State-of-the-art treatment of postpartum bipolar disorder

Management of Psychiatric Disorders during the Perinatal Period.

Bipolar disorder is a chronic, typically early onsetting group of mental disorders with a lifelong risk of relapse. It is characterized by recurrent periods of depression and pathologically elevated mood consisting of increased energy and activity during which patients may experience sleep loss, over-confidence, impaired concentration, extreme talkativeness, and engage in irresponsible risk-taking behavior. As a result, it is often problematic to undertake usual activities and maintain interpersonal relationships (World Health Organization [WHO], 2001). An estimated 2.4% of the world’s population suffer from some form of bipolar disorder, with a lifetime prevalence of 0.6% for bipolar I disorder and 0.4% for bipolar II disorder, while 1.4% of the total population has a lifetime prevalence of subsyndromal bipolar disorder (Merikangas et al., 2011). Bipolar disorders are categorized into bipolar I and bipolar II depending on a patient history of major depressive and hypomanic episodes only (bipolar II), or depressive and manic episodes in addition to hypomanic and mixed episodes (bipolar I). Subsyndromal symptoms may be diagnosed as bipolar disorder not otherwise specified. Patients with bipolar disorder encounter many difficulties in leading a normal lifestyle, even with the support of family, friends and carers, and therefore tend to have a low quality of life (QoL), which is powerfully influenced by two factors: the nature of mental illness itself and treatment-related comorbidities. Features of social disability that may trouble patients with bipolar disorder include problems in developing and sustaining friendships and difficulties in maintaining intimate relationships with a partner. Furthermore, the inability to manage money, housework, and coping with an emergency (Kai and Crosland, 2001) impedes a normal lifestyle. Possibly as a consequence of poor QoL, “self

This study investigated the association between continued mood-stabilizing treatment (lithium and anticonvulsants) in bipolar disorder (BD) and the risk of suicide. Using linkage of national registers, the association between continued mood-stabilizing treatment and suicide was investigated among all patients discharged nationwide from hospital psychiatry as an in- or outpatient in a period from 1995 to 2000 in Denmark with a diagnosis of BD. A total of 5,926 patients were included in the study and among these 51 patients committed suicide eventually during the study period. Although the rate of suicide was higher during periods when patients purchased anticonvulsants (293 suicides per 100,000 person-years) than during periods with lithium (136 suicides per 100,000 person-years), the suicide rate decreased with the number of prescriptions in a rather similar way for patients first treated with lithium and patients first treated with anticonvulsants: patients who continued treatment with mood-stabilizing drugs had a decreased rate of suicide compared to patients who purchased mood stabilizers once only [rate ratio for anticonvulsants = 0.28, 95% confidence interval (CI) = 0.19-0.41; rate ratio for lithium = 0.20, 95% CI = 0.10-0.38]. Further, the rate of suicide decreased consistently with the number of additional prescriptions. Switch to or augmentation with lithium to patients initiated on anticonvulsants was associated with a significantly reduced rate of suicide (rate ratio = 0.28, 95% CI = 0.20-0.40), whereas a switch to or augmentation with anticonvulsants to patients first started on lithium showed no additional effect on the suicide rate. Although continued treatment with anticonvulsants and continued treatment with lithium was associated with a rather similar reduction in the rate of suicide, the results suggest that treatment with lithium may have some superiority in relation to prevention of suicide.

