Pharmacotherapy of postpartum depression

The postpartum period is an exceptionally high-risk time for the occurrence of episodes of depression in women with major depressive disorder or bipolar disorder. There is accumulating evidence that major depressive disorder with postpartum onset in some patients has a bipolar diathesis. This article reviews the pharmacological treatment of postpartum depression. Although the data are limited, studies have focused exclusively on the acute and prophylactic treatment of major depressive disorder. To date, there are no studies of bipolar depression with postpartum onset. A careful assessment of maternal and infant risks and benefits is required prior to initiation of pharmacological treatment. Strategies to reduce misdiagnosis of subtle forms of bipolar disorder are discussed and suggestions are made regarding possible treatment interventions. The urgent need to conduct further studies comparing the symptom patterns, response to treatment and illness course in women with major depressive disorders and bipolar depression with postpartum onset is highlighted.     

Lamotrigine in mood disorders

SUMMARY

Lamotrigine is an anticonvulsant drug with good efficacy and safety in the treatment of epilepsy. There is now substantial evidence that lamotrigine is also useful in treating resistant depression, rapid cycling bipolar affective disorder, depressive episodes in bipolar affective disorder and in the maintenance phase or prophylaxis of bipolar affective disorder. There are possible roles in managing mood changes in borderline personality disorder, reducing chronic pain and treating schizoaffective disorder.

The general range of doses found effective in affective disorders is from 50 to 300?mg daily.

Clinical use seems to involve a titration of dose upwards over several weeks until the desired ! effect is obtained.

However, further definitive double-blind, randomised controlled trials against gold standard treatments are required.

Lamotrigine has a preferable side-effect profile compared to standard agents for bipolar affective disorder such as lithium or carbamazepine. Further research is certainly warranted and, given its tolerability, could point to lamotrigine as the treatment of choice for some affective disorders.     

Lamotrigine in mood disorders

Lamotrigine is an anticonvulsant drug with good efficacy and safety in the treatment of epilepsy. There is now substantial evidence that lamotrigine is also useful in treating resistant depression, rapid cycling bipolar affective disorder, depressive episodes in bipolar affective disorder and in the maintenance phase or prophylaxis of bipolar affective disorder. There are possible roles in managing mood changes in borderline personality disorder, reducing chronic pain and treating schizoaffective disorder. The general range of doses found effective in affective disorders is from 50 to 300 mg daily. Clinical use seems to involve a titration of dose upwards over several weeks until the desired effect is obtained. However, further definitive double-blind, randomised controlled trials against gold standard treatments are required. Lamotrigine has a preferable side-effect profile compared to standard agents for bipolar affective disorder such as lithium or carbamazepine. Further research is certainly warranted and, given its tolerability, could point to lamotrigine as the treatment of choice for some affective disorders.     

Managing bipolar disorder in the elderly: defining the role of the newer agents

Clinical research in geriatric psychopharmacology has been a relatively neglected focus compared with the wealth of information on younger populations, and there is a dearth of published, controlled trials. Similarly, these are limited data in the area of geriatric bipolar disorder. Although there is an absence of rigorous, evidence-based information, preliminary data on older adults with bipolar disorder suggest some promising treatment options and important differences in older versus younger patients with bipolar illness. Lithium, while widely utilised in younger populations, is often poorly tolerated in the elderly. Clinical evidence regarding use of antiepileptic compounds in late-life bipolar disorder is generally compiled from bipolar disorder studies in mixed populations, studies in older adults with seizure disorders, and studies on dementia and psychotic conditions other than bipolar disorder. Valproate semisodium and carbamazepine are widely prescribed compounds in older adults with bipolar disorder. However, the popularity of these compounds has occurred in context of an absence of evidence-based data. The atypical antipsychotics have expanded the treatment armamentarium for bipolar disorder in mixed populations and may offer particular promise in management of bipolar illness in older populations as well. Olanzapine, risperidone, quetiapine, ziprasidone and aripiprazole are atypical antipsychotics that have been approved by the US FDA for the treatment of bipolar disorder; however, there are no published, controlled trials with atypical antipsychotics specific to mania in geriatric patients. Preliminary reports on the use of clozapine, risperidone, olanzapine and quetiapine suggest a role for the use of these agents in late-life bipolar disorder. Information with ziprasidone and aripiprazole specific to geriatric bipolar disorder is still lacking.     

