Bipolar depression: management options

Bipolar depression is the predominant abnormal mood state in bipolar disorder. However, despite the key pertinence of this phase of the condition, the focus of research and indeed of clinical interest in the management of bipolar disorder has been mainly on mania. Bipolar depression has been largely neglected, and early studies often failed to distinguish depression due to major unipolar depression from that due to bipolar disorder. Consequently, many treatments used in the management of major depression have been adopted for use in bipolar depression without any robust evidence of efficacy. The selective serotonin reuptake inhibitors (SSRIs), bupropion, tricyclic antidepressants and monoamine oxidase inhibitors are all effective antidepressants in the management of bipolar depression. They are all associated with a small risk of antidepressant-induced mood instability. The mood stabilisers lithium, carbamazepine and valproate semisodium (divalproex sodium) all appear to have modest acute antidepressant properties. Among these, lithium is supported by the strongest data, but the use of lithium in the treatment of bipolar depression as a monotherapeutic agent is limited by its slow onset of action. Recently, there has been a growing body of evidence suggesting that lamotrigine may have particular effectiveness in both the acute and prophylactic management of bipolar depression. Clinical management of bipolar depression involves various combinations of antidepressants and mood stabilisers and is partly determined by the context in which the depressive episode occurs. In general, 'de novo' and 'breakthrough' (where the patient is already receiving medication) bipolar depression may be successfully managed by initiating mood stabiliser monotherapy, to which an antidepressant or second mood stabiliser may be added at a later date, if necessary. Breakthrough episodes of bipolar depression occurring in patients receiving combination therapy (two mood stabilisers or a mood stabiliser plus an antidepressant) require either switching of ongoing medications or further augmentation. If this fails, then novel strategies or ECT should be considered. Bipolar depression is a disabling illness and the predominant mood state for the vast majority of those with bipolar disorder. It therefore warrants prompt management once suitably diagnosed, especially as it is associated with a considerable risk of suicide and in the majority of instances is eminently treatable.     

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.     

Duloxetine-induced hypomania: case report and brief review of the literature on SNRIs-induced mood switching

Manic switching during antidepressant treatment has been reported with every class of antidepressant drugs. Serotonin-noradrenaline reuptake inhibitors (SNRIs) have been increasingly used for the treatment of unipolar and bipolar depression and are well tolerated and sufficiently effective because of their dual mechanism of action. A case of duloxetine-induced hypomania in a non-bipolar patient is presented, and a brief review of all cases of SNRIs' induced mania and hypomania has been carried out. The available data suggest that SNRIs, especially venlafaxine, can induce mood switching in patients with bipolar depression and in certain patients with unipolar depression, but the potential of duloxetine and milnacipran to induce manic or hypomanic symptoms cannot be disregarded. Switching appears to be dose-related and treatment initiation with lower doses and upward titration when needed may be preferable in selected cases and may help minimizing the risk of mood switching.     

Antidepressant-Induced Mania with Concomitant Mood Stabilizer in Patients with Comorbid Substance Abuse and Bipolar Disorder

ABSTRACT

Antidepressant use in the treatment of bipolar disorder is controversial due the risks of affective switching and cycle acceleration. Studies of non-comorbid samples suggest that the risk can be mitigated with the use of a concomitant mood stabilizer. However, the majority of patients with bipolar disorder will experience a comorbid substance use disorder and little is known about these individuals because they are typically excluded from clinical trials. Patients entering a substance abuse treatment program who had a history of bipolar disorder were interviewed to evaluate antidepressant-induced affective switching with and without concomitant mood stabilizer. Among 41 comorbid participants, the total lifetime antidepressant-induced switch rate was 76%. The switch rate was 56% for patients taking a mood stabilizer and an antidepressant concomitantly. There was no difference between patients with bipolar I and bipolar II disorders.     