Back to table of contents Previous article Next article Clinical & ResearchFull AccessSpecial Report: Bipolar Disorder II—Frequently Neglected, MisdiagnosedTrisha Suppes, M.D., Ph.D., Holly A. Swartz, M.D., Sara SchleyTrisha SuppesSearch for more papers by this author, M.D., Ph.D., Holly A. SwartzSearch for more papers by this author, M.D., Sara SchleySearch for more papers by this authorPublished Online:23 Feb 2023https://doi.org/10.1176/appi.pn.2023.03.3.22AbstractUnlike its cousin, bipolar I disorder, which has been extensively studied and depicted in popular literature and on screen, bipolar II disorder is poorly understood, underdiagnosed, and insufficiently treated. This has often resulted in an over 10-year delay in diagnosis.Rick Prather/Art by Benjavisa Ruangvaree/Shutterstock/Bipolar II Disorder: Recognition, Understanding, and TreatmentEven experienced clinicians know surprisingly little about bipolar II disorder (BD II), despite its inclusion as a distinct entity in DSM since 1994. An abundance of studies supports conceptualization of BD II as a unique phenotype within the bipolar illness spectrum, although many fail to recognize it as distinct disorder apart from bipolar I disorder (BD I).Alternatively, BD II is considered a “lesser form” of BD I, despite numerous studies showing comparable illness severity and risk of suicide in these two BD subtypes. Perhaps because of its under-recognition, treatment studies of BD II are limited, and too often results from studies of patients with BD I are simply applied to those with BD II with no direct evidence supporting this practice. BD II is an understudied and unmet treatment challenge in psychiatry.In this review, we will provide a broad overview of BD II including differential diagnosis, course of illness, comorbidities, and suicide risk. We will summarize treatment studies specific to BD II, identifying gaps in the literature. This review will reveal similarities between BD I and II, including suicide risk and predominance of depression over the course of illness, but also differences between the phenotypes in treatment response, for example to antidepressants.We highlight the perspective of an expert by experience who discusses her lived experiences of BD II in an accompanying interview (Interview With an Expert by Lived Experience).Diagnosis HistoryAlternating states of mania and melancholia are among the earliest described human diseases, first noted by ancient Greek physicians, philosophers, and poets. Hippocrates (460-337 B.C.E.), who formulated the first known classification of mental disorders, systematically described bipolar mood states: melancholia, mania, and paranoia. More than two millennia later, Emil Kraepelin, recognized as one of the founders of modern psychiatry, described manic-depressive illness as a singular disease characterized by alternating cycles of mania or melancholia. However, Kraepelin was more focused on mood changes and cycling than the polarity of episodes per se. Thus, his concept included what we now term recurrent major depressive disorder (MDD). Nevertheless, his and other formulations from this period provide background for our modern concepts of bipolar disorder, differentiating it from unipolar depression (MDD and related disorders). The hiding in plain sight of patients with BD II was brought to awareness by David L. Dunner, M.D., in the 1960s. When examining a cohort of individuals with mood disorders in a study by the National Institute of Mental Health (NIMH), he identified a subgroup of patients with recurrent episodes of depression who also had a history of at least one period of hypomania and a strong family history of bipolar disorder. This subgroup was found to have a different course of illness compared with those with recurrent depression and a history of mania (BD I). Thanks to this work, BD II was recognized as a distinct disorder, separate from BD I. It finally entered the DSM lexicon in 1994 in DSM-IV and was added to ICD-10 even more recently. Table 1Conceptualization of bipolar disorders continues to evolve as the field learns more; for example, changes were made to the DSM-5 diagnostic criteria for BD such that Criteria A for both mania and hypomania now include increased energy as well as elevated or irritable mood (see Table 1). Thus, BD II is now recognized as a disorder of energy as well as mood.DSM focuses on categorial diagnoses—that is, thresholds for absence or presence of disease. In parallel to this framework, many have argued for considering bipolar disorders along a continuous spectrum of illness. Thus, the term bipolar spectrum is used to describe both the spectrum of severity across BD symptoms as well as combinations of mood symptoms with manic/hypomanic and depressive components. Some refer to BD II as a part of the bipolar spectrum. These concepts reflect a growing awareness that dimensional descriptions of mood disorders may better map onto continuous biological markers of disease, compared with DSM’s categorical approach, but the debate about diagnostic boundaries and disease etiology continues. Importantly, conceptualizations of BD as a spectrum condition versus discrete diagnostic categories (that is, BD I or BD II) are not mutually exclusive but rather speak to ongoing efforts to understand and best describe the phenomenology of BD. Differential Diagnosis The validity of BD II as a separate disorder has been reified through multiple empirical studies. The clinical diagnosis is reliably separable from BD I, as seen in APA clinical trials preparing for DSM-5 and in careful clinical interviews. In DSM-5 field trials to assess reliability of diagnoses, BD I was among the most recognizable, but BD II fell in the acceptable range and well above MDD as a reliable diagnostic entity. Family studies also support the diagnosis of BD II as an independent entity with distinct familial