Pharmacokinetic evaluation of armodafinil for the treatment of bipolar depression

Introduction: Bipolar disorder is a psychiatric illness with recurring episodes of mania and depression. Armodafinil , the R-enantiomer of modafinil, approved for treating excessive sleepiness associated with narcolepsy, obstructive sleep apnea and shift work disorder, is possibly effective as an adjunctive treatment for bipolar depression. Areas covered: This review covers the pharmacokinetics of armodafinil, with an emphasis on its use in bipolar depression. Its clinical efficacy in the treatment of bipolar depression is evaluated, along with current data regarding its safety and tolerability. Expert opinion: One placebo-controlled trial is available, in which armodafinil was efficacious as an adjunctive treatment in bipolar depression. Armodafinil shows a linear pharmacokinetic profile over a broad dose range of 50 - 400 mg (maximal plasma concentration and area under concentration-time curve). Compared with modafinil, an equivalent dose of armodafinil attains higher blood concentrations 4 - 6 h post-dose. The possibility of drug interactions is generally low, although interactions have been shown with some drugs used in bipolar disorder, through mild CYP3A4-induction and CYP2C19-inhibition. Armodafinil is well tolerated and presents a possible new treatment option for bipolar depression. However, further investigation is still needed in order to confirm its efficacy and to clarify its role in the treatment of bipolar depression.     

Ziprasidone in bipolar disorder

Ziprasidone is a second-generation antipsychotic currently marketed for the treatment of schizophrenia and bipolar mania. It has a unique receptor profile that includes high-affinity antagonist activity at 5-hydroxytryptamine (5-HT) 2A, D2, 1D and 2C receptors, a potent agonist activity at 5-HT_1A receptors and a relatively high affinity for the 5-HT and noradrenaline transporters. The efficacy of ziprasidone in bipolar mania (current episode, manic or mixed) has been well demonstrated in three placebo-controlled trials. In a three-arm controlled study, ziprasidone was shown to be efficacious in dysphoric mania, whereas haloperidol was comparable to placebo. Open-label treatment for up to 52 weeks supported the sustained efficacy of ziprasidone in bipolar disorder. Combined with lithium, ziprasidone has been shown to be efficacious as an augmenting agent in the acute treatment of mania, with sustained efficacy up to 1 year. Ziprasidone was very well tolerated by patients with bipolar disorder and did not cause increased weight, glucose or lipid levels.     

Lamotrigine in the treatment of bipolar disorder

Lamotrigine has undergone a remarkable series of systematic studies since 1994 that now establish it as an efficacious, well-tolerated treatment in bipolar disorder. Its efficacy principally addresses both acute and maintenance phase benefits on depressive symptomatology. These benefits have been demonstrated in placebo-controlled studies, rapid cycling patients, bipolar I and II patients and monotherapy as well as in combination therapy, although this has been less well studied. The drug is exceptionally well-tolerated in long-term treatment, although initial dosing requires gradual dosage escalation to avoid the risk of inducing serious rashes with features within the spectrum of Stevens–Johnson syndrome. Administration with valproate requires a slower dosage titration, whereas, as with many drugs, administration with carbamazepine requires a more rapid dosage increase. In contrast to marketed antidepressants, lamotrigine appears not to induce manic or hypo-manic episodes, nor to increase cycling frequency. This combination of properties makes it a first-choice treatment for acute bipolar depression and continuation treatment, especially, but not limited to, prophylaxis against recurrent depression and depressive symptoms. Lamotrigine appears not to have acute antimanic properties. A small number of studies suggest a broader spectrum of efficacy, including in some axis I disorders that are comorbidly associated with bipolar disorder.     

Lamotrigine in the treatment of bipolar disorder

Lamotrigine has undergone a remarkable series of systematic studies since 1994 that now establish it as an efficacious, well-tolerated treatment in bipolar disorder. Its efficacy principally addresses both acute and maintenance phase benefits on depressive symptomatology. These benefits have been demonstrated in placebo-controlled studies, rapid cycling patients, bipolar I and II patients and monotherapy as well as in combination therapy, although this has been less well studied. The drug is exceptionally well-tolerated in long-term treatment, although initial dosing requires gradual dosage escalation to avoid the risk of inducing serious rashes with features within the spectrum of Stevens-Johnson syndrome. Administration with valproate requires a slower dosage titration, whereas, as with many drugs, administration with carbamazepine requires a more rapid dosage increase. In contrast to marketed antidepressants, lamotrigine appears not to induce manic or hypo-manic episodes, nor to increase cycling frequency. This combination of properties makes it a first-choice treatment for acute bipolar depression and continuation treatment, especially, but not limited to, prophylaxis against recurrent depression and depressive symptoms. Lamotrigine appears not to have acute antimanic properties. A small number of studies suggest a broader spectrum of efficacy, including in some axis I disorders that are comorbidly associated with bipolar disorder.     

