Evaluating aripiprazole as a potential bipolar disorder therapy for adults

Introduction: Second generation antipsychotics (SGAs) have emerged as new treatment options for bipolar disorders (BDs). Aripiprazole (ARI) is already an SGA approved therapy for the treatment of BD type-I, both as a monotherapy as well as an add-on therapy in acute mania and in long-term maintenance therapy.

Areas covered: The authors provide a systematic review that illustrates ARI’s pharmacological profile including its efficacy on various aspects of BD in adults. It also reviews its role in bipolar treatment algorithms and provides a focus on future research developments and further potential uses of the compound. Additional aspects such as safety and tolerability are also considered.

Expert opinion: Compared with haloperidol, ARI shows fewer extrapyramidal symptoms (EPS), but has a slightly lower efficacy in mania. It has a better metabolic parameter profile and fewer cardiovascular adverse events than other SGAs although the add-on treatment shows a higher risk of EPS. Presently, data doesn’t support its use as a first choice maintenance monotherapy but it may be useful as a combination therapy for BD patients with comorbidities such as drug abuse and obsessive-compulsive disorders. Studies on ARI in bipolar depression are disappointing. However, future studies on the drug, at a low dose combined with a stabilizer or antidepressant may prove interesting.     

Aripiprazole for the treatment of bipolar disorder: a review of current evidence

Introduction: Several medications are available for the treatment of different phases of bipolar disorder, yet many of the drugs that are currently approved carry a substantial burden of side effects or do not lead all treated patients to remission.

Areas covered: This paper comprises a review and commentary regarding the use of oral and intramuscular aripiprazole in the acute and maintenance phases of bipolar disorder. Basic principles in dosing, switching, management of side effects and co-administration of aripiprazole with other medications are provided. This paper presents practical strategies to translate the data from clinical research into clinical practice.

Expert opinion: Aripiprazole has proven to be an effective medication for the acute treatment of manic and mixed episodes, as well as for the prophylactic–maintenance phase of bipolar disorder in patients recovering from a manic/mixed episode. Choosing the appropriate dosing and tapering strategy, addressing the side effects, controlling withdrawal symptoms from previous medications and using adjunctive medications when necessary are key to successful treatment with aripiprazole.     

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.     

Prepubertal bipolar disorder: available pharmacological treatment options

Awareness of bipolar spectrum disorders in children is rapidly increasing, with a more precise definition of their clinical subtypes and early signs. Paediatric bipolar disorder can lead to an important impairment in scholastic, familial and social functioning, and to a higher risk for substance abuse and suicide. In the context of a multimodal approach, the core treatment of early-onset bipolar disorder is pharmacological. This review focuses on the empirical evidence for pharmacotherapy in paediatric bipolar disorder. Mood stabilisers, including lithium, and older and newer anticonvulsivants will be considered, in mono- or polypharmacy. Atypical antipsychotics will be considered in more severe and/or treatment-resistant manic or mixed episodes. Finally, the prophylaxis of intercritical phases and the management of specific challenging conditions, such as bipolar depression and attention deficit hyperactivity disorder, with bipolar comorbidity, will be reviewed.     

抗抑郁药物在双相情感障碍治疗中的应用

抗抑郁药物在双相情感障碍中的应用备受关注。抗抑郁药物治疗双相抑郁急性期疗效较为肯定,但有转躁等问题;长期治疗的预防效果尚有待进一步研究。本文从循证医学角度,综述抗抑郁药物在双相情感障碍(主要是双相抑郁)急性期和维持期治疗中的疗效以及转躁情况,阐述双相情感障碍治疗中抗抑郁药物合理使用的重要性和必要性。     

Lamotrigine in the treatment of bipolar disorder

Lamotrigine is a novel anticonvulsant agent that has recently been introduced as a long-term treatment in bipolar disorder. Its role in the treatment of epilepsy is based on its actions to decrease ion channel conductance and antagonise glutamatergic function. Therefore, it has a mode of action unlike other agents used on a long-term basis in mood disorders. The evidence for efficacy is stronger for the prevention of depressive, rather than manic, episodes. The pivotal trials are in bipolar I disorder, but there is interest in its actions in patients with bipolar II and spectrum conditions. Its efficacy in other psychiatric conditions remains to be properly established. It is well tolerated and, with careful prescribing, the incidence of rash occurs no more than with placebo; however this is still a concern. Although usually well tolerated, headache, insomnia and drowsiness are probably the most common side effects.     

