Anticonvulsants in the treatment of mood disorders: assessing current and future roles

Anticonvulsants are frequently used in the treatment of affective illnesses, especially for patients refractory to or intolerant of other treatments. The differential therapeutic roles of anticonvulsants, however, remain largely undetermined. The author reviews the available efficacy data for carbamazepine, oxcarbazepine, valproate, lamotrigine, gabapentin and topiramate. Valproate is efficacious in the monotherapy of acute manic presentations but confirmatory evidence of the efficacy of valproate in long-term maintenance has been elusive. Valproate and possibly carbamazepine, may provide a therapeutic advantage over lithium in non-classic bipolar conditions such as mixed mood states and rapid cycling conditions. Lamotrigine is unique among the anticonvulsants in its monotherapy efficacy for bipolar I depression. Emerging data also suggest a role for lamotrigine in the adjunctive treatment of depressive mixed states and rapid cycling conditions in the absence of prominent manic symptoms. Controlled trials have found gabapentin ineffective for acute mania and refractory bipolar conditions. The role of gabapentin in the treatment of other aspects of affective illness remains uncertain. Definitive statements regarding the differential psychotropic use of topiramate and oxcarbazepine are not possible, though active investigation is underway to better characterise the utility of topiramate. The author suggests that current diagnostic models utilised in controlled trials may limit identification of differential therapeutic benefits. Caution is advised in generalising from the ability or inability of an agent to demonstrate antimanic activity. Future studies of newer anticonvulsants should include dimensional perspectives and soft bipolar presentations, as the greatest contribution of the newer anticonvulsants may be in treatment of mood conditions other than acute mania.     

Anticonvulsants in the treatment of mood disorders: assessing current and future roles

Anticonvulsants are frequently used in the treatment of affective illnesses, especially for patients refractory to or intolerant of other treatments. The differential therapeutic roles of anticonvulsants, however, remain largely undetermined. The author reviews the available efficacy data for carbamazepine, oxcarbazepine, valproate, lamotrigine, gabapentin and topiramate. Valproate is efficacious in the monotherapy of acute manic presentations but confirmatory evidence of the efficacy of valproate in long-term maintenance has been elusive. Valproate and possibly carbamazepine, may provide a therapeutic advantage over lithium in non-classic bipolar conditions such as mixed mood states and rapid cycling conditions. Lamotrigine is unique among the anticonvulsants in its monotherapy efficacy for bipolar I depression. Emerging data also suggest a role for lamotrigine in the adjunctive treatment of depressive mixed states and rapid cycling conditions in the absence of prominent manic symptoms. Controlled trials have found gabapentin ineffective for acute mania and refractory bipolar conditions. The role of gabapentin in the treatment of other aspects of affective illness remains uncertain. Definitive statements regarding the differential psychotropic use of topiramate and oxcarbazepine are not possible, though active investigation is underway to better characterise the utility of topiramate. The author suggests that current diagnostic models utilised in controlled trials may limit identification of differential therapeutic benefits. Caution is advised in generalising from the ability or inability of an agent to demonstrate antimanic activity. Future studies of newer anticonvulsants should include dimensional perspectives and soft bipolar presentations, as the greatest contribution of the newer anticonvulsants may be in treatment of mood conditions other than acute mania.     

Oxcarbazepine. A review of its pharmacology and therapeutic potential in epilepsy, trigeminal neuralgia and affective disorders.

