Management options for bipolar disorder in children and adolescents

During recent years there has been a dramatic increase in the use of psychotropic medication for the treatment of bipolar disorder (BPD) in children. There is an emerging set of data to support this use.Mood stabilizers, including lithium and valproic acid (valproate sodium), have generally formed the mainstay of treatment in children and adolescents with BPD. However, the atypical antipsychotics, such as risperidone, aripiprazole, and quetiapine may be more effective as first-line treatment options and in some ways easier to use than the traditional mood stabilizers. As in adults, mood stabilization is often difficult to achieve in pediatric patients with BPD, and combined treatment with mood stabilizers and atypical antipscyhotics is commonly used. Data from controlled trials of psychotropic medications in children and adolescents with BPD are very limited, and hence, in the majority of cases physicians base their treatment decisions on data from case reports, case series, or open trials. More controlled studies of both monotherapy and polypharmacotherapy for BPD in children and adolescents are needed.     

Atypical antipsychotics and mood stabilization in bipolar disorder

The available literature on the use of atypical antipsychotics for the treatment of bipolar disorder was reviewed. All uncontrolled and controlled reports were identified through a comprehensive Medline search. Based on the available evidence, olanzapine was found to be the most appropriate atypical antipsychotic agent utilized for the treatment of manic bipolar patients, although there is also preliminary data suggesting the efficacy of risperidone and clozapine. The preliminary data evaluating the efficacy of quetiapine and ziprasidone in bipolar disorder are still very limited. Double-blind controlled studies with atypical antipsychotics in the long-term treatment of bipolar disorder are still largely not available, but will be critical to determine the effectiveness of these agents in the maintenance treatment of bipolar disorder. There are recent uncontrolled suggestions that olanzapine may have beneficial effects in depressed bipolar patients, which deserve further investigation in controlled studies. In conclusion, atypical antipsychotics, due to lower potential for neurotoxicity and preliminary evidence suggesting better efficacy than typical antipsychotics, are increasingly having a more prominent role in the pharmacological management of bipolar patients. Nonetheless, until there is systematic data from long-term controlled follow-up studies on the comparative efficacy of these agents with mood stabilizers, atypical antipsychotics should be cautiously utilized, and preferably in combination with a mood stabilizer for the maintenance phase of treatment. Electronic Publication     

Off-label use of atypical antipsychotics in personality disorders

INTRODUCTION: Personality disorders are among the most persistent and challenging disorders to treat within psychiatry. There is emerging evidence that some personality disorders, particularly borderline personality disorder and, to a lesser extent, schizotypal personality disorder, may benefit from treatment with atypical antipsychotics as well as mood stabilizers. This review examines the evidence for atypical antipsychotics for personality disorders and discusses strengths and limitations of this approach. AREAS COVERED: Searches of Medline and PsycInfo yielded 57 articles related to use of atypical antipsychotics for treatment of personality disorders. Most were relatively small randomized, controlled trials examining atypical antipsychotics for borderline personality disorder; however, the search also yielded two Cochrane reviews examining pharmacotherapy for borderline personality disorder and antisocial personality disorder as well as three other meta-analyses. EXPERT OPINION: There is some evidence that atypical antipsychotics are effective for treating symptom domains in personality disorders, in particular psychotic-like symptoms, impulsivity, aggression and anger. There is no evidence that they improve overall illness severity. Given the high rate of comorbidity between personality disorders and axis I disorders, atypical antipsychotics are best used when these symptom domains are prominent and there is a comorbid axis I condition for which an atypical antipsychotic is indicated.     

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.     

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.     

Treatment-refractory bipolar disorder: classification to aid in clinical management

Bipolar disorder is an illness with complex symptomatology that encompasses severe symptoms of mood and thought disorder and can limit the cognitive range of human brain functioning. The Diagnostic and Statistical Manual, 4th edition and International Classification of Mental Disorder recommend subgroups of bipolar disorder based on symptoms, illness severity, and frequency of episodes. Pharmacological agents commonly used in the management of bipolar disorder include lithium; anticonvulsants, such as valproate, carbamazepine and lamotrigine; and recent years have witnessed increasing use of atypical antipsychotics. There are several intra- and inter-class differences in these compounds, especially relating to polarity of mood episode under consideration. Monotherapy trials have focused on efficacy of the compounds; few have explored combination therapy, especially in patients failing to respond or inadequately responding to one agent. Clinicians have frequently prescribed two or more compounds to stabilize moods. Monotherapy treatment of bipolar manic episode with various compounds including atypical antipsychotics, mood stabilizers such as lithium, valproic acid and carbamazepine yielded response rates of 50%. However, combination therapy of atypical antipsychotics with valproic acid or lithium offered an additional 20% improvement in the response rates. The article will review published data on augmentation studies, comment on case reports published in treatment-refractory bipolar disorder, and propose a new classification guideline for staging treatment-refractory bipolar disorder.     