heritability, according to a 1976 study by Dunner et al. and a 1990 study by J. Raymond DePaulo, M.D., et al., and the authors of this report. Finally, genetic studies have found correlations suggesting the heterogeneity between BD I and BD II is “nonrandom,” supporting the concept of distinct conditions. BD II diagnosis requires at least one lifetime hypomanic episode and one major depressive episode. Despite clarity of BD II diagnostic criteria, clinicians struggle to accurately identify it in practice. BD II is often either missed or incorrectly diagnosed, resulting in an over 10-year delay in diagnosis. Difficulties in accurate diagnosis arise from several sources. First, DSM-5 criteria for the depressive phase of BD II are identical to those required for a major depressive episode, which make BD II and MDD cross-sectionally indistinguishable. This is particularly notable as MDD diagnoses make up a substantial percent of the incorrect diagnoses for patients with BD II. Second, hypomania, which by definition is a less severe form of mania, may be difficult for patients to distinguish from a “normal” mood state when accompanied by extra energy and good mood. Third, mixed hypomanic mood states are very common in BD II, and in fact more common than euphoric hypomanic states. Mixed mood states are characterized by the presence of symptoms of opposite polarity during a depressive or hypomanic episode. In a mixed hypomania, patients might believe they are simply irritable and angry in the context of depression rather than recognizing the additional hypomanic symptoms warranting a diagnosis of mixed hypomanic state. Finally, patients rarely present for treatment in the midst of a hypomanic episode, a mood state that is either perceived as ego-syntonic or simply not identified as part of their illness during mixed hypomania. The primary reason patients with BD II seek care is depression. Depression dominates the course of BD II, both in the early and late stages. However, retrospectively identifying episodes of hypomania during a depressive episode can be challenging. Further, many individuals see hypomania (either the euphoric or mixed variant) as part of “normal” mood rather than part of a bipolar spectrum, contributing to misreporting of mood episodes. Especially after unrelenting episodes of depression, it is understandable that many would perceive hypomania as a return to baseline. However, under-recognition of hypomania contributes to incorrect diagnoses. In sum, many individuals with BD II fail to recall, recognize, or report histories of hypomania, leading to an MDD (mis)diagnosis. In psychiatry, all diagnoses are a one-way road. Individuals who have ever met criteria for a manic episode will continue to carry the diagnosis of BD I—even without further manic episodes. Similarly, patients who have a distant episode of hypomania and at least one prior major depressive episode would be considered to have BD II disorder, even in the absence of additional hypomanic episodes that meet symptom and duration criteria. Thus, accurate diagnosis of BD II relies on careful history taking. To improve diagnostic acumen, it is essential that clinicians systematically screen all patients with MDD for BD and ask careful questions about prior episodes of hypomania.Course of Illness and Comorbidity Kraepelin noted before the medication era that the course of illness for patients with BD generally progresses into more persistent and severe depression with aging. While he was primarily referring to manic-depressive illness, which we would call BD I today, the same principle applies to patients with BD II. In the NIMH collaborative study by Lewis Judd, M.D., et al., which included long-term follow-up of up to 20 years, patients with BD II experienced a course of illness characterized by more depressive episodes and fewer well intervals over time. Table 2There is a longstanding debate in the literature whether patients with BD II suffer the same impairments and risks as those with BD I. BD II was previously—and incorrectly—labeled a “less severe” version of BD I. In fact, studies consistently show comparable disease burden in BD I and II. A recent Swedish study by Alina Karanti, M.D., et al. reported higher rates of depressive episodes, illness onset at a younger age, and significantly higher rates of psychiatric comorbidity (anxiety disorders, eating disorders, and ADHD) among patients with BD II compared with those with BD I. In this Swedish sample, (n>8,700) no differences were noted in substance abuse between BD I and BD II. Interestingly, individuals with BD II generally obtained more education and achieved a higher level of independence than those with BD I. Table 3High rates of psychiatric comorbidity in patients with BD II further compound the challenge of differential diagnosis. There is considerable overlap between BD II and anxiety disorders. Attention-deficit/hyperactivity disorder also frequently co-occurs. Approximately 20% of individuals with BD II also meet criteria for borderline personality disorder (BPD), and up to 40% of those with BPD are incorrectly diagnosed as having BD I or II. Tables 2 and 3 show estimated co-occurring psychiatric illnesses for patients with BD II. The diagnosis of BD II requires a careful clinical interview of both past and current symptomatology.Suicide is a significant risk for all patients with BD, and historically patients with BD I were viewed as having a higher risk than BD II due to the extremities of mania. However, data from a number of sources support that suicide risk is high across all patients with BD, and relatively little difference is found in risk for patients with BD I versus BD II. Older studies have suggested this risk may be higher for patients with BD II than BD I, and, indeed, the Swedish bipolar registry database study recently indicated that the rate of suicide