Oxcarbazepine is the 10-keto analogue of carbamazepine but has a distinct pharmacokinetic profile. In contrast to the oxidative metabolism of carbamazepine, oxcarbazepine is rapidly reduced to its active metabolite, 10,11-dihydro-10-hydroxy-carbamazepine. With the possible exception of the P450IIIA isozyme of the cytochrome P450 family, neither oxcarbazepine nor its monohydroxy derivative induce hepatic oxidative metabolism. Direct comparison of oxcarbazepine and carbamazepine has shown no difference in efficacy between these 2 agents in terms of reducing seizure frequency in patients with partial epilepsy with or without secondary generalisation, or with tonic-clonic seizures. Substitution of oxcarbazepine for carbamazepine in multiple antiepileptic drug regimens improved seizure control in some patients with refractory epilepsy; however, the rise in serum concentrations of concurrent antiepileptic agents secondary to elimination of carbamazepine-associated hepatic enzyme induction may have also played a role. Substitution of oxcarbazepine for carbamazepine was associated with improved cognition and alertness in some patients with epilepsy. Limited data indicate that oxcarbazepine may be a useful alternative to carbamazepine in the management of trigeminal neuralgia. Experience in patients with acute mania is promising, but the value of oxcarbazepine in managing affective disorders, particularly as a prophylactic agent, is not established. Oxcarbazepine may be better tolerated than carbamazepine; however, the current published database is small and the potential for oxcarbazepine to induce the type of serious idiosyncratic reactions occasionally associated with carbamazepine is unknown. Hyponatraemia has been reported in patients treated with oxcarbazepine. Although apparently asymptomatic, fluid restriction may be deemed necessary in some patients to reduce the risk of precipitating seizures secondary to low serum sodium. Thus, oxcarbazepine appears to be an effective substitute for carbamazepine in those patients intolerant of this agent, or experiencing significant drug interactions. Wider clinical experience should help clarify the long term efficacy and tolerability of oxcarbazepine. Pharmacokinetic advantages over current antiepileptic drugs, carbamazepine in particular, may then favour oxcarbazepine for consideration as a first-line agent in the management of partial and tonic-clonic epilepsy.     

The place of anticonvulsant therapy in bipolar illness

 With the increasing recognition of lithium’s inadequacy as an acute and prophylactic treatment for many patients and subtypes of bipolar illness, the search for alternative agents has centered around the mood stabilizing anticonvulsants carbamazepine and valproate. In many instances, these drugs are effective alone or in combination with lithium in those patients less responsive to lithium monotherapy, including those with greater numbers of prior episodes, rapid-cycling, dysphoric mania, co-morbid substance abuse or other associated medical problems, and patients without a family history of bipolar illness in first-degree relatives. Nineteen double-blind studies utilizing a variety of designs suggest that carbamazepine, or its keto-congener oxcarbazepine, is effective in acute mania; six controlled studies report evidence of the efficacy of valproate in the treatment of acute mania as well. Fourteen controlled or partially controlled studies of prophylaxis suggest carbamazepine is also effective in preventing both manic and depressive episodes. Valproate prophylaxis data, although based entirely on uncontrolled studies, appear equally promising. Thus, both drugs are widely used and are now recognized as major therapeutic tools for lithium-nonresponsive bipolar illness. The high-potency anticonvulsant benzodiazepines, clonazepam and lorazepam, are used adjunctively with lithium or the anticonvulsant mood stabilizers as substitutes or alternatives for neuroleptics in the treatment of manic breakthroughs. Preliminary controlled clinical trials suggest that the calcium channel blockers may have antimanic or mood-stabilizing effects in a subgroup of patients. A new series of anticonvulsants has just been FDA-approved and warrant clinical trials to determine their efficacy in acute and long-term treatment of mania and depression. Systematic exploration of the optimal use of lithium and the mood-stabilizing anticonvulsants alone and in combination, as well as with adjunctive antidepressants, is now required so that more definitive treatment recommendations for different types and stages of bipolar illness can be more strongly evidence based. Received: 20 May 1996 / Final version: 19 July 1996     

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.     

Effectiveness and Tolerability of Carbamazepine vs. Oxcarbazepine as Mood Stabilizers

Abstract

Background.?Patients with bipolar illness or maniac-type schizoaffective disorder often present a variety of symptoms and mixed responses to treatment. Several anticonvulsants have been found effective in the treatment of mood disorders. In the early 70's, the clinical efficacy of carbamazepine in the treatment of acute mania was reported. Oxcarbazepine has been available in the United States since 2000. Both drugs display a different spectrum of properties and side effect profiles. Objective.?To compare the effectiveness and tolerability of carbamazepine and oxcarbazepine in a naturalistic setting. Methods.?A retrospective and concurrent chart review of all patients treated with carbamazepine or oxcarbazepine (n = 33) as mood stabilizers between 01 and 12 2002. The effectiveness was evaluated using the Positive And Negative Syndrome Scale (PANSS). Tolerability was assessed according to side effects recorded on charts. Patients with charts that were not complete were excluded from this study. Results.?There were no significant differences in efficacy between groups on positive (F = 3.575, P = 0.075), negative (F = 2.641, P = 0.121), or the general subscales (F = 1.111, P = 0.306) of the PANSS. Patients in both groups developed gastrointestinal upset and headache, but no significant differences in tolerability between the two therapies were found (χ² = 0.466, df = 1, P = 0.659) and (χ² = 0.195, df = 1, P = 0.367 respectively). Conclusion.?In summary, the patient charts reviewed demonstrated that carbamazepine, as well as, oxcarbazepine are equally effective and tolerable as mood stabilizers.     

