functioning, insight, depressive and manic symptoms and relapse, and use of healthcare resources. Fifty participants were randomized to either the Beating Bipolar intervention plus treatment-as-usual or just treatment-as-usual. The intervention was delivered over a four-month period and outcomes were assessed six months later. There was no significant difference between the intervention and control groups on the primary outcome measure (total WHOQOL-BREF score) but there was a modest improvement within the psychological subsection of the WHOQOL-BREF for the intervention group relative to the control group. There were no significant differences between the groups on any of the secondary outcome measures. Beating Bipolar is potentially a safe and engaging intervention which can be delivered remotely to large numbers of patients with bipolar disorder at relatively low cost. It may have a modest effect on psychological quality of life. Further work is required to establish the impact of this intervention on insight, knowledge, treatment adherence, self-efficacy and self-management skills.

Long-term treatment of bipolar disorder

Lithium was one of the first effective drugs to be introduced to psychotherapeutics, and it remains an important treatment both for mania and for the prophylaxis of bipolar disorder. Its action in preventing recurrences appears greater against mania than against depression. A major trend in recent years has been the recognition that antipsychotic drugs are useful not only in mania and hypomania, but in preventing both mania and depression in patients with bipolar I disorder. The antiepileptic agent lamotrigine is useful in preventing depression and to a lesser extent in preventing mania in bipolar I disorder and in bipolar II rapid cycling. The place of valproate or carbamazepine in long-term treatment has not been firmly established. The effectiveness of lithium is limited by side effects and poor compliance. There is growing evidence that certain antipsychotic agents are associated with better compliance and greater effectiveness than lithium, although their metabolic and endocrine side effects can be problematic. Recent Guidelines recognise the role of antipsychotics in the long-term management of bipolar disorder, alongside lithium, lamotrigine and sometimes antidepressants.

Lithium specificity in bipolar illness: a classic agent for the classic disorder

For over half a century, lithium has been the gold standard amongst the pharmacological armamentarium used to treat bipolar disorder. Its ascendancy in this regard has been attributed partly to its primacy of discovery and clinical implementation; however, it is important to consider how it has achieved success and retained its prominence and whether this is because of its unique profile and specificity of actions. In this paper, we briefly discuss the clinical evidence in support of lithium specificity and argue for its continuing use in those patients most likely to benefit, namely, patients with 'classic' bipolar disorder. Further, we suggest that accurate characterization of 'lithium responders' through focused research is likely to yield novel treatments and assist in better understanding of the pathophysiology of the illness. In addition, the unique antisuicidal actions of lithium warrant further examination, as do its impressive properties as a prophylactic agent. This is particularly so given the high morbidity associated with bipolar disorder and its potential for suicide. Hence, in this paper, after describing the changing diagnostic backdrop against which much of the research to date has been conducted, we discuss the clinical therapeutic profile of lithium in both the acute and long-term management of bipolar disorder and its phenotypic specificity of action. We demonstrate that lithium possesses significant clinical and therapeutic efficacy that is very individual and thus remains the treatment of choice for bipolar disorder when used specifically in select patients.

Antidepressant-like effect of lamotrigine is reversed by veratrine: A possible role of sodium channels in bipolar depression

Lamotrigine has been found to be efficacious in the acute management of bipolar depression and long-term management of bipolar disorder, especially in delaying depressive recurrence, either as monotherapy or as adjunctive therapy. Lamotrigine is also an antiepileptic drug, and is efficient in the treatment of focal epilepsies. It is thought to act by inhibition of glutamate release through blockade of voltage-sensitivity sodium channels and stabilization of the neuronal membrane. Objectives: The scope of this study was to determinate if sodium channels are important for lamotrigine and other antidepressant to exert their antidepressant-like function. Methods: This study assessed the effects of veratrine, a Na + channel opener on antidepressant effect of lamotrigine and others antidepressants: two tricyclic antidepressants (TCAs): imipramine, a mixed serotonergic noradrenergic reuptake inhibitor, desipramine, a specific noradrenergic reuptake inhibitor and a SSRI: paroxetine, the most potent selective serotonergic reuptake inhibitor, using an animal model of depression, the forced swimming test. Veratrine (0.125 mg/kg) and lamotrigine (16, 32 mg/kg) or antidepressants (16, 32 mg/kg) were given i.p. 45 and 30 min, respectively, before the test. Results: We observed that when combined with veratrine the antidepressant-like effect of lamotrigine was reversed, but the antidepressant-like effect of the imipramine, desipramine and paroxetine was not changed, indicating that the mechanism of action of lamotrigine is different from that of antidepressants.