attempts was significantly higher in patients with BD II though no data on completed suicides were provided. Overall, the reports from the International Society for Bipolar Disorders Task Force on Suicide found that the risk for suicide was estimated at 164 of 100,000 per year in patients with BD versus 10 of 100,000 per year in the general population (see the reference by Ayal Schaffer, M.D., at the end of this report).Treatment of BD II Treatment guidelines for bipolar disorder often give only a passing nod to distinguishing appropriate treatments for BD I versus BD II. The combined guidelines by the Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) were unusual in making a point of distinguishing the evidence base for BD I versus BD II. They are reported in a 2018 paper by Lakshmi N. Yatham, M.D., et al. (see reference at end of article).These guidelines have a separate section devoted to BD II, and they clearly state that one cannot directly apply studies on patients with BD I to management of patients with BD II. The conclusion of these guidelines is that there are too few controlled studies in patients with BD II to make detailed evidence-based recommendations or develop evidence-based treatment algorithms. Below is a brief overview of our current knowledge of treatments for patients with BD II with medication and/or psychotherapy.Table 4AntidepressantsIt is worth highlighting that, while monotherapy antidepressants would be viewed as an inappropriate practice for patients with BD I depression, studies suggest that the risks and benefits may be different for those with BD I and BD II. In at least one study, risk of switching to hypomania was no greater with lithium than with sertraline monotherapy. Other studies have shown antidepressant monotherapy to be an efficacious monotherapy for BD II. Meta-analyses on risk of antidepressant-induced switches are inconclusive, though the risk of treatment-emergent (hypo)mania due to medication appears to be less in patients with BD II than in patients with BD I depression receiving monotherapy antidepressants. Absent conclusive data on antidepressant switch rates, without a past record of good response to antidepressant monotherapy, current treatment guidelines suggest starting with lithium or a mood stabilizer before adding or switching to antidepressant monotherapy. Additionally, it is important to note that antidepressants in some patients may worsen the overall course of illness and may not be efficacious in some patients with BD II. Any patient who experiences hypomania or mania (which must be distinguished from transient activation symptoms) while on antidepressant medication should be presumed to be on the bipolar spectrum. AntipsychoticsMost atypical antipsychotics have not been studied for the treatment of both BD I and BD II depression, with two notable exceptions. Quetiapine registration trials included individuals with BD II, with post-hoc analyses demonstrating efficacy of quetiapine monotherapy for BD II depression. Lumateperone is the first antipsychotic formally studied for depression response in patients with BD II since quetiapine trials in the early 2000s. Lumateperone, in randomized, controlled trials, performed as well or better for BD II than BD I, according to a 2021 study by Joseph R. Calabrese, M.D., et al. Cariprazine and lurasidone, while both FDA approved to treat bipolar depression, were never formally studied in patients with BD II. There have been case series supporting their use in BD II depression, but no randomized, controlled trials have been carried out. FDA approval to treat patients with BD II depression with lumateperone came in 2021, 15 years after quetiapine was approved. This glacial rate of accruing new FDA-approved compounds for BD II speaks to the need for more studies in this population.Lithium and AnticonvulsantsWhile we might expect lithium to be the frontrunner treatment for managing BD II, study results are varied. Certainly, for hypomania and maintenance treatment of patients with BD II, lithium is a top choice. Lithium has a disappointingly poor track record for treating BD II depression with little indication that response rates are superior to those of antidepressants and atypical antipsychotics. Lamotrigine has good evidence for preventing new depression episodes in the context of BD (both BD II and I). The evidence, however, is less robust for treating acute depression in patients with BD II. In clinical practice, many clinicians prescribe lamotrigine, especially as an adjunctive treatment, for BD II depression, but our ability to make firm recommendations with confidence about lamotrigine is limited.Other TherapiesRapid-acting therapies are on the rise across all treatments for depression. There has been a recent surge of clinical work and research examining transcranial magnetic stimulation (TMS), ketamine, and psychedelics and related compounds. More work is needed specifically focused on BD II depression before firm conclusions may be drawn.There is limited evidence supporting the use of TMS for BD II depression. This evidence base is developing, and more information is forthcoming on the utility of TMS for BD II depression.Ketamine and Psychedelic StudiesRacemic ketamine has been in use for many years as an anesthetic and more recently was approved by the FDA as intranasal esketamine (the s-enantiomer of racemic ketamine) as a treatment for MDD. Three small studies of racemic ketamine suggest that it is effective for BD II depression. A 2022 observational study by Farhan Fancy et al. assessing patients with BD I versus BD II treated with racemic ketamine included more than 60 patients (n=35 BD II). In this largest open observational study to date involving ketamine and BD, patients with BD II demonstrated a more robust response than those with BD I. More studies are in development exploring this new