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.     

Newer anticonvulsants: comparative review of drug interactions and adverse effects

The tolerability and drug interaction profiles of 6 new anticonvulsants: oxcarbazepine, vigabatrin, lamotrigine, gabapentin, tiagabine and topiramate, are reviewed. In general, these new anticonvulsants are well tolerated and drug interaction problems are minor with the exception of the risk of failure of oral contraceptives during treatment with oxcarbazepine or topiramate. In this review, the clinical implications of the tolerability of these drugs are discussed for different patient groups. The choice of which new anticonvulsant for which patient depends upon individual factors, in particular, seizure type, tolerability and practical administration factors. Treating elderly patients may be complicated by an increased sensitivity to adverse effects as these patients very often receive polytherapy for accompanying diseases. Drugs with very simple pharmacokinetic properties may be preferred in this group. Women of childbearing age face specific problems related to the epilepsy and to treatment with anticonvulsants. These include impaired fertility, failure of oral contraceptives and the risk of birth defects. Some new anticonvulsants may be suggested in preference to classical drugs to avoid these problems, but the human experience with newer anticonvulsants is still limited and, therefore, so is knowledge of the risk of congenital malformations in the offspring of mothers taking anticonvulsants. Psychiatric and behavioural changes frequently complicate treatment of patients with mental retardation. Some of the new anticonvulsants, in particular those affecting the gamma-aminobutyric acid (GABA) system such as vigabatrin, seem to exacerbate this problem and should be used with caution in these patients.     

Current aspects of valproate in bipolar disorder

For more than 30 years, lithium has been the drug of choice for the treatment of bipolar disorder. However, it has numerous adverse effects, a relatively slow onset of action, many common drug-drug interactions, and a narrow therapeutic index. Because of these problems, researchers looked for alternative and/or adjunctive treatments in bipolar disorder, focusing on the anticonvulsants carbamazepine and valproate. The existing data of valproate are reviewed pointing out its promises and limitations in psychiatric diseases. Growing data indicate that valproate is a well tolerated and effective agent in bipolar disorder. Controlled studies prove its use in acute mania, often with a rapid onset of action. Open studies suggest that the drug also reduces the frequency and intensity of recurrent manic and depressive episodes over extended periods. Its acute and prophylactic antidepressant effects are probably minor to its antimanic efficacy. Recent data support the specific therapeutic efficacy of valproate in certain subtypes of bipolar illness: rapid cycling variant, mixed mania, bipolar disorder associated with panic attacks, comorbid alcohol or substance abuse, with neurological features or secondary to organic illnesses. These features make valproate interesting as an alternative treatment for patients who generally respond less well to lithium or as a useful adjunct in the treatment of complicated patients who do not respond to single agents. However, further controlled studies are warranted to provide clear guidelines for the treatment with valproate.     

Antidepressant properties of anticonvulsant drugs for bipolar disorder

A growing number of anticonvulsant drugs are receiving attention as possible mood stabilizers. This attention is based mainly on the assumption that the antimanic efficacy of anticonvulsants makes them suitable as mood stabilizers. However, their antidepressant properties have received less scrutiny. In this review, current evidence concerning the acute and prophylactic efficacy of divalproex, carbamazepine, gabapentin, lamotrigine, and topiramate in bipolar depression is evaluated. Clinical outcome data are considered, together with limitations of existing studies and the concept of unmet clinical needs. Findings in placebo-controlled trials suggest an acute and prophylactic antidepressant effect with lamotrigine monotherapy and more modest antidepressant benefits with other agents administered as monotherapies. Results of published studies are considered with respect to the conceptualization of mood stabilization as arising from antimanic and antidepressant efficacy in bipolar disorder.     