Polytherapy in bipolar disorder

Bipolar disorder is a life-long condition that is associated with frequent recurrence/relapse of symptoms. Although putative mood stabilisers, such as lithium, are considered to improve the natural course of bipolar disorder, complete long-term remission is rarely achieved. In order to effectively control mood symptoms and to reduce relapse, clinicians often use polypharmacy to treat patients with bipolar disorder. In this article, we examine the recent literature on treatment strategies in bipolar disorder to determine if combination treatments provide additional benefit over monotherapy for the management of various phases of bipolar disorder. The evidence suggests that for acute mania a combination of lithium or valproate and an atypical antipsychotic is the most effective approach, with approximately 20% more patients responding to the combination than to monotherapy with any antimanic agent. Few studies have examined the use of combination therapy in comparison to monotherapy for bipolar depression. The limited evidence suggests that lithium plus an antidepressant appears to be more effective than lithium alone in those with lower serum lithium concentrations. Similarly, the combination of olanzapine plus fluoxetine is more effective than olanzapine alone. There is consensus that antidepressant monotherapy is not appropriate because of concerns of a manic switch, but monotherapy with lithium or lamotrigine may be adequate for mild to moderate bipolar depression. For maintenance treatment, commonly used agents, such as lithium, valproate or olanzapine appear to be most effective in preventing manic relapses, whereas lamotrigine is more effective in preventing depressive relapses. As a result of these findings, it makes intuitive sense to combine lamotrigine with lithium, valproate or an atypical antipsychotic to achieve better mood stability. However, the efficacy and safety of such combinations have not been systematically compared with monotherapy. Preliminary studies suggest that lithium plus valproate may be more effective than lithium alone in preventing affective relapses. Similarly, the combination of lithium or valproate plus olanzapine seems to be more effective than monotherapy with a mood stabiliser in preventing manic episodes.     

A review of acute treatments for bipolar depression

Bipolar patients generally spend much more time in the depressed phase of their illness than the manic phase, and there are many more bipolar type II and bipolar spectrum disorder patients than there are bipolar type I. Additionally, there is a significant risk of suicide in bipolar patients when depressed. The treatment of the depressed phase of bipolar disorder is therefore a matter of some priority. Here, we review current evidence supporting the use of five groups of treatments: anti-depressants; lithium; anti-convulsants (valproate, and carbamazepine, lamotrigine, gabapentin); anti-psychotics; and other treatments (electroconvulsive therapy, benzodiazepines, sleep-deprivation, and dopamine agonists). From this review, it is apparent that the literature regarding the treatment of bipolar depression is significantly limited in several key areas. Nonetheless, from the evidence currently available, the treatments with the best evidence for efficacy are selective serotonin reuptake inhibitors (SSRIs) and lamotrigine. There is also some evidence in favour of bupropion and moclobemide. Although lithium and olanzapine monotherapies can also be beneficial, they appear less efficacious than antidepressants. One of the major concerns about treatment with antidepressants has been the risk of precipitating a switch into mania. However, recent studies suggest that, if a mood stabilizer and antidepressant are given concurrently, then the risk of switching is minimized. There is also recent evidence for an independent antidepressant action for at least one atypical antipsychotic. Therefore, the conclusion from this review, in contrast to previous suggestions, is that a combination of an atypical antipsychotic and either an SSRI or lamotrigine may provide a useful first-line treatment for depressed bipolar disorder patients. Further research is clearly required to examine this approach and compare it with other possible treatment options.     

Antidepressant-associated mania: soon after switch from fluoxetine to mirtazapine in an elderly woman with mixed depressive features

Mirtazapine augmentation to a serotonin-reuptake inhibitor has been proposed to boost antidepressant effects and more likely to induce manic switch. Such a combined antidepressant therapy strategy should be used carefully if the patient's refractoriness is attributable to mixed depressive features. Mixed depression is more difficult to be treated by antidepressant monotherapy and related to higher risk of manic switch during treatment. We report a case with no previous history of bipolar disorder, whereas developed full-blown psychotic manic symptoms soon after switch from fluoxetine to mirtazapine. The patient's premorbid characters and clinical presentations suggested an implicit bipolarity that predisposed her to a manic switch. Her manic switch was likely to be triggered by a simulated combined effect because of complex drug interactions during shifting from fluoxetine to mirtazapine. For patients in mixed depressive states, mood stabilizers are preferable to antidepressants.     