use of an old drug; to date, there is no information on the role of esketamine for bipolar depression, let alone BD II.Recently, it’s been difficult to pick up a journal or look at other media without seeing something about psychedelics and related compounds. There is a surge of interest in psychedelics for MDD, although evidence about their effectiveness is still early and with rare exceptions involves small samples. There is one report on treatment of depression with psilocybin in patients with BD II. In this pilot study, 15 patients with BD II were given a one-time dose of psilocybin (25 mg) and provided preparatory, dosing, and integration therapy consistent with psilocybin studies in MDD. In this small open study by Scott Aaronson, M.D., et al., the rate of response at 3 and 12 weeks was more robust than has been observed in MDD studies. An ongoing study is assessing the durability of patients’ response to psilocybin administered one time for patients with BD II depression. While no notable adverse events or increased mood lability were noted in this small sample to date, further study is needed to assess benefits and harms.PsychotherapyMost information about psychotherapy for BD II is derived from trials of interventions for BD in general that also included a subset of individuals with BD II. A recent systematic review of psychotherapies for BD II identified over 1,000 individuals with BD II who participated in randomized, controlled trials testing psychosocial interventions to treat depression or prevent recurrence of mood symptoms. However, relatively few of these trials—only eight of 27—examined outcomes in those with BD II separately. From this review, we concluded that there is preliminary evidence supporting the efficacy of several evidence-based psychotherapies for BD II: cognitive-behavioral therapy, psychoeducation, family focused therapy, interpersonal and social rhythm therapy (IPSRT), and functional remediation. None of these psychotherapies have undergone rigorous testing in randomized, controlled trials focused specifically on BD II depression, with the exception of IPSRT, pointing to the need for additional research in this area. To our knowledge, no meta-analysis of psychotherapy for BD II has been published. IPSRT, the only psychosocial intervention to be tested in a randomized, controlled trial consisting of participants with BD II only (rather than a mixed patient population of BD I and II), focuses on helping individuals develop more regular routines to stabilize underlying disturbances in circadian rhythms. Because abnormalities in circadian biology have been implicated in the genesis of bipolar disorders, including BD II, a chronobiologic behavioral approach may be especially helpful to mitigate BD II symptoms.ConclusionsBD II is a relatively common disorder affecting approximately 0.4% of the population. Its prevalence, morbidity, and mortality are comparable to that of BD I. Evidence supports conceptualizing BD II as a distinct phenotype, separable from both BD I and MDD. Compared with BD I and MDD, far less is known about BD II and how to treat it. Further, despite being reliably diagnosed in DSM-5 field trials, BD II is frequently misdiagnosed in practice, resulting in a decade-long lag between onset of symptoms and appropriate diagnosis. A neglected condition, BD II causes unnecessary suffering in those who are misdiagnosed or for whom appropriate treatments are unclear. More research is urgently needed to improve identification and treatments for BD II. ■ResourcesDavid L. Dunner, M.D., et al. “Heritable Factors in the Severity of Affective Illness,” Biological Psychiatry, February 1976.J. Raymond DePaulo, M.D., et al. “Bipolar II Disorder in Six Sisters,” Journal of Affective Disorders, August 1990.Lewis Judd, M.D., et al. “Long-Term Symptomatic Status of Bipolar I vs. Bipolar II Disorders,” International Journal of Neuropsychopharmacology, June 2003.Alina Karanti, Ph.D., et al. “Characteristics of Bipolar I and II Disorder: A Study of 8766 Individuals,” Bipolar Disorders, June 2020.Ayal Schaffer, M.D., et al. “A Review of Factors Associated With Greater Likelihood of Suicide Attempts and Suicide Deaths in Bipolar Disorder: Part II of a Report of the International Society for Bipolar Disorders Task Force on Suicide in Bipolar Disorder,” Australian & New Zealand Journal of Psychiatry, November 2015.Lakshmi N. Yatham, M.D., et al. “Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 Guidelines for the Management of Patients With Bipolar Disorder,” Bipolar Disorders, March 2018.Joseph R. Calabrese, M.D., et al. “Efficacy and Safety of Lumateperone for Major Depressive Episodes Associated With Bipolar I or Bipolar II Disorder: A Phase 3 Randomized Placebo-Controlled Trial,” American Journal of Psychiatry, December 2021.Farhan Fancy, et al. “Real-World Effectiveness of Repeated Ketamine Infusions for Treatment-Resistant Bipolar Depression,” Bipolar Disorders, December 14, 2022.Scott Aaronson, M.D., et al. “COMP360 Psilocybin Therapy Shows Potential in Study in II Bipolar Disorder,” December Suppes, M.D., Ph.D., is a of psychiatry, at the and of the at A. Swartz, M.D., is a of at the of of and of the for at are of Bipolar II Disorder: Recognition, Understanding, and Treatment from APA APA may the at a is the of From to on the Bipolar is the of a and has with of

The growing interest in the diagnosis of bipolar disorder in youth has sparked subsequent interest and controversy related to the appropriate treatment of the disorder in this population. As such, authoritative bodies like the American Academy of Child and Adolescent Psychiatry (AACAP) have recently published practice parameters regarding the treatment of early-onset bipolar disorder. These guidelines advocate for first-line, primary psychopharmacological treatment with adjunct psychosocial therapy (McClellan et al., 2007).