Off-label use of atypical antipsychotics in personality disorders

Introduction: Personality disorders are among the most persistent and challenging disorders to treat within psychiatry. There is emerging evidence that some personality disorders, particularly borderline personality disorder and, to a lesser extent, schizotypal personality disorder, may benefit from treatment with atypical antipsychotics as well as mood stabilizers. This review examines the evidence for atypical antipsychotics for personality disorders and discusses strengths and limitations of this approach.

Areas covered: Searches of Medline and PsycInfo yielded 57 articles related to use of atypical antipsychotics for treatment of personality disorders. Most were relatively small randomized, controlled trials examining atypical antipsychotics for borderline personality disorder; however, the search also yielded two Cochrane reviews examining pharmacotherapy for borderline personality disorder and antisocial personality disorder as well as three other meta-analyses.

Expert opinion: There is some evidence that atypical antipsychotics are effective for treating symptom domains in personality disorders, in particular psychotic-like symptoms, impulsivity, aggression and anger. There is no evidence that they improve overall illness severity. Given the high rate of comorbidity between personality disorders and axis I disorders, atypical antipsychotics are best used when these symptom domains are prominent and there is a comorbid axis I condition for which an atypical antipsychotic is indicated.     

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.     

Mood stabilization and the role of antipsychotics

The pharmacological management of bipolar disorder is complex as a result of the cyclic nature of the condition. Long-term treatment is, however, essential to control the symptoms of depression and mania and to stabilize the cyclical mood changes. In particular the use of mood stabilizers in all phases of treatment has been acknowledged. 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 article will review the results from open and double-blind studies with quetiapine, ziprasidone, risperidone and olanzapine in the management of bipolar disorder.     

Special issues in the treatment of paediatric bipolar disorder

Paediatric bipolar disorder (PBD) is an increasingly diagnosed disorder affecting an estimated 1% of children and adolescents. Pharmacological treatment studies in PBD have lagged far behind those in adults. Children are currently treated with pharmacological agents, most of which have proven efficacy in adults. However, PBD is distinct from adult forms of bipolar disorder (BD) and may present unique treatment challenges. PBD often presents with rapid cycling and mixed manic states and a high co-morbidity with behavioural and attention disorders. Early onset depression may also be an early sign of PBD. Due to developmental considerations, the diagnosis of BD may be difficult to make in children without semi-structured interviews. This report discusses the special issues that should be considered when treating PBD and reviews the current literature regarding pharmacotherapy of this population. Mood stabilisers have been studied mostly in an open, uncontrolled fashion but there is growing evidence that lithium, divalproex and carbamazepine are effective in treating PBD. More recent treatment options include atypical antipsychotics and newer anticonvulsants. Other novel agents are currently being investigated in adult BD and may prove applicable to the paediatric form. Finally, based on the available data, a treatment algorithm for PBD is proposed.     

Special issues in the treatment of paediatric bipolar disorder

Paediatric bipolar disorder (PBD) is an increasingly diagnosed disorder affecting an estimated 1% of children and adolescents. Pharmacological treatment studies in PBD have lagged far behind those in adults. Children are currently treated with pharmacological agents, most of which have proven efficacy in adults. However, PBD is distinct from adult forms of bipolar disorder (BD) and may present unique treatment challenges. PBD often presents with rapid cycling and mixed manic states and a high co-morbidity with behavioural and attention disorders. Early onset depression may also be an early sign of PBD. Due to developmental considerations, the diagnosis of BD may be difficult to make in children without semi-structured interviews. This report discusses the special issues that should be considered when treating PBD and reviews the current literature regarding pharmacotherapy of this population. Mood stabilisers have been studied mostly in an open, uncontrolled fashion but there is growing evidence that lithium, divalproex and carbamazepine are effective in treating PBD. More recent treatment options include atypical antipsychotics and newer anticonvulsants. Other novel agents are currently being investigated in adult BD and may prove applicable to the paediatric form. Finally, based on the available data, a treatment algorithm for PBD is proposed.     

