A population-based study of the comparative effectiveness of second-generation antipsychotics vs older antimanic agents in bipolar disorder.

OBJECTIVES: Numerous antimanic treatments have been introduced over the past two decades, particularly second-generation antipsychotics (SGAs). However, it is not clear whether such newer agents provide any advantage over older treatments. METHODS: A historical cohort design investigated the nationwide population of outpatients with bipolar disorder treated in the Department of Veterans Affairs who were newly initiated on an antimanic agent between 2003 and 2010 (N=27 727). The primary outcome was likelihood of all-cause hospitalization during the year after initiation, controlling for numerous demographic, clinical, and treatment characteristics. Potential correlates of effect were explored by investigating time to initiation of a second antimanic agent or antidepressant. RESULTS: After control for covariates, those initiated on lithium or valproate monotherapy, compared to those beginning SGA monotherapy, were significantly less likely to be hospitalized, had a longer time to hospitalization, and had fewer hospitalizations in the subsequent year. Those on combination treatment had a significantly higher likelihood of hospitalization, although they also had a longer time to addition of an additional antimanic agent or antidepressant. CONCLUSIONS: The present analysis of a large and unselected nationwide population provides important complementary data to that from controlled trials. Although various mechanisms may be responsible for the results, the data support the utilization of lithium or valproate, rather than SGAs, as the initial antimanic treatment in bipolar disorder. A large-scale, prospective, randomized, pragmatic clinical trial comparing the initiation of SGA monotherapy to that of lithium or valproate monotherapy is a logical next step.

A network meta-analysis on comparative efficacy and all-cause discontinuation of antimanic treatments in acute bipolar mania.

BACKGROUND: Evidence synthesis methods enabling direct and indirect comparisons over the entire set of relevant clinical data produce quantitative point estimates for the treatments contrasts between competing interventions, and provide a hierarchical rank ordering between them. We aimed to provide evidence-based guidance on the efficacy and all-cause discontinuation of antimanic treatments. METHOD: We conducted a network meta-analysis within a Bayesian framework. We searched all standard literature databases without language restrictions up to 15 January 2014 to identify reports of short-term, randomized, blinded trials of putative antimanic drugs as monotherapy for adults with bipolar-I mania. RESULTS: Altogether, 14256 manic patients randomized to one of 18 active treatments or placebo provided 95 direct comparisons on 128 data points. For the primary outcome, standardized mean difference as Hedges' g (standardized mean difference; SMD), the hierarchies indicated by surface under the cumulative ranking (SUCRA) probabilities were in agreement with the point estimates for all antimanic drugs identified as effective. For the 12 effective antimanic drugs on clinical use, SMDs against placebo ranged from 0.32 to 0.66 without superiority of one over another, except for risperidone v. aripiprazole and valproate. Aripiprazole, olanzapine, quetiapine, risperidone, and valproate had less all-cause discontinuation rates than placebo. Sensitivity analysis by drug class indicated similar efficacy profiles for haloperidol, second-generation antipsychotics, and mood stabilizers. CONCLUSIONS: Hierarchical rank ordering by comparative efficacy and risk of all-cause discontinuations should help to guide antimanic treatment choices by clinicians, healthcare policy makers, and guideline developers.

Efficacy of pharmacotherapy in bipolar disorder: a report by the WPA section on pharmacopsychiatry.

The current statement is a systematic review of the available data concerning the efficacy of medication treatment of bipolar disorder (BP). A systematic MEDLINE search was made concerning the treatment of BP (RCTs) with the names of treatment options as keywords. The search was updated on 10 March 2012. The literature suggests that lithium, first and second generation antipsychotics and valproate and carbamazepine are efficacious in the treatment of acute mania. Quetiapine and the olanzapine-fluoxetine combination are also efficacious for treating bipolar depression. Antidepressants should only be used in combination with an antimanic agent, because they can induce switching to mania/hypomania/mixed states/rapid cycling when utilized as monotherapy. Lithium, olanzapine, quetiapine and aripiprazole are efficacious during the maintenance phase. Lamotrigine is efficacious in the prevention of depression, and it remains to be clarified whether it is also efficacious for mania. There is some evidence on the efficacy of psychosocial interventions as an adjunctive treatment to medication. Electroconvulsive therapy is an option for refractory patients. In acute manic patients who are partial responders to lithium/valproate/carbamazepine, adding an antipsychotic is a reasonable choice. The combination with best data in acute bipolar depression is lithium plus lamotrigine. Patients stabilized on combination treatment might do worse if shifted to monotherapy during maintenance, and patients could benefit with add-on treatment with olanzapine, valproate, an antidepressant, or lamotrigine, depending on the index acute phase. A variety of treatment options for BP are available today, but still unmet needs are huge. Combination therapy may improve the treatment outcome but it also carries more side-effect burden. Further research is necessary as well as the development of better guidelines and algorithms for the step-by-step rational treatment.