Postpartum mood disorders represent a significant mental health and public health problem. Prominent among these disorders are postpartum bipolar disorder (PPBD) and postpartum depression (PPD). Both of these disorders are underrecognized and undertreated. PPD is more common than PPBD, but both have deleterious consequences for mother and child. Compared to the empirical literature pertaining to PPD, the number of studies examining PPBD is small. This chapter begins with a discussion of the limited research pertaining to PPBD followed by an overview of the vast PPD literature. Topics covered in this chapter include distinctive features, risk factors, consequences, antidepressant medication, and psychotherapeutic interventions for these postpartum mood disorders. Continued research on the etiology and treatment of postpartum mood disorders and on ways to mitigate the negative impact of these disorders on children is critical.

BIPOLAR DISORDER, ONE OF THE MOST COMMON SEvere mental illnesses, includes type 1 (with mania and usually recurrent depression) and type 2 (recurrent major depression with hypomania). Lifetime prevalence for type 1 bipolar disorder is approximately 1%, but inclusion of more broadly defined conditions increases this rate to 2% to 5%. Bipolar disorder can begin in childhood or adolescence, continues throughout life, and is extraordinarily costly—financially as well as clinically and socially. The course of bipolar disorder is episodic but highly variable, with potential for high levels of severity and recurrence intensity, disproportionately high depressive morbidity, and comorbidity with substance abuse and anxiety disorders. Bipolar depression can be present during 20% to 30% of patients’ time, even during prophylactic treatment, and is closely associated with disability and mortality. Bipolar disorder proves fatal in a high proportion of patients from complications of risk-taking behavior, comorbid stress-sensitive medical illnesses, and especially suicide. These characteristics mark bipolar disorder as a major unsolved public health challenge. Treatment for bipolar disorder was revolutionized in the early 1970s by the introduction of US Food and Drug Administration (FDA)–approved long-term prophylactic treatment with lithium carbonate for preventing recurrences of mania and bipolar depression. Lithium remains the international standard of comparison for an increasing number of innovative treatments introduced in recent years, including several anticonvulsants and modern antipsychotics. However, evidence for long-term prophylactic effectiveness of agents other than lithium remains limited, and comparisons of specific agents in particular phases of bipolar disorder are needed. No currently available treatment provides full protection from recurrences of manic, mixed manic-depressive, major depressive, or highly prevalent milder depressive states. Among patients with type 1or 2 bipolar disorder, longterm lithium monotherapy can reduce mania or hypomania and depression similarly, by about two thirds. Most other agents with proposed mood-stabilizing effects appear to be more effective against mania and hypomania than against bipolar depression, with the possible exception of lamotrigine. For example, in well-designed comparisons with other agents, divalproex has yielded considerably less long-term protective effects against bipolar depression or mixed dysphoric-agitated states than against mania, although divalproex has been shown to limit depression by some measures. Addition of an antidepressant is unlikely to resolve the problem of residual depression, owing to inconsistent responsiveness of bipolar depression to antidepressants and their risk of inducing mania or emotional instability in patients with bipolar disorder. As a cause of premature death in patients with bipolar disorder, suicide represents an extraordinarily high risk, with an estimated rate of 0.40% per year vs the international general population average of 0.017% per year, with a standardized mortality ratio of 22. For comparison, the average standardized mortality ratio for suicide is about 20 among persons with unipolar major depression and 8.4 for those with schizophrenia. Moreover, suicide