Oxcarbazepine in bipolar disorder: a critical review of the literature

Oxcarbazepine (OXC) is a keto-congener of carbamazepine, which has fewer side effects and drug interactions. However, the efficacy of OXC in treating bipolar disorder is not as well established as that of carbamazepine. This article is a systematic literature review of all studies regarding OXC and bipolar disorders, with particular attention to papers published in the last 6 years. Using the terms ‘oxcarbazepine and bipolar disorder’, ‘oxcarbazepine and mania’ or ‘oxcarbazepine and bipolar depression’, a computer-aided search of MEDLINE for the years 2000 – 2006 has been conducted. Since its introduction as an antiepileptic drug in early 2000, clinical research regarding the potential role of OXC in the treatment of bipolar disorder remains limited. There is a lack of double-blind, placebo-controlled studies. Studies recently published have small samples of patients, with insufficient follow-up periods and other methodological weaknesses. The efficacy of OXC in bipolar disorder has not been widely studied. Some authors recommend using OXC as monotherapy or as add-on therapy in refractory mania, although results are not conclusive. It is unknown whether OXC has efficacy in the maintenance treatment of bipolar disorder. OXC can be particularly useful as an add-on treatment in bipolar disorder patients for whom previous treatments have failed, or in patients who have difficulty tolerating adequate dosages of standard approved treatments.     

Evidence for the use of vilazodone in the treatment of major depressive disorder

Introduction: Major depressive disorder (MDD) is characterized by dysfunction in cognition, behavior, and physical functioning, and is associated with a chronic clinical course. There are barriers to successful treatment, which often result in early discontinuation and relapse. Adverse effects (AEs) remain the most commonly cited reason for discontinuation of treatment with conventional antidepressants, particularly early on in therapy. This often translates into relapse of symptoms or recurrence of the depressive episode. The delay to therapeutic response also has a meaningful implication for treatment adherence.

Areas covered: This article focuses on the implications of a novel entity for the treatment of depression; the first new molecule developed for this indication in the last 10 years. Vilazodone is a novel dual-acting serotonergic antidepressant, which is a selective and potent inhibitor of serotonin reuptake, as well as a selective partial agonist of the 5-HT_1A receptor.

Expert opinion: The data available in the literature so far indicate clinical efficacy over placebo and a rather benign adverse event profile. Whether the early onset of clinical efficacy observed in one of the two pivotal studies represents a true or only a chance phenomenon, only future studies can tell. Adverse effects are mostly mild–moderate and most GI type AEs disappear in about one week, at a time when all patients are still on a clinically suboptimal daily dosage (10 mg/d during the first week). Sexual AEs did not differ from placebo. Vilazodone represents an interesting addition to the arsenal of available antidepressants.     

Clinically relevant treatment considerations regarding lithium use in bipolar disorder

Introduction: The goal of this paper is to provide a practical, clinically oriented review of lithium, a salt widely used to treat mania since the 1870s and formally approved as a mood stabilizer in 1970. Although lithium is still considered a first-line treatment for bipolar mania in most practice guidelines, its use may be overshadowed by newer psychotropic medications.

Areas covered: This paper addresses the historical use of lithium, modern indications for its use, guidelines for prescribing and monitoring continued lithium use, drug-drug interactions, and pharmacodynamics/pharmacokinetic properties. The paper also reviews the unique properties of lithium and their potential clinical importance.

Expert opinion: While the use of lithium does involve some unique risks to the patient, it may also has some unique advantages in certain patient populations. Two major findings that make lithium unique are its potential neuroprotective benefits and decreased risk of suicide in patients with mood disorders.     

