Novel treatments for bipolar disorder

Treatments other than lithium have recently emerged as equally important in the management of bipolar disorder. The spectrum of efficacy of newer treatments differs from lithium and among the novel drug treatments valproate, generally used as the better tolerated divalproex form, principally benefits manic symptomatology both acutely and in prophylaxis. Atypical antipsychotic drugs have demonstrated efficacy in reducing acute manic symptoms. No controlled evidence of efficacy in prophylaxis has been published. Lamotrigine has demonstrated efficacy in both acute bipolar depression and maintenance efficacy in rapid cycling bipolar patients, especially those patients with bipolar II disorder, which is principally manifested as depression. Randomised, double-blind, placebo- controlled studies provide good evidence that regimens of risperidone or olanzapine in combination with lithium or valproate provide greater improvement in acute mania than the mood stabilisers alone. Similarly, valproate combined with antipsychotics provided greater improvement in mania than antipsychotic medication alone and resulted in lower dosage of the antipsychotic medication. A positive but unclear placebo-controlled study of omega-3 fatty acids added to lithium in bipolar disorder needs confirmation in standard clinical trial paradigms. Several other drugs that were reported as beneficial in various facets of bipolar disorder in open trials have not differed from placebo when studied in randomised, placebo-controlled trials.     

Novel glutamatergic agents for major depressive disorder and bipolar disorder

Mood disorders such as major depressive disorder (MDD) and bipolar disorder (BPD) are common, chronic, recurrent mental illnesses that affect the lives and functioning of millions of individuals worldwide. Growing evidence suggests that the glutamatergic system is central to the neurobiology and treatment of these disorders. Here, we review data supporting the involvement of the glutamatergic system in the pathophysiology of mood disorders as well as the efficacy of glutamatergic agents as novel therapeutics.     

Comparative efficacy and tolerability of drug treatments for bipolar disorder

Lithium has been the backbone of treatment for bipolar disorder for several decades, although recent advances have identified a number of other medications that have efficacy in treating various phases of the illness. These include the antiepileptic drugs valproate semisodium (divalproex sodium) and carbamazepine and some new antiepileptic drugs (e.g. lamotrigine and topiramate), and the atypical antipsychotics (e.g. olanzapine, clozapine and risperidone). Conventional antipsychotics continue to be used frequently in bipolar disorder, although they may be somewhat less effective than other treatments. Otherwise, to date, none of these treatments have been shown to be consistently more effective than any other, so that drug adverse effects and tolerability often dictate which agents are used in an individual patient. Drugs commonly used for the treatment of bipolar disorder are generally tolerated by most patients in large samples. However, the unique adverse effect signature of a drug will often suggest that it will be less tolerable in some patients than in others. Identifying a specific treatment for a specific patient requires a careful individualised assessment of the risk of adverse effects for that patient's unique circumstances.     

Mood stabilizers and atypical antipsychotics: bimodal treatments for bipolar disorder

Treatment options for bipolar disorder have rapidly expanded over the last decade, but providing optimal management remains an elusive goal. The authors reviewed the literature on the efficacy of agents with the best clinical evidence supporting their use in bipolar disorder, including the mood stabilizers lithium, valproate, lamotrigine, and carbamazepine, as well as the atypical antipsychotics olanzapine, risperidone, quetiapine, ziprasidone, and aripiprazole. Most medications appear to be more effective for symptoms of mood elevation than for symptoms of depression. The efficacy, tolerability, and safety profiles of agents must be considered when making clinical decisions. Several agents, including lithium, valproate, olanzapine, quetiapine, and risperidone, can cause problematic weight gain. In addition, the use of atypical antipsychotics has been associated with an increased risk of metabolic abnormalities such as dyslipidemia, hypergylycemia, and diabetes mellitus. In most patients, monotherapy offers inadequate efficacy. Further investigation of combinations of agents such as mood stabilizers and atypical antipsychotics may yield valuable insights into the potential of combination therapies to enhance clinical outcomes in patients with bipolar disorder.     

Novel routes to bipolar disorder drug discovery

Introduction: Bipolar disorder (BD) is a severe and chronic medical condition typified by episodic recurrent mania (or hypomania) in addition to major depression. BD is associated with a number of negative outcomes including premature death, reduced quality of life and can also lead to other complications including impaired cognitive function. Unfortunately, the currently available pharmacological treatments for BD are insufficient for many with the condition.