Utilizing pharmacodynamic properties of second-generation antipsychotics to guide treatment

Second-generation antipsychotics (SGAs) are used for the treatment of multiple psychiatric disorders including schizophrenia, bipolar depression, bipolar mania, autism and major depressive disorder. Additionally, their off-label use has been expanding to include other disorders as well, including post-traumatic stress disorder, obsessive compulsive disorder, generalized anxiety disorder, eating disorders and personality disorders. All SGAs share common properties; however, each individual SGA has a unique pharmacodynamic profile that may be utilized to guide and individualize treatment.     

Serotonin and anxiety: current models

Evidence for the importance of the serotonin system in anxiety disorders has increased substantially in recent years. Although preclinical research has provided an important source of hypotheses, clinical work on the value of selective serotonin reuptake inhibitors (SSRIs) in these conditions has been particularly persuasive. In this paper, a number of models of serotonin in the anxiety disorders are reviewed, and the clinical advantages of the SSRIs in anxiety disorders are emphasized. Models of serotonin in anxiety disorders include: 1) a 'see-saw model'; 2) an 'amygdala model'; and 3) a 'basal ganglia model'. While any simplistic schema in this complex area must fail, these various models have some heuristic value for the clinician. From a clinical perspective, the availability of the SSRIs has proved a significant step forward in the treatment of the anxiety disorders such as panic disorder, obsessive-compulsive disorder, post-traumatic stress disorder, and social anxiety disorder (social phobia); certainly these agents offer several advantages over previously existing pharmacotherapeutic alternatives such as the benzodiazepines and tricyclic antidepressants.     

Atypical antipsychotics in the treatment of bipolar disorder

Atypical antipsychotic medications are widely used for the treatment of bipolar disorder. Most empirical support suggests that these medications are efficacious in the treatment of acute mania, but there is considerably less support for the utility of these drugs in other phases of bipolar disorder. However, it is likely that several of these drugs will demonstrate efficacy in relapse prevention, and perhaps antidepressant efficacy in bipolar disorder as more studies are conducted. Atypical antipsychotics offer different side effect profiles than older antipsychotics, which may be of benefit for some patients. Consequently, atypical antipsychotics provide an important treatment option for bipolar patients.     

The use of antipsychotics in children and adolescents with bipolar disorders

The use of antipsychotics, particularly the atypical antipsychotics, has increased dramatically in child and adolescent populations over the last decade. This class of psychotropics has been used to treat a variety of psychiatric disorders in pediatric populations, including bipolar disorder (BPD). The present clinical guidelines for treating BPD in younger populations closely follow those for managing adult BPD, as reasoning for using the atypicals is many times initially based on the outcomes of adult studies and indications. As in adult populations, metabolic parameters such as body mass index, blood glucose levels and fasting lipid profiles should be routinely monitored throughout the course of treatment. Of the several studies undertaken thus far, it appears that atypical antipsychotics are efficacious in the treatment of pediatric BPD. However, the number of controlled studies demonstrating their efficacy in younger subjects is limited and further investigation is required to evaluate if effectiveness and potential for side effects differ significantly than that for adult populations.     

Ziprasidone in bipolar disorder

Ziprasidone is a second-generation antipsychotic currently marketed for the treatment of schizophrenia and bipolar mania. It has a unique receptor profile that includes high-affinity antagonist activity at 5-hydroxytryptamine (5-HT) 2A, D2, 1D and 2C receptors, a potent agonist activity at 5-HT1A receptors and a relatively high affinity for the 5-HT and noradrenaline transporters. The efficacy of ziprasidone in bipolar mania (current episode, manic or mixed) has been well demonstrated in three placebo-controlled trials. In a three-arm controlled study, ziprasidone was shown to be efficacious in dysphoric mania, whereas haloperidol was comparable to placebo. Open-label treatment for up to 52 weeks supported the sustained efficacy of ziprasidone in bipolar disorder. Combined with lithium, ziprasidone has been shown to be efficacious as an augmenting agent in the acute treatment of mania, with sustained efficacy up to 1 year. Ziprasidone was very well tolerated by patients with bipolar disorder and did not cause increased weight, glucose or lipid levels.     