Comorbidity in bipolar disorder: a framework for rational treatment selection

Bipolar disorders are heterogeneous disorders often requiring multimodality treatment. The expanding pharmacopeia for bipolar disorders invites the need for a treatment framework that both recognizes and anticipates the multidimensionality and comorbidity of the illness. No available neurotherapeutic agent is singularly efficacious for the complete mélange of bipolar symptomatology. An apparent paradox has emerged in the management of bipolar disorder; whilst results from rigorous controlled monotherapy trials suggest that a disparate assortment of neurotherapeutic agents are efficacious in distinct phases of bipolar disorder, the majority of tertiary-treated bipolar patients receive polypharmacotherapeutic regimens. The evidentiary base for polypharmacotherapy is sparse and has recently become an area of active research focus. In the interim, clinicians are encouraged to invoke an organizational schema for the treatment of bipolar disorder that considers the spectrum of effectiveness of putative and established mood stabilizers. This schema should be further informed by the treatment data for comorbid and accessory conditions. The authors propose a schema to provide the impetus for further work in the area.     

Cloning,expression and pharmacology of a truncated splice variant of the human 5-HT7 receptor (h5-HT7(b))

1. The rat 5-hydroxytryptamine (5-HT)₇ receptor displays two splice variations, a long form, and a truncated splice isoform, arising from the introduction of a stop codon near the carboxy-terminus. The human 5-HT₇ receptor gene contains at least two introns and encodes a 445 amino acid 5-HT receptor.
2. A truncated splice variation in the human 5-HT₇ receptor was isolated from a human placental cDNA library. In accordance with current NC-IUPHAR nomenclature guidelines, it is suggested that this receptor be denoted as the h5-HT_7(b) receptor and the long form of the receptor as h5-HT_7(a).
3. The h5-HT_7(b) receptor was stably expressed in HEK 293 cells and ligand affinities were determined by displacement of [³H]-5-carboxyamidotryptamine (5-CT; K_d=0.28±0.06 nM, B_max=7.3±1.7 pmol mg⁻¹ protein). The rank order of affinities (pK_i) for a series of ligands was: 5-carboxamidotryptamine (5-CT, 9.65)>5-hydroxytryptamine (5-HT, 9.41)>methiothepin (8.87)>mesulergine (7.87)>8-hydroxy-2(di-n-propylamino)tetralin (8-OH-DPAT, 6.85)>ketanserin (6.44).
4. The h5-HT_7(b) receptor coupled positively to adenylyl cyclase in HEK 293 cells. This response was elicited by a number of agonists with the following order of potency (pEC₅₀): 5-CT (8.7±0.11)>5-MeOT (5-methoxytryptamine; 8.1±0.20)>5-HT (7.5±0.13)>tryptamine (5.6±0.36)>8-OH-DPAT (5.3±0.28)>5-methoxytryptamine (5.0±0.06). This rank order was comparable to that observed in the radioligand binding studies.
5. In a similar fashion to that described for the 5-HT_7(a) receptor, PCR studies suggested that the 5-HT_7(b) receptor mRNA is found in great abundance throughout the brain, in the small intestine and aorta.
6. It is concluded that the h5-HT₇ receptor, like the rat receptor, exists as splice variants exhibiting similar pharmacology, signal transduction and distribution. It is thus likely that there exists a complex physiological role for alternate splicing products of the 5-HT₇ receptor gene.

     

Lamotrigine (Lamictal IR) for the treatment of bipolar disorder

Introduction: Sodium glucose co-transporter 2 (SGLT2) inhibitors are a new class of glucose-lowering agents developed for the treatment of type 2 diabetes mellitus (T2DM). These agents have a mechanism of action that is independent of pancreatic β-cell function or the degree of insulin resistance; consequently, SGLT2 inhibitors have the potential to be used not only as monotherapy but also in combination with any of the existing classes of glucose-lowering agents, including insulin. As part of the extensive clinical development programs for modern T2DM therapies, SGLT2 inhibitors have been studied in combination with the most commonly used classes of glucose-lowering medications.

Areas covered: This report summarizes the key clinical trials data for combination therapies using SGLT2 inhibitors currently approved in the United States and/or the European Union, namely, dapagliflozin, canagliflozin, and empagliflozin.