Recognizing and treating depression in children and adolescents.

PURPOSE: The clinical presentation and neurobiology of depression in youth and its appropriate treatment, as well as strategies for improving therapeutic benefit and preventing adverse outcomes, including suicide, are reviewed. SUMMARY: Functionally impairing depression occurs in 2-10% of children and adolescents. A diagnosis of depression should be considered when a physically healthy child exhibits depressed mood or anhedonia, multiple somatic complaints, or behavioral changes, such as bullying, aggression, and social withdrawal. Risk factors for depression include childhood trauma, genetic susceptibility, and environmental stressors. Antidepressants and cognitive behavioral therapy are the most effective treatments for adolescents with depression. Youth are at risk for the same adverse effects as adults but have an increased risk of behavioral activation, or switch, to mania and suicidal thoughts and behaviors early in treatment. Compared with other antidepressants, fluoxetine has the most evidence for safety and efficacy, particularly in adolescents 12 years or older. There is very little evidence for the effectiveness of any antidepressant in children 11 years and younger. Youth receiving antidepressants should be monitored closely for new-onset or worsening suicidality, particularly during the first two weeks after starting medication, and for three months of therapy. Behavioral activation, aggression, worsening depression, anxiety, insomnia, or impulsivity can herald a switch to mania or suicidality. CONCLUSION: Depression in youth is common and treatable and responds best to multimodal treatment combining patient and family education, cognitive behavioral therapy, and antidepressant medication. The potential benefits of antidepressants outweigh the risks for adolescents. Family and psychotherapeutic interventions are most effective for prepubertal children.     

PHARMAC and treatment of bipolar depression--the limits of utilitarianism

Bipolar disorder affects 1.6% of the population. The majority of the burden of illness for people with bipolar disorder is due to depression. Suicide rates for people with bipolar disorder are 15 times higher than in the general population, and the majority of these deaths occur during depressive episodes. More effective prevention of such depressive episodes is important. Lamotrigine is an anticonvulsant and a mood stabiliser that is more effective at preventing depressive relapses than most other mood stabilising drugs. Its use for this purpose has been recommended by English language treatment guidelines since 2002. Lamotrigine is approved for use in the prophylaxis of depression in bipolar disorder and for epilepsy. PHARMAC subsidises its use in treatment-resistant epilepsy (subject to a 'special authority' application) but not in bipolar disorder. The New Zealand Mental Health Strategy and the imminent New Zealand Suicide Strategy identify reducing suicide as a key goal. Among other initiatives, this requires effective treatment of bipolar depression, yet a treatment likely to support this is not currently subsidised.     

抗抑郁药物在双相情感障碍治疗中的应用

抗抑郁药物在双相情感障碍中的应用备受关注。抗抑郁药物治疗双相抑郁急性期疗效较为肯定,但有转躁等问题;长期治疗的预防效果尚有待进一步研究。本文从循证医学角度,综述抗抑郁药物在双相情感障碍(主要是双相抑郁)急性期和维持期治疗中的疗效以及转躁情况,阐述双相情感障碍治疗中抗抑郁药物合理使用的重要性和必要性。     

ECNP consensus meeting. Bipolar depression. Nice, March 2007.