心境稳定剂在精神疾病治疗中的应用

目前临床上常用的心境稳定剂包括锂盐、抗惊厥药物和非典型抗精神病药物。此外,现还新上市了一些具有潜在心境稳定作用的药物或辅助用药。本文概要介绍主要心境稳定剂及其在精神疾病治疗中的应用。     

Long-term use of atypical antipsychotics in bipolar disorder

Bipolar disorder is a chronic disease that may require lifetime treatment. The maintenance therapy of bipolar disorder can be challenging for the treating clinician. Currently, according to the American Psychiatric Association (APA) guidelines, lithium, valproic acid, lamotrigine, carbamazepine, oxcarbazepine, and the antipsychotics are recommended for the maintenance treatment of bipolar disorder. The antipsychotics are recommended to be continued only if the clinician decides that they are necessary for the control of persistent psychosis or for prophylaxis against recurrence. Although the APA guidelines provide sufficient evidence for the use of these mood stabilizers, newer drugs such as the atypical antipsychotics are being investigated for use in the maintenance phase of treatment of bipolar disorder.     

Pharmacotherapy of borderline personality disorder: a systematic review for publication purpose

Borderline Personality Disorder (BPD) is a common disorder in psychiatric practice and drugs are widely used in its treatment, targeting symptom clusters, such as affective dysregulation, impulsive-behavioural dyscontrol, and cognitive-perceptual symptoms. In last period, a growing number of studies on pharmacological treatment of BPD have been performed, but different proposals of treatment guidelines are not completely in accordance on drug indications for BPD patients. This article reviews double-blind randomized controlled trials comparing active drugs versus placebo and drugs versus drugs, published between 1990 and 2010 and focused on the treatment of borderline personality disorder. Different classes of psychoactive agents, such as antipsychotics, mood stabilizers, antidepressants, and dietary supplementation were tested in BPD patients. More recent evidences suggest that mood stabilizers (topiramate, valproate and lamotrigine), second generation antipsychotics (olanzapine and aripiprazole) and omega-3 fatty acids can be useful to treat affective symptoms and impulsive-behavioural dyscontrol in BPD patients. Moreover, antipsychotics significantly improve cognitive symptoms in patients with BPD. SSRIs were found effective in decreasing severity of depressed mood, anxiety and anger, mainly in subjects with a concomitant affective disorder. Effects of antidepressants on impulsive behaviours are uncertain. Further studies are needed to improve methods of trials and confirm these findings.     

Psychiatric comorbidities in children with attention deficit hyperactivity disorder: implications for management

Attention deficit hyperactivity disorder (ADHD) is frequently comorbid with a variety of psychiatric disorders. These include oppositional defiant disorder and conduct disorder (CD), as well as affective, anxiety, and tic disorders. ADHD and ADHD with comorbid CD appear to be distinct subtypes; children with ADHD/CD are at higher risk of antisocial personality and substance abuse as adults. Stimulants are often effective treatments for aggressive or antisocial behavior in patients with ADHD, but mood stabilizers or atypical antipsychotics may be used to treat explosive aggressive outbursts. Response to stimulants is not affected by comorbid anxiety, but children with ADHD/anxiety disorder may show greater benefit from psychosocial interventions than those with ADHD alone. The degree of prevalence of major depressive disorder (MDD) and bipolar disorder among children with ADHD is controversial, but a subgroup of severely emotionally labile ADHD children who present serious management issues for the clinician clearly exists. Antidepressants may be used in conjunction with stimulants to treat MDD, while mood stabilizers and atypical antipsychotics are often required to treat manic symptoms or aggression. After resolution of the manic episode, stimulant treatment of the comorbid ADHD may be safely undertaken. Recent research suggests that stimulants can be safely used in children with comorbid ADHD and tic disorders, but the addition of anti-tic agents to stimulants is often necessary. Clinicians who work with patients with ADHD should be prepared to deal with a wide range of emotional and behavioral problems beyond the core symptoms of inattention and impulsivity/hyperactivity.     

Treatment of bipolar affective disorder in clinical practice

A case note survey of 100 outpatients with a clinical diagnosis of bipolar affective disorder in a UK inner city teaching hospital revealed monotherapy with a mood stabilizer in only 23% of patients, mostly lithium (15%). Overall, 51% of patients were prescribed lithium, 19% carbamazepine and 5% valproate with only 8% receiving a combination of two mood stabilizers. Treatment appeared to be inadequate in 13/51 of patients on lithium, 9/19 of those on carbamazepine and 1/5 of those on valproate. Antipsychotics were used as monotherapy in 20% of patients and combined with a mood stabilizer in 43% of patients. Only 6% of patients were on atypical antipsychotics. These findings suggest that the treatment for many patients does not match recommendations. Clearer evidence on the place of combination mood stabilizers and adjunctive antipsychotics, particularly atypicals is needed in the treatment of bipolar affective disorder.     