Bipolar disorder pharmacotherapy

Treatment options in the management of bipolar disorder continue to proliferate. Currently, all of the commonly prescribed atypical antipsychotics are indicated for the treatment of mania. Quetiapine and olanzapine/fluoxetine in combination are US FDA approved in the treatment of bipolar depression. Aripiprazole and lamotrigine have been FDA approved as maintenance therapies in the long-term management of bipolar disorder. Topiramate and gabapentin have been effectively discredited as first-line options in acute mania. This update seeks to summarize recent developments in bipolar disorder pharmacotherapy, offer insight into the nuance of using these newer agents effectively, review risks and benefits of using standard antidepressants in the treatment of bipolar depression and draw to the attention of readers the strengths and limitations of some of the studies that are shaping contemporary psychiatry’s approach to the patient with bipolar disorder.

The Evolving Paradigm for Bipolar Disorder

Article AbstractClick to enlarge pageBipolar disorder is a recurrent illness, and treatment of bipolar disorder is challenging. Although no cure exists, effective acute and maintenance management of the illness can reduce morbidity and mortality associated with the illness. The following presentations by experts in the field address the selection of appropriate treatment for the acute and long-term management of bipolar disorder based on trial data for atypical antipsychotics and mood stabilizers.

Role of aripiprazole in treating mood disorders

Atypical antipsychotics have been used to treat patients with schizophrenia for many years, but now there is increasing evidence of their utility in the treatment of mood disorders. In the past few years, several atypical agents have received regulatory approval for use in mania. The evidence shows that atypical antipsychotics are effective in the treatment of manic symptoms, either alone or in combination with traditional mood stabilizers, such as lithium and divalproex. Although emerging data indicate that atypical antipsychotics will be a promising addition to those therapies that are currently available for managing patients during the maintenance phase of bipolar illness, their potential in the long-term management of bipolar disorder remains to be fully explored. Aripiprazole is a recently released antipsychotic medication that differs from other atypical antipsychotic agents by its mode of action as a dopamine D2 partial agonist. It is administered orally and has a long half-life. Randomized studies have demonstrated the efficacy of aripiprazole compared with placebo in the treatment of acute relapse of schizophrenia and schizoaffective disorder, maintenance treatment of schizophrenia, treatment of acute mania, and prevention of manic relapse in patients who responded to the drug during a manic episode. Further studies are ongoing in bipolar and unipolar depression. Aripiprazole is generally well tolerated compared with other antipsychotic medications, although commonly reported side effects include extrapyramidal symptoms and motoric activation similar to akathisia. Further studies and postmarketing data will be helpful in providing additional information regarding the comparative safety, efficacy and tolerability of aripiprazole in the treatment of affective disorders.

Role of treatment alliance in the clinical management of bipolar disorder: Stronger alliances prospectively predict fewer manic symptoms

The strength of the treatment alliance between patients and their clinicians may play a unique role in the management of bipolar disorder. However, few empirical studies have examined the alliance in bipolar disorder or its effects on patient outcomes. This study investigates variables associated with a strong treatment alliance in bipolar disorder, and the prospective effects of treatment alliance on patients' mood symptoms and treatment attitudes. Participants were 58 longitudinally followed individuals with Bipolar I disorder. We found that alliance ratings covaried with depressive symptoms, such that alliance strength increased as depressive symptoms decreased, and stronger alliances were associated with more social support. Tests of temporal association indicated that stronger alliances predicted fewer manic symptoms 6 months later. Stronger alliances also predicted less negative attitudes about medication and less of a sense of stigma about bipolar disorder. Thus, a strong treatment alliance may help to reduce manic symptoms over time. It may be that a strong treatment alliance encourages patients' greater acceptance of bipolar disorder and psychopharmacological interventions, and thus contributes to improved medication adherence and clinical outcomes. Considered in sum, these findings suggest that the treatment alliance is an integral component of the long-term management of bipolar disorder.