DIAGNOSIS AND EPIDEMIOLOGY: DSM-IV, specifically its text revision DSM-IV-TR, remains the preferred diagnostic system. When employed in general population samples, prevalence estimates of bipolar disorder are relatively consistent across studies in Europe and USA. In community studies, first onset of bipolar mood disorder is usually in the mid-teenage years and twenties, and the occurrence of a major depressive episode or hypomania is usually its first manifestation. Since reliable criteria for delineating unipolar (UP) and bipolar (BI) depression cross-sectionally are currently lacking, there is a longitudinal risk - probably over 10% - that initial UP patients ultimately turn out as BP in the longer run. Its early onset implies a severe potential burden of disease in terms of impaired social and neuropsychological development, most of which is attributable to depression. BIPOLAR DEPRESSION IN CHILDREN: Bipolar I disorder is rare in prepubertal children, when defined according to unmodified DSM-IV-TR criteria. A broad diagnosis of bipolar disorder risks confounding with other childhood psychopathology and has less predictive value for bipolar disorder in adulthood than the conservative definition. Nevertheless, empirical studies of drug and other treatments and longitudinal studies to assess validity of the broadly defined phenotype in children and adolescents are desirable, rather than extrapolation from adult bipolar practice. The need for an increased capacity to conduct reliable trials in children and adolescents is a challenge to Europe, whose healthcare system should allow greater participation and collaboration than other regions, via clinical networks. ECNP will aspire to facilitate such developments. BIPOLAR DEPRESSION IN ADULTS - UNIPOLAR/BIPOLAR CONTRAST: Despite some differences in symptom profiles and severity measures, a cross-sectional categorical distinction between bipolar (BP) and unipolar (UP) depression is currently impossible. For regulatory purposes, a major depressive episode, meeting DSM-IV-TR criteria, remains the same diagnosis, irrespective of the overall course of the disorder. However, in refining diagnosis in future studies and DSM-V, a probabilistical approach to the UP/BP distinction is more likely to be informative as recommended by the International Society for Bipolar Disorders (ISBD). Anxiety is a commonly present, often at syndromal levels, in bipolar populations. Thus, RCT inclusion criteria for trials not targeting anxiety, should accept co-morbid anxiety disorders as part of the history and even current anxiety symptoms, where these are not dominating the mental state at recruitment to a study. Rapid cycling patients defined as those suffering from 4 or more episodes per year, may also be recruited into trials of bipolar depression without impairing assay sensitivity. Illness severity critically affects assay sensitivity. The minimum scores for entry into a bipolar depression trials should be >20 on HAM-D (17 item scale). However, efficacy is best detected in patients with HAM-D >24 at baseline. THE USE OF RATING SCALES IN BIPOLAR DEPRESSION: There is some dissatisfaction with the HAM-D or MADRS as the preferred primary outcome for trials, although they probably capture global severity adequately. Secondary measures to capture so-called atypical symptoms (such as hypersomnia or hyperphagia), or specific psychopathology more common in bipolar participants (such as lability of mood), could be informative as secondary measures. TREATMENT STUDIES IN BIPOLAR DEPRESSION: Monotherapy trials against placebo remain the gold-standard design for determining efficacy in bipolar depression. The confounding effects of co-medication are emerging from the literature on antidepressant studies in bipolar depression, often conducted in combination with antimanic agents to avoid possible switch to mood elevation. Three arm trials, including the compound to be tested, placebo, and a standard comparator, are generally preferred in order to ensure assay sensitivity and a better picture of benefit-risk ratio. However, in the absence of any gold-standard, two-arm trials may be enough. If efficacy happens to be proven as monotherapy, new compounds may be tested in adjunctive-medication placebo-controlled designs. Younger adults, without an established need for long-term medication, may be particularly suitable for clinical trials requiring placebo controls. The conversion rate of initial UP depression, converting to become BP in the long run is estimated to be 10%. Switch to mania or hypomania may be the consequence of active treatment for bipolar depression. Some medicines such as the tricyclic antidepressants and venlafaxine may be more likely to provoke switch than others, but this increased rate of switch may not be seen until about 10 weeks of treatment. Twelve week trials against placebo are necessary to determine the risk of switch and to establish continuing effects. Careful assessment at 6-8 weeks is required to ensure that patients who are failing to respond do not continue in a study for unacceptable periods of time. To capture a switch event, studies should include scales to define the phenomenology of the event (e.g. hypomania or mania) and its severity. These may be best applied shortly after the clinical decision that switch is occurring. Long-term treatment is commonly required in bipolar disorder. Trials to detect maintenance of effect or continued response in bipolar depression should follow a 'relapse prevention' design: i.e. patients are treated in an index episode with the medicine of interest and then randomized to either continue the active treatment or placebo. However, acute withdrawal of active medication after treatment response might artificially enhance effect size due to active drug withdrawal effects. A short taper is usually desirable. Longer periods of stabilisation are also desirable for up to 3 months: protocol compliance may then be difficult to achieve in practice and so will certainly make studies more difficult and expensive to conduct. The addition of a medicine to other agents during or after the resolution of a depressive or manic episode, and its subsequent investigation as monotherapy against placebo to prevent further relapse (as in the lamotrigine maintenance trials) is clinically informative. Assay sensitivity and patient acceptability are enhanced if the outcome in long-term studies is 'time to intervention for a new episode' for discontinuation designs.     