Therapeutic effects of GABA-ergic drugs in affective disorders. A preliminary Report

A possible antimanic efficacy of the GABA-ergic anticonvulsant valproate was examined by use of a double-blind, placebo-controlled ABA design. A marked improvement was observed after valproate medication in a group of 5 acutely ill manic patients. Similar results were obtained in 7 trials examining the antimanic property of the keto-derivative of carbamazepine (oxcarbazepine) in 6 patients with acute mania, whereas no antimanic effect could be observed in a treatment with diazepam and with THIP. Combination of THIP and diazepam in another patient showed a slight antimanic effect. Additionally, a possible prophylactic effect of long-term treatment using valproate was examined. In 8 of 9 patients exhibiting a bipolar affective or schizoaffective psychosis, who did not properly respond to lithium treatment, a prophylactic effect of valproate medication could be demonstrated. The results point to the view that anticonvulsants, possibly due to GABA-ergic effects, may be beneficial in affective disorders.     

Oxcarbazepine for epilepsy--a useful new choice?

Oxcarbazepine* (Trileptal-Novartis), an anti-epileptic first marketed in the UK in 2000, is licensed for use both as adjunctive (add-on) therapy and as monotherapy for adults and children aged 6 years or over with partial-onset epileptic seizures, with or without secondary generalisation. The company claims that oxcarbazepine has "comparable efficacy" to carbamazepine with "greater tolerability", and causes "fewer withdrawals due to side effects compared to most established antiepileptic drugs". Here we discuss the place of oxcarbazepine in the treatment of epilepsy.     

奥卡西平的药代动力学及其立体选择性

奥卡西平是一种治疗癫痫部分发作和全身强直阵孪性癫痫发作的新药。与传统抗癫痫药物相比，奥卡西平有不良反应少、自身诱导及对肝药酶的诱导作用小等优点。本文系统地介绍了奥卡西平在人体内吸收、分布、代谢和排泄的药代动力学特征，对年龄、性别、肝肾功能损伤等影响因素进行了描述，同时综述了奥卡西平及其活性代谢产物10-羟基卡马西平在动物及人体内药代动力学的立体选择性。     

Oxcarbapezine: anticonvulsant profile and safety

Oxcarbazepine is a molecule chemically related to carbamazepine that shares most of the pharmacological and therapeutic effects of carbamazepine while displaying a more favorable profile regarding tolerability and drug-drug interactions. In contrast to carbamazepine, oxcarbazepine is metabolized through cytochrome P450-independent reductases, and is thus devoid of inductive effects on hepatic oxidative metabolism. Oxcarbazepine has been shown to be useful both as monotherapy and adjunctive therapy in patients with partial seizures with or without secondary generalization. The drug has been documented as safe and effective in adults as well as children aged 4-16 years. Additional data suggests that oxcarbazepine might improve cognition and psychomotor performance and might increase alertness, in contrast to the cognition/psychomotor impairment observed with some other antiepileptic drugs. Both the pharmacokinetic advantages over other anticonvulsant drugs and the lack of pharmacological interactions with oxcarbazepine may point to this drug as a first-line treatment for the management of partial and tonic-clonic epilepsy.(c) 2001 Prous Science. All rights reserved.     