Expert opinion: When given as add-on combination therapy with other glucose-lowering agents, or as monotherapy, SGLT2 inhibitors produced modest but clinically meaningful reductions in glycated hemoglobin, body weight, and systolic blood pressure. These changes have been sustained over long-term follow-up. SGLT2 inhibitors have a generally favorable safety profile similar to that of placebo, and are well tolerated. The risk of hypoglycemia appears to depend on coadministered glucose-lowering agents: when used as monotherapy, the frequency is comparable to that of placebo, but an increased risk is associated with concomitant use of sulfonylureas or insulin. In addition, an increased risk of genitourinary infections has been reported with SGLT2 inhibitors. However, these infections are usually mild, nonrecurrent, and respond to standard treatment.     

Iloperidone,asenapine and lurasidone: a primer on their current status

Introduction: Three newer atypical antipsychotic drugs were FDA-approved in 2009 and 2010 in the following order: iloperidone, asenapine and lurasidone. The three drugs are indicated for the treatment of acute schizophrenia. Asenapine is also approved for treatment of manic or mixed episodes associated with bipolar I disorder, for the maintenance treatment of schizophrenia and as an adjunctive therapy with lithium or valproate for the acute treatment of manic or mixed episodes associated with bipolar I disorder in adults.

Areas covered: This review compares and contrasts the current preclinical, clinical, safety and tolerability profiles of the three newer drugs, as reported in published preclinical and clinical studies, product labels, poster presentations and press releases.

Expert opinion: Preclinical studies have reported that the three drugs have variable affinities for a wide range of neurotransmitter receptors, and are active in animal models predictive of antipsychotic activity. Asenapine is the first antipsychotic to be administered sublingually, whereas iloperidone requires titration to minimize orthostatic hypotension. Asenapine and lurasidone are associated with dose-related akathisia, whereas iloperidone is not. The three drugs appear to have relatively benign metabolic profiles. The availability of the three novel antipsychotics should provide additional options for improved treatment of schizophrenia and other psychotic disorders.     

Drugs under early investigation for the treatment of bipolar disorder

Introduction: Despite the availability of several treatment options for bipolar disorder (BD), patients suffer from chronic, subsyndromal symptoms, quite frequent polarity shifts, cognitive impairment and poor community function. Overall, the current treatment outcomes for BD highlight the need to develop targeted, more effective and safe treatments.

Areas covered: This review focuses on compounds currently under investigation for BD, covering compounds tested through animal studies to those in Phase II clinical trials over the past 5 years. These drugs concern all phases of BD treatment, that is, mania, depression, maintenance, and cognitive dysfunction.

Expert opinion: Limitations exist in applying valid preclinical bipolar models and study designs. Research emphasis is given mainly on bipolar depression, with few compounds showing some evidence of efficacy. Non-effectiveness in current studies of mania and maintenance treatment reflects the need for novel compounds. Glycogen synthase kinase 3, casein kinase 1, inositol monophosphatase inhibition, histone deacetylase inhibition pathways are known targets that should proceed from preclinical to the clinical trial level.     

Olanzapine monotherapy for acute depression in patients with bipolar I or II disorder: results of an 8‐week open label trial

We evaluated the efficacy, tolerability, and safety of olanzapine monotherapy in 20 adult patients with bipolar I or II disorder, depressed phase. Patients received open‐label olanzapine monotherapy (mean modal dose, 15 mg/day) for 8 weeks. Assessments of psychopathology (Montgomery–Asberg Depression Rating Scale [MADRS], Quick Inventory of Depressive Symptomatology [QIDS‐SR‐16], Young Mania Rating Scale [YMRS]), clinical global state (Clinical Global Impressions [CGI] scale), and safety/tolerability were performed at baseline, and at 1, 2, 4, 6, and 8 weeks. Seventeen patients (85.0%) completed the study. Improvement in MADRS total scores was observed after the first week of treatment, and at all remaining follow‐up time points (p ≤ 0.005). Parallel improvement in QIDS‐SR‐16 (p < 0.001) and CGI‐Severity (p < 0.001) was observed between baseline and study endpoint. Nine (45%) subjects achieved positive treatment response, eight of whom (40%) also achieved symptom remission. There were significant increases in weight (+3.2 kg, p = 0.001) and body mass index (+1.1 kg/m², p = 0.001), but not fasting glucose or lipids, with the exception of reduced triglyceride levels in the overall sample, and reduced HDL cholesterol in females. Olanzapine may be an effective, well‐tolerated option for treating acute non‐psychotic depression across a variety of bipolar disorder subtypes. Copyright © 2009 John Wiley & Sons, Ltd.     