Factors associated with initial treatment response with antidepressants in bipolar disorder

Introduction

Controversy in antidepressant (AD) use in bipolar depression relies in its potential induction of mood switches and ineffectiveness. Responders to acute AD add-on treatment maintain response with continued treatment, whilst partial/non-responders fail to reach remission despite continuation treatment. We aimed to identify response predictors to acute AD addition in bipolar depression in order to optimize treatment choice in bipolar depression and avoid unnecessary AD exposure of people unlikely to respond.

Methods

Two hundred and twenty-one DSM-IV-TR depressed bipolar - type I and II - patients were treated with AD on an observational study. AD response was defined as an at least 50% drop from baseline of their HDRS17 score after 8 weeks of treatment. One hundred and thirty-eight patients (138, 62.4%) fulfilled response criteria (RI) whilst 83 patients (37.6%) did not (NRI). In all cases AD therapy was on top of previously prescribed stabilizers and/or atypical antipsychotics.

Results

RI patients were more likely to have had previous response to ADs, whereas NRI had a higher number of previous mood switches with ADs during past depressive episodes. Psychotic symptoms were more frequent amongst RI, whilst lifetime history of atypical depression was more frequent amongst NRI. NRI had more total, depressive, and hypomanic, but not manic or mixed, episodes in the past than RI. Analyzed through a logistic regression, higher previous response to ADs and lower rate of past hypomanic episodes in RI were the variables explaining intergroups (RI vs. NRI) differences.

Discussion

Taking into account the proper caution in the use of Ads in bipolar disorder, there is a subgroup of bipolar patients who might benefit from adjunctive Ads. Looking at specific clinical factors during the course of the illness could help physicians in deciding whether to use an antidepressant in a bipolar depressed patient already treated with mood stabilizers.     

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.     

Quetiapine. A me-too neuroleptic; no panacea

Quetiapine, a so-called atypical neuroleptic, is authorised in the European Union for use in the standard indications of neuroleptics. However, it is the only neuroleptic licensed for the treatment and prevention of depressive episodes in patients with bipolar disorder, and as add-on therapy for depressive episodes inadequately improved by an antidepressant. In patients with schizophrenia, the authors of two meta-analyses, one including 12 trials (3443 patients) and the other 21 trials (4101 patients), concluded that quetiapine was not clearly more effective than other conventional or atypical neuroleptics. In bipolar patients with manic episodes, the results of two trials suggest that quetiapine monotherapy is not more effective than haloperidol or lithium. Two placebo-controlled trials of add-on quetiapine therapy in patients receiving a mood stabiliser (lithium or divalproate sodium) yielded conflicting results. In bipolar patients with a depressive episode, the only available trial, versus placebo and versus paroxetine in 740 patients, failed to provide conclusive evidence. In two trials with controversial designs, in which quetiapine was added to a mood stabiliser in order to prevent new depressive or manic episodes in bipolar patients, quetiapine appeared to be more effective than placebo: about 15% to 20% more patients were stabilised on quetiapine than on placebo. There are no trials to show whether quetiapine is more effective in preventing manic episodes than a neuroleptic. In a trial including 1226 patients in whom quetiapine was effective during a first depressive or manic episode, quetiapine appeared to be more effective than lithium in preventing a depressive episode (relapse rate 8.9% versus 13.5%) but not a manic episode. These comparisons may be biased, however. Two placebo-controlled trials assessed quetiapine add-on therapy in patients in whom an antidepressant was inadequately effective. The conflicting results obtained in these two trials rule out drawing firm conclusions as to the efficacy of quetiapine. Overall, quetiapine has the adverse effect profile common to atypical neuroleptics. However, hypercholesterolaemia is more frequent than with risperidone, and both clinical trials and post-marketing data have shown that quetiapine carries a risk of hypothyroidism. Animal studies suggested a risk of cataracts, but this adverse effect has not yet been confirmed in humans. The risk of sudden cardiovascular death appears similar to that reported with other neuroleptics. A retrospective survey suggests that the consequences of acute overdose are more severe with quetiapine than with other neuroleptics. Quetiapine is metabolised by cytochrome P450 isoenzyme CYP3A4, creating a high risk of pharmacokinetic interactions. In practice, quetiapine has not been shown to provide a therapeutic advantage over other treatments, although additional trials in the prevention of depressive episodes are warranted in selected patients.     