attempts by patients with bipolar disorder have an increased lethal potential. Among patients with bipolar disorder, rates of suicide attempts are only 5 times the rates of completed suicides, whereas in the general population, rates of suicide attempts are 10 to 20 times the rates of completed suicides. Suicide in patients with bipolar disorder is strongly associated with depressive and dysphoric-agitated (mixed) states. Suicidal risk may be greater in type 2 bipolar disorder, characterized by less severe episodes of elevated mood than type 1 but with severe recurrent depression, often misdiagnosed as nonbipolar major depression and not consistently treated with mood-stabilizing agents. Long-term use of lithium is the only treatment consistently associated with much lower rates of suicide and lifethreatening suicide attempts in bipolar disorder. In a recent meta-analysis of 22 studies with data permitting

Antipsychotics are commonly used in the treatment of bipolar affective disorder. The use of conventional antipsychotic agents, though effective as antimanic agents, is associated with a number of limitations such as their acute side effect profile and their unsufficient mood stabilizing activity. In addition, exposure to conventional neuroleptics poses a risk for the development of tardive dyskinesia, especially in mood disorder patients. Growing evidence suggests that the novel, so-called atypical neuroleptics may offer a number of advantages in the treatment of bipolar disorder, including their thymoleptic activity and minimal risk for acute and long-term extraypyramidal symptoms. Clinical experience with clozapine and olanzapine as mood stabilizers suggests greater antimanic than antidepressant properties, while risperidone may have greater antidepressant properties with some liability for triggering or exacerbating mania. The mood stabilizing properties of further atypical drugs are currently under investigation. This review focuses on the use of atypical antipsychotics in the treatment of bipolar disorder. We also present an overview concerning potential pharmakokinetic interactions based on the cytochrome P450 enzyme system when antipsychotics are combined with other mood stabilizing compounds. In conclusion, atypical antipsychotics should come to play an increasingly important role in the acute and long-term management of bipolar disorder, but there is a clear need for further controlled trials in this indication.

Synaptic, intracellular, and neuroprotective mechanisms of anticonvulsants: are they relevant for the treatment and course of bipolar disorders?

The objectives of this article are to review the prevalence, natural history, pathophysiology, and treatment of comorbid bipolar disorder with alcoholism and other psychoactive substance use disorders (PSUDs). All identified bibliographies through a literature search of all Medline files and bibliographies of selected articles focusing on the prevalence, natural history, course, prognosis, inter-relationship, and treatment of bipolar disorder with comorbid alcoholism and other PSUDs were reviewed. Comorbidity of bipolar disorder and alcoholism and other PSUDs is highly prevalent. The presence of this so called 'dual diagnoses' creates a serious challenge in terms of establishing an accurate diagnosis and providing appropriate treatment interventions. The inter-relationship between these disorders appears to be mutually detrimental. The course, manifestation, and treatment of each condition are significantly compounded by the presence of the other condition. Substance abuse and alcoholism appear to significantly complicate the course and prognosis of bipolar disorder resulting in increased suffering, disability, and costs. On the other hand, bipolar disorder may be a risk factor for developing PSUDs. Although, there are a number of hypotheses explaining the pathophysiological mechanism involved in such comorbidities, our understanding of the exact nature of such neurobiological mechanisms is still limited. While the antikindling agents and targeted psychotherapeutic techniques may be useful intervention strategies, there is still a significant lack of empirically based treatment options for these patients.