Association between mood stabilizers and hypothyroidism in patients with bipolar disorders: a nested, matched case-control study.

OBJECTIVES: This study investigated whether lithium, carbamazepine, and valproate increased the risk for hypothyroidism using Taiwan's National Health Insurance Dataset. METHODS: The sample included 557 bipolar disorder patients with incident hypothyroidism first diagnosed between 1998 and 2004, and 2,228 sex-, age-, and index date-matched bipolar disorder patients without hypothyroidism from 1996-2004. We compared the use of lithium, carbamazepine, and valproate before the onset of hypothyroidism between the two groups using a conditional logistical regression model. RESULTS: Compared with patients who had never used any of the three mood stabilizers, patients were more likely to have hypothyroidism if they only used carbamazepine [odds ratio (OR) = 1.68; 95% confidence interval (CI): 1.07-2.65]; or comedication of lithium and valproate (OR = 2.40; 95% CI: 1.70-3.40), lithium and carbamazepine (OR = 1.52; 95% CI: 1.10-2.08), and three mood stabilizers (OR = 2.34; 95% CI: 1.68-3.25). There was a dose-response relationship between the number of mood stabilizers and risk for hypothyroidism (OR = 1.34, 95% CI: 1.21-1.49) and a significant interaction between lithium and valproate on the risk for hypothyroidism (p = 0.020). CONCLUSIONS: Our findings indicate that lithium, carbamazepine, and valproate may increase the risk for hypothyroidism, particularly if combined, and suggest regular monitoring of thyroid function and monotherapy of mood stabilizers for treating patients with bipolar disorders.

[Mood stabilizers]. / Stimmungsstabilisierer.

Within recent years the diagnostic concept of bipolar disorders has profoundly changed. The original view of one manic-depressive illness has become more and more a spectrum disorder ranging from personality traits to the full clinical feature of manic-depressive illness. Therefore, prevalence has increased in the general population. However, for differential treatment approaches with mood stabilisers the clinical distinction between bipolar I and bipolar II disorders becomes more and more relevant and, importantly, rapid cycling is a critical criterion for a differential indication of mood stabilisers. In acute treatment the psychopathological features such as euphoric versus dysphoric mania, the severity and the frequency of episodes play an important role for the choice of the mood stabiliser. According to international guidelines Lithium and Valproat are first-line treatment options. In addition, Lamotrigin has become a first-line treatment in special issues such as long-term treatment of bipolar depression. Carbamazepin, however, has lost its first-line place due to the evidence-based data situation and due to the side-effect profile. Within recent years the atypical anti-psychotics were investigated in bipolar disorder. Meanwhile, most of them have an indication for the treatment of acute mania, some of them for bipolar depression. Some studies also point to an efficacy in long-term prophylactic treatment. In summary, the psychopharmacological indications for the differential use of mood stabilisers are becoming more and more complex, therefore clear guidelines are needed.

[Bipolar disorder, pregnancy and the postpartum--risks and possibilities of pharmacotherapy]. / Psychopharmaka in Schwangerschaft und Stillzeit--Risiken und Möglichkeiten bei Frauen mit einer bipolaren affektiven Störung.

Pregnancy and the postpartum are times of increased risk for women with bipolar disorder to develop mood episodes, especially depressions that may require pharmacotherapy. If mood stabilizing agents are discontinued prior or due to pregnancy, the risk for relapse increases dramatically. On the other hand, there is no psychotropic drug that is completely risk-free for the unborn. Some mood stabilizing medications are teratogenic, others can cause severe perinatal complications. Thus, the decision whether to treat the pregnant women with psychotropic drugs is difficult to make. In this paper, the reproductive risks of mood stabilizing agents, antidepressants, neuroleptics and benzodiazepines for the fetus are reviewed. During the postpartum period severe mood disorders can occur. The signs and symptoms of these disorders are reviewed and therapeutic strategies are discussed.