Areas covered: This review focuses on known therapeutic targets of mood stabilizing drugs including: the glycogen synthase kinase-3 (GSK-3), the phosphoinositide pathway and protein kinase C (PKC), the brain-derived neurotrophic factor (BDNF), and histone deacetylases (HDACs). This article also presents new promising therapeutic targets including: the glutamatergic pathway, mitochondrial modulators, neuropeptide-converting endopeptidases, the insulin transduction pathway, the purinergic system and the melatoninergic system.

Expert opinion: Challenges in improving methods and tools to generate, integrate and analyze high-dimensional data are required to allow opening novel routes to BD drug discovery. Through the application of systems biology approaches and the use of bioinformatical tools to integrate all omics data, it will be possible in the near future to gain deeper insights into pathophysiology of BD. This will in turn lead to the identification and exploitation of new potential therapeutic approaches.     

Drug treatments for bipolar disorder: 1--Acute manic or depressive episodes

Bipolar disorder is a severe, chronic mental illness characterised by repeated episodes of mania or hypomania, depression or mixed affective states. Depending on the clinical context, treatment may involve drugs, psychological therapies, social interventions and/or electroconvulsive therapy (ECT). Here we concentrate on the role of drug treatments for acute manic or depressive episodes in adults with bipolar disorder. A second article will consider their role as maintenance and preventive therapy, and in special situations such as pregnancy.     

The armamentarium of treatments for bipolar disorder: a review of the literature

To assess current pharmacotherapeutic options for bipolar disorder, with particular emphasis on the use of antipsychotic agents, Medline and EMBASE were searched between January 1980 and December 2005 using the keywords "schizoaffective disorder" and "bipolar disorder", combined with various antidepressants, antipsychotics, lithium or other mood stabilizers. English-language articles, review articles and original research articles were reviewed. Most data are available for the "mood stabilizers" lithium and valproate. However, these agents have important limitations regarding their tolerability and efficacy in certain groups. Newer anticonvulsants, especially lamotrigine, have demonstrated efficacy across mood-symptom domains. Antidepressants are not generally favoured as monotherapy in patients with bipolar depression or schizoaffective disorder, due to their potential to induce switching to manic states. However, data are emerging for the efficacy of selective serotonin reuptake inhibitors for bipolar depression in combination with atypical antipsychotics. Atypical antipsychotics may also be used as monotherapy or in conjunction with mood stabilizers for the treatment of acute mania and for continuing maintenance therapy. The choice of antipsychotic may be influenced by the therapeutic situation; formulations that facilitate administration in the acute scenario can provide rapid tranquillization, whereas those that enhance compliance may have a place in maintenance therapy. Our results suggest a growing role for atypical antipsychotics in the treatment of bipolar disorder and further data are anticipated.     

Drug treatments for bipolar disorder: 2--maintenance, prevention and special situations

In last month's issue, we discussed drug treatment for acute mood episodes (mania, hypomania, depression or mixed states) in patients with bipolar disorder. We pointed out that prescribers have to keep in mind that patients will often need treatment long term. Here we consider the role of drug therapy for maintenance and prevention in patients with bipolar disorder. We also discuss some common clinical situations that pose particular problems and dilemmas with regard to drug treatment.     

Emerging drugs for bipolar disorder

Importance of the field: Bipolar disorder (BD) is a chronic mental illness characterized by the alternation of abnormal mood episodes with periods of remission. It results in important functional and psychosocial disability, as well as high rates of suicide. For many patients with BD, existing treatments do not provide sufficient management, and high rates of relapse and lingering residual symptoms are common.

Areas covered in this review: The present article is a comprehensive literature review focusing on novel pharmacological treatments for BD. The database PubMed (1990 – 2010) was searched, using the MeSH terms ‘bipolar disorder’ and ‘therapeutics’. In addition, a manual search of bibliographical cross-referencing was performed. The papers obtained through the search strategy described above were manually screened for original articles, reviews and case reports emphasizing novel treatments for BD.

What the reader will gain: New pharmacological approaches are discussed here in detail, highlighting their possible mechanisms of action, their potential use in the different phases of the disease and their effect on specific symptoms, such as cognitive impairment.

Take home message: Most of the emergent drugs for BD seem to be particularly promising in the treatment of bipolar depression, and there is a trend in the identification of drugs targeting less explored pathophysiological mechanisms found in BD. However, results regarding most of them are still preliminary, and additional studies are necessary to clarify their real role in the clinical management of BD.     