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Back to table of contents Previous article Next article Book ReviewsFull AccessBipolar Disorder in Later LifeStephen L. Pinals M.D.Jason B. Strauss M.D.Stephen L. Pinals M.D.Search for more papers by this authorJason B. Strauss M.D.Search for more papers by this authorPublished Online:1 Jan 2008https://doi.org/10.1176/ps.2008.59.1.119AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail The lack of evidence-based research available to guide clinicians in treating people with geriatric mental illnesses is striking. This is very much the case with regard to late-life bipolar disorder. Contrary to the popular notion that bipolar disorder "burns out" over time, this condition is becoming increasingly prevalent among elderly people as this segment of the population grows. Martha Sajatovic from Case Western Reserve University and Frederic Blow from the University of Michigan, two leaders in this burgeoning field, fill a gaping void with their book Bipolar Disorder in Later Life . Sajatovic and Blow recruited many experts and colleagues in geriatric bipolar research to create a comprehensive, cohesive, and crisply written work. This text will be of significant value to any clinician caring for this population, including general and geriatric psychiatrists, as well as geriatricians at all levels of training and expertise. The editors' stated purpose is to "present the most up-to-date knowledge available, provide frameworks and resources with which to understand bipolar disorder in late life, and offer guidance to address the paucity of data on this topic." This purpose is achieved in an eminently readable manner, because the book is divided into four parts. In the first section, the editors introduce us to the epidemiology and assessment of late-life bipolar disorder. This is followed by a concise synopsis of the use and utility of mood-rating scales in assessing mania in geriatric bipolar disorder, provided by Robert Young and colleagues.The second section concentrates on the treatment of late-life bipolar disorder, beginning with a summary of the different presentations of mania seen among elderly persons. The authors review the limited data that exist on the biological treatment of late-life bipolar disorder. Indeed, to date there has not been a single placebo-controlled trial of any agent in this population. Nevertheless, the authors do an excellent job of piecing together the available information to provide a framework for clinicians to treat geriatric bipolar disorder, focusing on minimizing potential adverse effects. The rest of this section includes valuable chapters on psychosocial interventions and treatment adherence.The third section focuses on the many challenges of treating geriatric patients with bipolar disorder with active substance abuse and medical comorbidities. Helen Kales provides a useful and clearly written summary of the various medical conditions that often accompany the presentation of late-life bipolar disorder. This section concludes with a timely and interesting account of how culture may affect the diagnosis and treatment of bipolar disorder among elderly persons.Among the concluding chapters is a review of the significant obstacles that researchers face in filling the gaps that remain in geriatric bipolar research and care. The reader is made aware of the uneven quality of psychiatric and medical care in this special population and the dearth of adequate quality control indicators to assess these issues.Bipolar Disorder in Later Life is an exceptionally well-written and thorough review of this emerging focus of research. Both clinicians and academicians will find it to be a necessary and useful work in its own right, and we hope that it leads to continued advances in the field. Dr. Pinals is associate director of geriatric psychiatry at Cambridge Health Alliance and a clinical instructor in psychiatry at Harvard Medical School, Cambridge, Massachusetts, and Dr. Strauss is a geriatric psychiatry fellow at Cambridge Health Alliance. FiguresReferencesCited byDetailsCited byNone Volume 59Issue 1 January, 2008Pages 119-120PSYCHIATRIC SERVICES January 2008 Volume 59 Number 1 Metrics PDF download History Published online 1 January 2008 Published in print 1 January 2008

Lithium is the oldest and still one of the most frequently prescribed mood stabilizers in the treatment of bipolar disorder. Nonetheless, the evidence for lithium efficacy in older patients with bipolar disorder is almost entirely extrapolated from younger adult patients. Here we review the literature on lithium in older patients with bipolar disorder, concentrating on the past 3years. A definitive study demonstrating the efficacy and safety of lithium in older patients with bipolar disorder is still missing. However, several lines of indirect evidence suggest that it is beneficial and advantageous over other mood stabilizers in the acute and maintenance treatment of late-life bipolar disorder. In addition, lithium may have unique properties as a regenerative therapeutic with specific benefits in reducing the cognitive impairment and suicide rates associated with bipolar disorder across the adult lifespan. Aging-associated pharmacokinetic and pharmacodynamic changes as well as increased rates of medical comorbidities and polypharmacy predispose older patients to a higher risk of lithium toxicity. Careful monitoring and adjustment of lithium dosage is especially important in older adults to minimize the risk of toxicity.

Economic Grand Rounds: The Economic Burden of Bipolar Disorder

The authors conducted an 18-month naturalistic prospective follow-up study of 37 adolescents whose bipolar I illness had been stabilized with lithium carbonate during inpatient hospitalization. Thirteen of the patients discontinued prophylactic lithium therapy shortly after discharge. The relapse rate of bipolar illness in these 13 patients was nearly three times higher than the rate in patients who continued lithium prophylaxis without interruption. Early relapse among lithium-treated patients was associated with a greater risk of relapsing again. The authors discuss the theoretical and clinical implications of these findings.