The new antiepileptic drugs: pharmacological and clinical aspects

In recent years several new drugs (oxcarbazepine, lamotrigine, topiramate, gabapentin, zonisamide, tiagabine, fosphenytoin, vigabatrin and felbamate) have been added to the therapeutic armamentarium against epilepsy. Some of these represent structural modifications of pre-existing compounds, others were developed with the specific objective of modifying neurotransmitter function, and many more were found to be clinically useful even though their mode of action is unclear or differs from that originally planned. The pharmacokinetics of these drugs differ widely from one agent to another. Some (gabapentin and vigabatrin) are eliminated unchanged in urine and have little or no interaction potential; others (tiagabine, lamotrigine, topiramate, oxcarbazepine, zonisamide, felbamate) are subject to induction of metabolism by concomitant anticonvulsants; lamotrigine is vulnerable to metabolic inhibition by valproate, and felbamate is a powerful enzyme inhibitor in addition to being an inducer of the metabolism of carbamazepine and steroid oral contraceptives. All new antiepileptic drugs have been found to be effective in improving seizure control in patients with partial and secondarily generalized seizures. However, lamotrigine, topiramate, zonisamide and felbamate appear to have broader efficacy against both partial and many generalized seizure types, while vigabatrin is also valuable in the management of infantile spasms. In monotherapy studies, new drugs have not been found to be more efficacious than older agents, but some may offer limited advantages in terms of improved tolerability. On the other hand, serious toxicity restricts considerably the use of vigabatrin and felbamate. Overall, new drugs represent valuable tools in the fight against epilepsy, but because of limited experience and cost considerations their first-line use cannot be recommended in most situations.     

Safety and tolerability of mood-stabilising anticonvulsants in the elderly

The authors review current research on the safety and tolerability of anticonvulsant medications used for individuals over the age of 60 years with affective disorders, agitation and other psychiatric disorders. Three anticonvulsants currently approved in the US for treatment of bipolar affective disorder are reviewed: valproate, lamotrigine and extended-release carbamazepine. The authors discuss the pharmacokinetics, pharmacodynamics, drug-drug interactions and the impact of ageing for each drug. There are few studies of anticonvulsant medications in elderly patients with bipolar disorder or other psychiatric conditions. Therefore, the authors summarise adverse events of greatest prevalence and/or greatest severity based on data derived predominately from studies of geriatric patients with epilepsy and/or other non-psychiatric indications. Guidelines are offered for the safe use of these medications in the elderly, based on research literature.     

Oxcarbazepine: new preparation. An alternative to carbamazepine in partial epilepsy

(1) The reference treatment for partial epilepsy in adults and children is carbamazepine. (2) Oxcarbazepine is available in the European Union for the treatment of partial epilepsy in adults and children aged over 6 years, alone or in combination with other antiepileptic drugs. (3) The clinical file on oxcarbazepine monotherapy of recent-onset generalised or partial epilepsy mainly contains data from one trial versus carbamazepine, two trials versus phenytoin, and one trial versus valproate sodium. In these trials, 52-60% of patients had no seizures on oxcarbazepine, a proportion not significantly different from that obtained with the comparators. Oxcarbazepine may, in fact, be slightly less effective than carbamazepine. (4) For refractory partial epilepsy (especially forms refractory to carbamazepine), oxcarbazepine is more effective than a placebo, when combined with the inadequately effective treatment, as shown in two trials. Two dose-finding studies show that 2 400 mg/day oxcarbazepine is more effective than 300 mg/day. (5) In trials comparing single-drug treatments there were fewer withdrawals for adverse events among patients on oxcarbazepine than among those on carbamazepine or phenytoin. Compared with carbamazepine, the risk of cutaneous hypersensitivity reactions seems to be lower with oxcarbazepine, while the risk of hyponatraemia is higher. This risk of hyponatraemia necessitates laboratory monitoring. (6) The risk of clinically significant interactions appears to be lower on oxcarbazepine than on carbamazepine, and is limited mainly to combined contraceptives (contraceptive inefficacy) and phenytoin. (7) In practice, carbamazepine remains the reference treatment for partial epilepsy, but oxcarbazepine is one of several second-line options, either alone or in combination with other antiepileptics.     

奥卡西平和卡马西平治疗脑卒中后继发性癫痫疗效与安全性的Meta分析

目的 系统评价奥卡西平与卡马西平治疗脑卒中后继发性癫痫的疗效和安全性。方法 计算机检索PubMed、Cochrane Library、EMbase、万方、中国知网、维普、中国生物医学文献数据库（CBM）等收录的奥卡西平和卡马西平治疗脑卒中后继发性癫痫的相关文献,检索时限为建库以来到2017年8月,使用RevMan5.3软件进行Meta分析。结果 共纳入6项研究,包含517例患者。Meta分析结果显示：奥卡西平组控制癫痫的总体有效率高于卡马西平组,差异有统计学意义（RR=1.44,95%CI：1.29~1.60,P<0.000 01）;奥卡西平组总不良反应发生率低于卡马西平组,差异有统计学意义（RR=0.39,95%CI：0.26~0.57,P<0.000 01）;皮疹、头晕、嗜睡、恶心、呕吐发生率的比较差异均无统计学意义。结论 奥卡西平治疗脑卒中后继发性癫痫的疗效优于卡马西平,安全性较卡马西平好。由于本研究纳入的文献数量和样本量较少,因此还需更多大样本、多中心的高质量临床随机对照试验（randomized controlled trials,RCT）进一步研究验证。     