Current concepts in clinical therapeutics: major affective disorders, Part 1

The epidemiology, pathophysiology, diagnosis and clinical features, and treatment of unipolar (depressive) and bipolar (manic-depressive) affective disorders are described. Disturbances of mood are the most common psychiatric disorders in adults, with 18-23% of women and 8-11% of men having at least one major depressive episode. Genetic factors are important in both depression and manic-depressive illness. Depression is characterized by a persistent dysphoric mood accompanied by feelings of sadness or hopelessness nearly every day for at least two weeks. The essential feature of a manic episode is an elevated, expansive, or irritable mood associated with symptoms such as hyperactivity and lack of judgment. Treatment involves nonpharmacologic and pharmacologic interventions. Psychotherapy in patients with depression is most useful in improving social functions, while antidepressant drugs reduce relapse rates. Electroconvulsive therapy is indicated in depressed patients at immediate risk of suicide or extreme incapacitation. Tricyclic antidepressants (amitriptyline, imipramine, doxepin, notriptyline, desipramine, trimipramine), second-generation antidepressants (maprotiline, amoxapine, trazodone, bupropion), monoamine-oxidase inhibitors (phenelzine, isocarboxazid, tranylcypromine, pargyline), and lithium are useful in treating patients with affective disorders. Tricyclic agents are the mainstay of treatment for depression; newer second-generation agents should be used in specific subgroups of patients. Lithium is the drug of choice for prophylaxis in bipolar patients, whereas combinations of lithium and tricyclic agents are useful during acute episodes of depression in bipolar patients. Major affective disorders occur commonly and require a careful balance of pharmacologic and nonpharmacologic interventions for proper therapy.     

Manic/hypomanic switch during acute antidepressant treatment for unipolar depression

A significant proportion of patients with unipolar depression clinically develop manic or hypomanic switch during acute antidepressant treatment. Elucidation of its prevalence and predicting factors is of clinical relevance during acute antidepressant treatment of such patients. We retrospectively studied patients with unipolar depression who were admitted to our department during the 6-year period from 1997 to 2002 and who had fewer than 3 previous episodes before admission. The clinical background of the consecutive patients with manic/hypomanic switch (n = 37) who met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria was compared with that of patients without manic/hypomanic switch (n = 245). The prevalence rate of manic/hypomanic switch was 13.1%. The switch group was composed of 23 men and 14 women, whose average age was 48.8 +/- 12.3 years (range, 26-78 years). Manic/hypomanic switch was most frequently observed between 2 and 3 weeks after the antidepressant was increased to the ongoing dose. Antidepressants were decreased in 13 patients and discontinued in 23. Manic/hypomanic episodes lasted from 1 to 8 weeks. The patients in the switch group included a greater proportion of male subjects and had a higher frequency of family history of bipolar disorders than those in the nonswitch group. The mean doses of antidepressants were not significantly different between these groups. The higher frequency of manic/hypomanic switch occurring around the period when antidepressants begin to show clinical effects and the higher frequency of family history of bipolar disorders might suggest a biological susceptibility to antidepressants in patients of the switch group.     