Atypical antipsychotics: newer options for mania and maintenance therapy

Vieta E, Goikolea JM. Atypical antipsychotics: newer options for mania and maintenance therapy. Bipolar Disord 2005: 7 (Suppl. 4): 21-33. (c) Blackwell Munksgaard, 2005Atypical antipsychotics have been used to treat patients with schizophrenia for many years, but now there is increasing evidence of their utility in the treatment of bipolar disorder. In the past few years several atypical agents have received regulatory approval for use in bipolar mania. Through a review of randomized controlled trials for five commonly used atypical drugs, olanzapine, risperidone, quetiapine, ziprasidone and aripiprazole, this article evaluates their efficacy in the acute and maintenance phases of bipolar disorder. The evidence shows that atypical antipsychotics are effective in the treatment of manic symptoms, either alone or in combination with traditional mood stabilizers such as lithium and divalproex. Although emerging data indicate that atypical antipsychotics will be a promising addition to those therapies that are currently available for managing patients during the maintenance phase of bipolar illness, their potential in the long-term management of bipolar disorder remains to be fully explored. Atypical antipsychotics appear to have broadly similar efficacy against manic symptoms of bipolar disorder, but there are important differences in their tolerability profiles, which are likely to be of particular relevance during long-term treatment. A brief assessment of tolerability issues surrounding the use of atypical agents in bipolar disorder and other aspects of treatment that have impact on the clinical effectiveness of the therapy are considered.

Rethinking the treatment paradigm for bipolar depression: the importance of long-term management.

The need for long-term management of bipolar disorder is evident. Bipolar patients spend more time depressed than manic; however, few agents used for maintenance therapy of bipolar disorder have demonstrated good efficacy in delaying relapse into depression. This article provides a comprehensive review of open-label and randomized, controlled studies examining prophylactic efficacy in bipolar disorder, especially bipolar depression. Lithium, considered the gold standard for bipolar disorder maintenance therapy may be more effective in delaying manic relapse than in delaying depressive relapse. Evidence for the efficacy of divalproex and carbamazepine in delaying depressive relapse is yet to be fully elucidated. Lamotrigine has demonstrated efficacy in delaying time to depressive relapse. Unpublished studies show olanzapine's efficacy in preventing manic recurrence, while its efficacy in preventing depressive recurrence is yet to be proven. As patients with bipolar disorder are prone to experiencing depressive episodes, more attention needs to be focused on preventing depressive relapse. To date, three agents--lithium, lamotrigine, and olanzapine--have been shown to have prophylactic benefits in treating this highly recurrent disorder.

Atypical antipsychotics in the treatment of bipolar affective disorders

Antipsychotics are commonly used in the treatment of bipolar affective disorder. The use of conventional antipsychotic agents, though effective as antimanic agents, is associated with a number of limitations such as their acute side effect profile and their unsufficient mood stabilizing activity. In addition, exposure to conventional neuroleptics poses a risk for the development of tardive dyskinesia, especially in mood disorder patients. Growing evidence suggests that the novel, so-called atypical neuroleptics may offer a number of advantages in the treatment of bipolar disorder, including their thymoleptic activity and minimal risk for acute and long-term extraypyramidal symptoms. Clinical experience with clozapine and olanzapine as mood stabilizers suggests greater antimanic than antidepressant properties, while risperidone may have greater antidepressant properties with some liability for triggering or exacerbating mania. The mood stabilizing properties of further atypical drugs are currently under investigation. This review focuses on the use of atypical antipsychotics in the treatment of bipolar disorder. We also present an overview concerning potential pharmakokinetic interactions based on the cytochrome P450 enzyme system when antipsychotics are combined with other mood stabilizing compounds. In conclusion, atypical antipsychotics should come to play an increasingly important role in the acute and long-term management of bipolar disorder, but there is a clear need for further controlled trials in this indication.