Efficacy and tolerability of pharmacotherapies for borderline personality disorder

Borderline personality disorder is a pervasive pattern of instability of interpersonal relationships, affects and self-image, as well as marked impulsivity. Although psychotherapy is needed to attain lasting improvements in a patient's personality and overall functioning, practice guidelines state that pharmacotherapy is indicated to manage state symptoms and trait vulnerabilities. Three psychopathological dimensions are the main targets for pharmacotherapy of borderline personality disorder: affective dysregulation, impulsive-behavioural dyscontrol and cognitive-perceptual symptoms. Guidelines recommend the use of antidepressant agents and mood stabilizers for affective dysregulation and impulsive-behavioural dyscontrol, and antipsychotics for cognitive-perceptual symptoms. This review aims to report and discuss data from clinical trials, reviews and meta-analyses concerning drug efficacy and tolerability in the treatment of borderline personality disorder. Investigations that considered antidepressant agents mainly focused on SSRIs, which are recommended as first-line treatments for affective instability and impulse dyscontrol. Both open-label and randomized controlled studies have been performed, predominantly concerning the efficacy of fluoxetine and fluvoxamine. Other classes of antidepressants, such as TCAs and MAOIs, were investigated as alternative treatments for borderline personality disorder, but the risk of adverse effects and toxicity is a limitation to their use in clinical practice. Increasing amounts of data have recently been collected on the use of mood stabilizers to control mood instability and impulsivity in patients with borderline personality disorder. More substantial data were derived from controlled trials of valproate semisodium, although other drugs such as lithium, carbamazepine, oxcarbazepine and lamotrigine were tested with promising results. Several first-generation antipsychotics were studied in open-label and controlled trials, with good effects on behavioural dyscontrol and psychotic-like symptoms. Selection biases and heterogeneity of drugs and methods somewhat limited the value of these results. More recent investigations have examined atypical antipsychotics, with most of these studies being open-label trials with small sample sizes; however, a few controlled studies have been performed using olanzapine, showing improvements in impulsivity, anger and hostility. In conclusion, a large number of different drugs have been evaluated in the treatment of patients with borderline personality disorder. Initial findings are encouraging for many of these drugs. However, data need to be replicated in further controlled studies with head-to-head comparisons and long-term follow-ups. Many questions remain to be answered.     

Atypical antipsychotics for the treatment of bipolar disorder: more shadows than lights

Atypical antipsychotics are utilised more frequently for the treatment of bipolar disorder than first-generation antipsychotics because of their improved neurological tolerability. Furthermore, recent studies suggest that psychiatric outcomes are improved in patients treated with atypical agents. The aim of this article is to review the studies evaluating the effectiveness of atypical antipsychotics in treating acute bipolar episodes (bipolar mania, bipolar depression and mixed episodes), as well as those investigating the effectiveness of atypical antipsychotics as maintenance treatment for the disorder. Because of several relevant methodological limitations affecting the vast majority of clinical trials, evidence-based information about the effectiveness of atypical antipsychotics in treating bipolar disorder is somewhat discouraging. Moreover, data indicating effectiveness in managing the acute manic phase and in long-term maintenance treatment are quantitatively robust only for olanzapine. However, olanzapine seems to have no advantages in terms of tolerability and therapy compliance when compared with classical mood stabilisers or first-generation antipsychotics. In addition, only a few studies have investigated the efficacy of atypical antipsychotics for treating bipolar depression. Hence, information regarding the effectiveness of such medications in treating this specific phase of bipolar disorder should be considered as still preliminary. Given this situation, further independent and well-designed studies are urgently needed before definitive conclusions on the effectiveness of most atypical antipsychotics in the different clinical situations characterising the natural course of bipolar disorder can be drawn.