Combination of mood stabilizers with quetiapine for treatment of acute bipolar disorder: an open label study

OBJECTIVES: The atypical antipsychotics are being increasingly used to control acute manic episodes, and data are emerging to support their mood-stabilizing and antidepressant properties. This study investigated the short-term efficacy of quetiapine as an add-on therapy in the treatment of acute mania. METHOD: This study was a 4-week, open-label, add-on, prospective investigation using quetiapine in addition to mood stabilizers. Data on 18 patients fulfilling DSM-IV diagnostic criteria for bipolar I disorder were analysed. The Young mania rating scale (YMRS), the Hamilton scale for depression (HDRS), the brief psychiatric rating scale (BPRS) and extrapyramidal symptom rating scale (ESRS) were applied at baseline and at weeks 1, 2 and 4. The clinical global impression scale (CGI) was evaluated at baseline and week 4. RESULTS: The addition of quetiapine produced a statistically significant improvement on the YMRS, HDRS, BPRS and CGI score at week 4 from baseline (p<0.005). Quetiapine was well tolerated, with no subjects discontinuing because of side effects. CONCLUSIONS: The combination of quetiapine was associated with a substantial symptomatic improvement in patients with acute mania. Randomized placebo-controlled prospective studies are needed.     

Serotonin receptors in platelets of bipolar and schizoaffective patients: effect of lithium treatment

Rationale Abnormalities of serotonin (5HT) function have been implicated in mood disorders, and lithium treatment may produce its beneficial effects by modifying serotonergic mechanisms. It has also been observed that 5HT_2A receptors are upregulated both in the postmortem brain and platelets of patients with depression and suicidal behavior. However, the role of 5HT_2A receptors in bipolar disorders and in the mechanism of action of lithium is unclear.Objective The major objective of this study was to examine if abnormalities of 5HT_2A receptors are associated with bipolar or schizoaffective disorders and if treatment with lithium would cause changes in the 5HT_2A receptors.Methods 5HT_2A receptors were studied in the platelets obtained from drug-free normal control subjects and patients with bipolar (n=41) or schizoaffective (n=20) disorders during a drug-free washout period and after treatment (4.0±0.44 weeks) with lithium (n=16). The B_max and K_D of 5HT_2A receptors were quantitated by binding techniques using [¹²⁵I]lysergic acid diethylamide (LSD) as a ligand.Results We observed that the 5HT_2A receptor B_max was increased in platelets obtained from drug-free bipolar or schizoaffective patients as compared with normal control subjects. The 5HT_2A receptor density was even more increased in bipolar or schizoaffective suicidal patients, and the 5HT_2A receptor B_max in the non-suicidal bipolar or schizoaffective subgroup also was significantly higher than in normal control subjects. Treatment with lithium caused a significant increase in the B_max of platelet 5HT_2A receptors in bipolar or schizoaffective patients.Conclusions Our studies indicate that increased 5HT_2A receptors may be associated with the pathophysiology of bipolar illness and that treatment with lithium further increases the density of 5HT_2A receptors. Whether this increase in 5HT_2A receptors caused by lithium is associated with its therapeutic mechanism of action is unclear. It is also not clear whether the increase in 5HT_2A receptors in bipolar or schizoaffective patients, or in suicidal bipolar or schizoaffective patients, is a trait or state marker.     

3-(4-(Tetrahydropyridin-1-yl)butyl)oxindoles as 5-HT7 receptor ligands

On the basis of specific criteria, serotonin (5-HT) receptors are categorised into seven major families (5-HT₁ – 5-HT₇), of which 5-HT₇ receptors represent one of the newest populations. Although evidence suggests that 5-HT₇ receptors, which are found both centrally and peripherally, might be involved in various central disorders, such as depression, psychosis and cognitive impairment, as well as in circadian rhythm, sleep physiology and cardiovascular function, only recently have selective agents been identified to better assess their role. 5-HT₇ receptors are certainly viable targets for drug development. Egis Pharmaceuticals identified a series of oxindole analogues that bind at 5-HT₇ receptors and are claimed to be of possible benefit in the treatment of central disorders.     

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.