Evidence-based pharmacotherapy of eating disorders

The objective was to review scientific evidence for efficacy and safety of pharmacotherapy in adults or children with an eating disorder (ED). We conducted a computer search for all randomized controlled trials (RCTs) published between 1960 and May 2010 for treatment of anorexia nervosa (AN), bulimia nervosa (BN) or binge-eating disorder (BED). For drugs for which no RCT was found, open trials or case reports were retrieved. Clinically relevant RCTs in the treatment of AN have used atypical antipsychotics, selective serotonin reuptake inhibitors (SSRIs), and zinc supplementation. Olanzapine demonstrated an adjunctive effect for in-patient treatment of underweight AN patients, and fluoxetine helped prevent relapse in weight-restored AN patients in 1/2 studies. For treatment of BN, controlled studies have used SSRIs, other antidepressants, and mood stabilizers. In 9/11 studies, pharmacotherapy yielded a statistically significant although moderate reduction in binge/purge frequency, and some additional benefits. For BED, RCTs have been conducted using SSRIs and one serotonin norepinephrine reuptake inhibitor (SNRI), mood stabilizers, and anti-obesity medications. In 11/12 studies, there was a statistically significant albeit limited effect of medication. Meta-analyses on efficacy of pharmacotherapy for BN and BED support moderate effect sizes for medication, but generally low recovery rates. Treatment resistance is an inherent feature of AN, where treatment should focus on renourishment plus psychotherapy. For BN and BED, combined treatment with pharmacotherapy and cognitive behaviour therapy has been more effective than either alone. Data on the long-term efficacy of pharmacotherapy for EDs are scarce. Short- and long-term pharmacotherapy of EDs still remains a challenge for the clinician.     

Efficacy of atypical antipsychotics in bipolar disorder

Bipolar disorder is a severe and recurrent disorder. Atypical antipsychotics have emerged as both an alternative and adjunct to conventional mood stabilisers. The manic phase of the illness is the best studied, and it appears that a class effect with regards to efficacy is present in both monotherapy and augmentation studies.Evidence for efficacy of atypical antipsychotics in depression is emerging. At this stage controlled data are available for both olanzapine and quetiapine. Maintenance data demonstrating efficacy are available for olanzapine. Atypical antipsychotics have utility in treating acute agitation and aggression in manic episodes of bipolar disorder. Subgroup analyses from trials treating manic phase bipolar disorder, and an open-label study of rapid cycling, have suggested that atypical antipsychotics may be useful for the treatment of mixed states and rapid cycling. Several studies have suggested that atypical antipsychotics may be useful in treatment-refractory episodes of bipolar disorder.The current available data suggest greater efficacy of the atypical antipsychotics in mania than in depression, although the data are fairly clear that induction of depression is not an issue with the atypical antipsychotics. A number of trials are underway that will hopefully address many of the questions still pending.     

Preventative strategies for early-onset bipolar disorder: towards a clinical staging model

Bipolar disorder is a chronic and typically recurring illness with significant psychosocial morbidity. Although the aetiological factors that contribute to the onset of mania, and by definition bipolar I disorder, are poorly understood, it most commonly occurs during the adolescent period. Putative risk factors for developing bipolar disorder include having a first-degree relative with a mood disorder, physical/sexual abuse and other psychosocial stressors, substance use disorders, psychostimulant and antidepressant medication exposure and omega-3 fatty acid deficiency. Prominent prodromal clinical features include episodic symptoms of depression, anxiety, hypomania, anger/irritability and disturbances in sleep and attention. Because prodromal mood symptoms precede the onset of mania by an average of 10 years, and there is low specificity of risk factors and prodromal features for mania, interventions initiated prior to onset of the disorder (primary prevention) or early in the course of the disorder (early or secondary prevention) must be safe and well tolerated upon long-term exposure. Indeed, antidepressant and psychostimulant medications may precipitate the onset of mania. Although mood stabilizers and atypical antipsychotic medications exhibit efficacy in youth with bipolar I disorder, their efficacy for the treatment of prodromal mood symptoms is largely unknown. Moreover, mood stabilizers and atypical antipsychotics are associated with prohibitive treatment-emergent adverse effects. In contrast, omega-3 fatty acids have neurotrophic and neuroprotective properties and have been found to be efficacious, safe and well tolerated in the treatment of manic and depressive symptoms in children and adolescents. Together, extant evidence endorses a clinical staging model in which subjects at elevated risk for developing mania are treated with safer interventions (i.e. omega-3 fatty acids, family-focused therapy) in the prodromal phase, followed by pharmacological agents with potential adverse effects for nonresponsive cases and secondary prevention. This approach warrants evaluation in prospective longitudinal trials in youth determined to be at ultra-high risk for bipolar I disorder.