The role of mood stabilisers in the treatment of the depressive facet of bipolar disorders.

It was previously shown that available mood stabilisers are used to treat bipolar depression. As part of the natural course of illness, patients with bipolar disorder often suffer from episodes of depression more frequently and for longer durations than mania. A major challenge in the treatment of bipolar depression is the tendency for antidepressant medications, particularly tricyclic antidepressants, to precipitate episodes of mania, or to increase cycle frequency or symptom intensity. Thus, exploring the utility of mood stabilisers as monotherapy for bipolar depression is important. The aim of this review it to collate data involving the effects of some mood stabilisers like lithium, carbamazepine, valproate and lamotrigine in depressive aspects of bipolar disorder, but as well using an animal model of depression, to understand their mechanism of action.

Bipolar depression: an overview.

Depressive episodes are significant in bipolar illness since patients can spend up to one-third of their lives in depression. Although the treatment of bipolar depression remains an understudied area, new data from randomized, controlled trials and naturalistic studies have expanded the range of treatments available. The main aim in the treatment of bipolar depression is the prevention of the patient switching to mania and cycle acceleration, and antidepressant therapy may be contraindicated because of the risk for switching. Guidelines for the acute treatment of bipolar depression emphasize treatment with a mood stabilizer, of which lithium has been the most thoroughly studied in randomized, controlled trials in acute bipolar depression. Lamotrigine has also demonstrated significant efficacy in recent studies and has been approved by the FDA.

[Criteria defining antimanic drugs (psychopharmacological specificity and/or nonspecificity?)]. / Critériologie pour la définition des médicaments antimaniaques (spécificité et/ou aspécificité psychopharmacologique?).

The question as to whether specific antimanic drugs differ in their action profile from nonspecific drugs is addressed in regard to symptomatic, nosographic, regulatory and physiopathological issues. Results from clinical studies have shown that mood stabilizers and typical neuroleptics differ as regards improvement of manic symptoms: the former appear to act more evenly on all symptoms of mania, showing a more total normalization of affect, ideation and behaviour whereas the latter tend to sedate patients or to cause a psychomotor retardation, leaving the core manic symptoms unaffected. This has been many times underlined, in particular for lithium, notwithstanding the fact that rating scales employed in clinical trials have often been charged to fall far short of being sensitive enough to pick up the qualitative changes in manic psychopathology. Antimanic drugs may also be more or less specific in their capacities to treat all facets of the manic episode (psychotic, depressive, irritable) whatever the bipolar subtype (bipolar I, II, rapid and non-rapid cycling, secondary bipolar disorder) or the disease stage (early and late episodes). In this respect divalproate seems to have a broader spectrum of efficacy than other available agents. Newer antipsychotics such as olanzapine are promising too. From a regulatory point of view, the current European requirements for a specific antimanic drug are more stringent than the US requirements of the Food and Drug Administration (FDA). Efficacy must be demonstrated in short-term studies showing an effect in acute mania; moreover it has to be shown that efficacy is to be maintained during the episode. So far, three armed randomized controlled trials are required, in which the test product is compared both with placebo and with a standard treatment. A possible design is a comparison of test product, placebo and active control for 3 weeks followed by a two-arm phase for the remaining 9 weeks, comparing only test product and active control. In addition, a specific antimanic has to demonstrate that it does not cause switching to depression. As regards physiopathology, integrative models of bipolar disorder, ie kindling and behavioural sensitization, offer an exciting perspective on the specificity issue; agents active in these models initialize a cascade of intracellular signaling that leads to changes in the expression of immediate early genes as well as late effector genes in corticolimbic structures: the former may contribute to acute symptomatology whereas the latter give rise to neuroanatomical reorganization which could underlie more stable changes in mood and cognition. Due to their action on intracellular messaging systems, dopamine D(1) receptors, serotonin 5HT(1a) or 5HT(2a) receptors, especially in orbitofrontal circuit, antimanic agents may exhibit a more specific activity than other drugs. This specificity could concern a whole spectrum of bipolarity which might be characterized by impulsivity.