Emerging drugs for bipolar disorder

Bipolar disorder is a relatively common condition characterised by recurrent episodes of mania and depression, and associated with high levels of morbidity and mortality. Although there have been substantial advances in the pharmacotherapeutics of this condition over the last 10 – 15 years, the benefits have been predominantly in terms of tolerability and safety, with no new treatments being demonstrated to be more effective than lithium – the prototype mood stabiliser. This article reviews current and emerging medications for bipolar disorder. Most of the emerging treatments in pharmaceutical industry developmental programmes are new or modified anticonvulsants or atypical antipsychotics. A number of possible future directions and challenges for the field are discussed. The treatment of bipolar disorder is unlikely to advance substantially until the causative pathogenetic molecular processes are elucidated.     

Novel treatments for pain

At present, the principal treatments for pain are non-steroidal anti-inflammatory drugs (NSAIDs) and opioids, but both of these classes suffer from drawbacks in clinical use. Some of the NSAIDs are associated with gastric damage as well as kidney and liver toxicity, and an increase in blood clotting time, while the opioids can produce tolerance and dependence, along with constipation, nausea, respiratory depression and sedation. In certain cases, both NSAID and opioid use are ineffective. There are some other less commonly used treatments including local anesthetics, anticonvulsants and tricyclic antidepressants, but, many recent strategies have involved the search for other NSAIDs and opioids which lack the unwanted side-effects present in both classes of drug. More recently, in addition to the classical strategies, some novel approaches have started to produce compounds which have entered the clinic, including cyclooxygenase-2 (COX-2) inhibitors and modulators of the alpha2delta subunit of L-type calcium channels.     

Emerging drugs for bipolar disorder

Bipolar disorder is a relatively common condition characterised by recurrent episodes of mania and depression, and associated with high levels of morbidity and mortality. Although there have been substantial advances in the pharmacotherapeutics of this condition over the last 10-15 years, the benefits have been predominantly in terms of tolerability and safety, with no new treatments being demonstrated to be more effective than lithium--the prototype mood stabiliser. This article reviews current and emerging medications for bipolar disorder. Most of the emerging treatments in pharmaceutical industry developmental programmes are new or modified anticonvulsants or atypical antipsychotics. A number of possible future directions and challenges for the field are discussed. The treatment of bipolar disorder is unlikely to advance substantially until the causative pathogenetic molecular processes are elucidated.     

Novel treatments for food allergy

Food allergy is a major cause of life-threatening hypersensitivity reactions. Currently, the strict avoidance of the allergenic food and ready access to self-injectable adrenaline is the standard of care for food allergy. Based on extensive characterisation of food allergens and a better understanding of the immunological mechanisms underlying allergic disease, promising therapeutic modalities for the treatment and eventual prevention of food allergy are being developed. Novel immunotherapeutic strategies include peptide immunotherapy, traditional Chinese medicine, mutated or homologous protein immunotherapy, DNA immunisation and immunisation with immunostimulatory sequences, which all strive to elicit a decreased T helper cell type 2-like response or tolerance by the immune system in response to a specific food allergen. Other approaches such as the anti-IgE therapy or the Fcgamma-Fcepsilon fusion protein aim at preventing the release of mediators by mast cells. It is the combination of these different approaches that would probably offer the best treatment option for food-allergic patients in a not too distant future.     

Novel treatments for cancer cachexia

Cancer cachexia is a debilitating and life-threatening syndrome characterised by anorexia, body weight loss, loss of adipose tissue and skeletal muscle, and accounts for ≥ 20% of deaths in neoplastic patients. Cancer cachexia significantly impairs quality of life and response to antineoplastic therapies, increasing the morbidity and mortality of cancer patients. Muscle wasting is the most important phenotypic feature of cancer cachexia and the principle cause of function impairment, fatigue and respiratory complications, and is mainly related to a hyperactivation of muscle proteolytic pathways. Existing therapeutic strategies have proven to be only partially effective. In the last decade, the correction of anorexia, the inhibition of catabolic processes and the stimulation of anabolic pathways in muscle has been attempted pharmacologically, giving encouraging results in animal models and through preliminary clinical trials.     

Novel treatments for cancer cachexia

Cancer cachexia is a debilitating and life-threatening syndrome characterised by anorexia, body weight loss, loss of adipose tissue and skeletal muscle, and accounts for > or = 20% of deaths in neoplastic patients. Cancer cachexia significantly impairs quality of life and response to antineoplastic therapies, increasing the morbidity and mortality of cancer patients. Muscle wasting is the most important phenotypic feature of cancer cachexia and the principle cause of function impairment, fatigue and respiratory complications, and is mainly related to a hyperactivation of muscle proteolytic pathways. Existing therapeutic strategies have proven to be only partially effective. In the last decade, the correction of anorexia, the inhibition of catabolic processes and the stimulation of anabolic pathways in muscle has been attempted pharmacologically, giving encouraging results in animal models and through preliminary clinical trials.