Atypical antipsychotics in the treatment of bipolar disorder

Atypical antipsychotic medications are widely used for the treatment of bipolar disorder. Most empirical support suggests that these medications are efficacious in the treatment of acute mania, but there is considerably less support for the utility of these drugs in other phases of bipolar disorder. However, it is likely that several of these drugs will demonstrate efficacy in relapse prevention, and perhaps antidepressant efficacy in bipolar disorder as more studies are conducted. Atypical antipsychotics offer different side effect profiles than older antipsychotics, which may be of benefit for some patients. Consequently, atypical antipsychotics provide an important treatment option for bipolar patients.     

The use of antipsychotics in children and adolescents with bipolar disorders

The use of antipsychotics, particularly the atypical antipsychotics, has increased dramatically in child and adolescent populations over the last decade. This class of psychotropics has been used to treat a variety of psychiatric disorders in pediatric populations, including bipolar disorder (BPD). The present clinical guidelines for treating BPD in younger populations closely follow those for managing adult BPD, as reasoning for using the atypicals is many times initially based on the outcomes of adult studies and indications. As in adult populations, metabolic parameters such as body mass index, blood glucose levels and fasting lipid profiles should be routinely monitored throughout the course of treatment. Of the several studies undertaken thus far, it appears that atypical antipsychotics are efficacious in the treatment of pediatric BPD. However, the number of controlled studies demonstrating their efficacy in younger subjects is limited and further investigation is required to evaluate if effectiveness and potential for side effects differ significantly than that for adult populations.     

The use of antidepressants in bipolar disorder patients with depression

Introduction: The proportion of time that bipolar patients experience depressive symptoms and clinical states, with associated psychosocial impairment and elevated risk of suicide, is significantly greater than the time spent in manic/hypomanic forms of bipolar disorders. Yet, manic states and symptoms have been the focus and interest of most clinical research over the past quarter century. Not a single antidepressant approved for treatment of major depressive disorder, as monotherapy, has received regulatory approval for treatment of bipolar depression as monotherapy, despite their common use in bipolar depression.

Areas covered: We reviewed randomized studies, particularly ones initially intended for registration purposes, and systematic treatment guidelines, in development of this guide to treatment decision and implementation of interventions for depression in bipolar disorders.

Expert opinion: The Expert Opinion section emphasizes strategies, not individual agents. The efficacious performance of mood stabilizers and second-generation antipsychotics as a component of the strategy is strongly supported by published studies. However, this section relies largely on secondary publications and our combined clinical experience, as few randomized, blinded studies have had, as their focus, the comparison of combined regimens for depression. This article summarizes the design features and results of studies dealing with depressive features and intervention strategies for bipolar disorders. The emphasis of the recommendations is on pragmatic treatment decisions that clinicians can make to enhance the probability of both short and long term benefits for patients.     

Risperidone long-acting injection as monotherapy and adjunctive therapy in the maintenance treatment of bipolar I disorder

Importance of the field: It is very rare for patients with bipolar disorder to have a single episode of mania or depression over a lifetime and the vast majority of these individuals need long-term prophylactic/maintenance treatment. However, treatment nonadherence is a major issue for close to half of subjects with bipolar disorder who are prescribed medications. Risperidone long-acting injection (LAI) has proven efficacious for the maintenance phase of bipolar disorder and may mitigate the problem of nonadherence in the substantial group of patients for whom this is a significant concern.

Areas covered in this review: This paper comprises a review and commentary regarding the use of risperidone LAI in bipolar disorder.

What the reader will gain: The reader will gain an understanding regarding the risks and benefits of risperidone LAI in bipolar disorder. We review the available evidence and discuss the strengths and weaknesses of published studies, providing an opinion about the clinical usefulness of risperidone LAI as well as suggestions for future research.

Take home message: The use of risperidone LAI, through improved adherence, has the potential to ameliorate the course of bipolar disorder.     