Antidepressant properties of anticonvulsant drugs for bipolar disorder

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

If at first you don't succeed: a review of the evidence for antidepressant augmentation, combination and switching strategies

Major depressive disorder is a common and disabling illness that leads to significant reductions in quality of life and considerable cost to society. Despite numerous advances in the pharmacological treatment of depression, many patients remain ill despite initial treatment. Beyond first-line treatment, current guidelines recommend either augmentation or switching of the initial antidepressant. In this narrative review, we summarize the data from randomized controlled trials and meta-analyses in order to concisely discuss how the impact of current research can be translated into clinical practice and, ultimately, into lasting improvements in patient outcomes. The augmentation strategies reviewed are lithium, thyroid hormone, pindolol, psychostimulants and second-generation antipsychotics. The data on switching from first-line antidepressants to other antidepressants are also reviewed, and include switching within the same class, switching to other first-line antidepressant classes and switching to less commonly prescribed antidepressants. Finally, the strategy of antidepressant combinations is examined. Overall, the strength of evidence supporting a trial of augmentation or a switch to a new agent is very similar, with remission rates between 25% and 50% in both cases. Our review of the evidence suggests several conclusions. First, although it is true that adjunctive lithium and thyroid hormone have established efficacy, we can only be confident that this is true for use in combination with tricyclic antidepressants (TCAs), and the trials were done in less treatment-resistant patients than those who typically receive TCAs today. Of these two options, triiodothyronine augmentation seems to offer the best benefit/risk ratio for augmentation of modern antidepressants. After failure of a first-line selective serotonin reuptake inhibitor (SSRI), neither a switch within class nor a switch to a different class of antidepressant is unequivocally supported by the data, although switching from an SSRI to venlafaxine or mirtazapine may potentially offer greater benefits. Interestingly, switching from a newer antidepressant to a TCA after a poor response to the former is not supported by strong evidence. Of all strategies to augment response to new-generation antidepressants, quetiapine and aripiprazole are best supported by the evidence, although neither the cost effectiveness nor the longer-term benefit of these strategies has been established. The data to guide later steps in the treatment of resistant depression are sparse. Given the wide variety of options for the treatment of major depressive disorder, and the demonstrated importance of truly adequate treatment to the long-term outcomes of patients facing this illness, it is clear that further well conducted studies are needed.     

Expert advice on the management of valproate in women with bipolar disorder at childbearing age

IntroductionThe perinatal period is associated with up to 2/3 relapses in untreated bipolar disorder (BD), with important consequences on the clinical BD outcome and on fetal and child development. Valproate (VPA), one of the most effective treatments in BD, is associated with the highest risk of serious neurodevelopmental disorders in exposed children. This has brought to tightened restrictions to its use by regulatory agencies and clinical guidelines.MethodsA panel of experts on the pharmacological treatment of BD conducted a non-systematic review of the scientific literature and clinical guidelines until March 2019, and provided specific evidence-based and experience-based clinical recommendations for VPA switching/discontinuation in BD women of childbearing potential.ResultsAfter the review of the evidence in a face-to-face meeting, the panel concluded that several clinical criteria need to be considered to make a clinical decision about VPA discontinuation and switch. The plateau cross-taper switch may be preferred. Abrupt switching may bear augmented risk of relapseConclusionsBD childbearing women treated with VPA must be managed on a personalized basis according to the clinical situation. It is mandatory to stop VPA during pregnancy. The duration of the discontinuation/switch process depends on different clinical variables. Lithium, lamotrigine, quetiapine, olanzapine or aripiprazole are good options for switch in stable BD patients in planned/unplanned pregnancy. In unstable BD patients planning pregnancy, stability is paramount. Prevention of post-partum episodes requires reinstatement of effective treatment before or after birth (in the case of VPA). VPA is still an option in the post-partum period and beyond.