Quetiapine: a pharmacoeconomic review of its use in bipolar disorder

This article briefly summarizes the burden of bipolar disorder and the clinical profile of quetiapine (Seroquel?) in the management of bipolar disorder, followed by a detailed review of pharmacoeconomic analyses. Quetiapine is an atypical antipsychotic that is available in numerous countries as immediate-release and extended-release tablets for the treatment of major psychiatric disorders, including bipolar disorder. Randomized, double-blind, placebo-controlled trials with quetiapine have demonstrated its efficacy in bipolar I and II disorders, and the drug has been generally well tolerated in clinical trials. Three cost-effectiveness analyses of maintenance therapy in bipolar I disorder, which used similar Markov models and incorporated data from key clinical trials and a number of other sources, showed that quetiapine, as adjunctive therapy with mood stabilizers (lithium or divalproex), was a cost-effective treatment option from the healthcare payer perspective in the UK and the US. Quetiapine either dominated comparators (typically mood stabilizers alone) or was associated with incremental cost-effectiveness ratios that were usually well below widely accepted thresholds of cost effectiveness. One of the studies evaluated extended-release quetiapine, although clinical efficacy data used in the Markov model were for the immediate-release formulation. In another analysis, which used a discrete-event simulation model and was conducted from the perspective of the UK healthcare payer, quetiapine monotherapy was cost effective compared with olanzapine monotherapy as maintenance treatment for all phases of bipolar I or II disorder. In this model, favourable results were also shown for quetiapine (with or without mood stabilizers) compared with a wide range of maintenance therapy regimens. Another modelled analysis conducted from the UK healthcare payer perspective showed that quetiapine was dominated by haloperidol in the short-term treatment of a manic episode in patients with bipolar I disorder. Both favourable and unfavourable results have been reported in cost analyses of quetiapine in bipolar disorder (type I or type not specified). Possible explanations for some of the variability in results of the pharmacoeconomic analyses include heterogeneity among the models in terms of input parameters or assumptions in the base-case analyses, country- or region-specific differences in estimates of healthcare resource use and associated costs, variability in treatment alternatives, and differences in the year of costing and discounting used in the analyses. In addition, some of the studies had short time horizons and focused on acute manic episodes only, whereas others were longer-term analyses that considered the full spectrum of health states in patients with bipolar disorder. Various limitations of the studies have been recognized, and results from one country may not be applicable to other countries. In conclusion, results of available pharmacoeconomic analyses provide evidence of the cost effectiveness of quetiapine as an adjunct to mood stabilizers for maintenance therapy in (primarily type I) bipolar disorder from a healthcare payer perspective in the UK and the US. Some evidence is available to support the cost effectiveness of quetiapine monotherapy or the use of extended-release quetiapine as adjunctive therapy with mood stabilizers in this setting, although further analyses appear to be warranted. Whether these findings apply to other geographical regions requires further study. Evidence for the long-term (>2-year) cost effectiveness of quetiapine in bipolar disorder is currently limited and further studies are also needed to address the cost effectiveness of quetiapine from a societal perspective and in bipolar II disorder.     

Costs of bipolar disorder

Bipolar disorder is a chronic affective disorder that causes significant economic burden to patients, families and society. It has a lifetime prevalence of approximately 1.3%. Bipolar disorder is characterised by recurrent mania or hypomania and depressive episodes that cause impairments in functioning and health-related quality of life. Patients require acute and maintenance therapy delivered via inpatient and outpatient treatment. Patients with bipolar disorder often have contact with the social welfare and legal systems; bipolar disorder impairs occupational functioning and may lead to premature mortality through suicide. This review examines the symptomatology of bipolar disorder and identifies those features that make it difficult and costly to treat. Methods for assessing direct and indirect costs are reviewed. We report on comprehensive cost studies as well as administrative claims data and program evaluations. The majority of data is drawn from studies conducted in the US; however, we discuss European studies when appropriate. Only two comprehensive cost-of-illness studies on bipolar disorder, one prevalence-based and one incidence-based, have been reported. There are, however, several comprehensive cost-of-illness studies measuring economic burden of affective disorders including bipolar disorder. Estimates of total costs of affective disorders in the US range from $US30.4-43.7 billion (1990 values). In the prevalence-based cost-of-illness study on bipolar disorder, total annual costs were estimated at $US45.2 billion (1991 values). In the incidence-based study, lifetime costs were estimated at $US24 billion. Although there have been recent advances in pharmacotherapy and outpatient therapy, hospitalisation still accounts for a substantial portion of the direct costs. A variety of outpatient services are increasingly important for the care of patients with bipolar disorder and costs in this area continue to grow. Indirect costs due to morbidity and premature mortality comprise a large portion of the cost of illness. Lost workdays or inability to work due to the disease cause high morbidity costs. Intangible costs such as family burden and impaired health-related quality of life are common, although it has proved difficult to attach monetary values to these costs.