guidelines on mood stabilizers...effects on rapid cycling ..... 40 pregnancy ..... 40 breastfeeding...

Guidelines on Mood Stabilizers

Johannes Gfesser and Sarah Kittel-Schneider

ContentsIntroduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2Guidelines on Bipolar Disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4Mood Stabilizers Sorted by Substance Class . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

Lithium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4Anticonvulsants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8Valproate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8Carbamazepine and Oxcarbazepine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11Lamotrigine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13Gabapentin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16Pregabalin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17Topiramate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

Second-Generation Antipsychotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19Quetiapine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19Aripiprazole . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22Olanzapine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24Risperidone and Paliperidone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26Ziprasidone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29Asenapine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31Lurasidone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33Cariprazine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35Clozapine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36

General Conclusion and Recommendation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38Acute Bipolar Depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38Acute Mania . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39

J. GfesserDepartment of Psychiatry, Psychotherapy and Psychosomatic Medicine, University Hospital ofFrankfurt, Goethe University, Frankfurt am Main, Germanye-mail: [email protected]

S. Kittel-Schneider (*)Klinik für Psychiatrie, Psychosomatik und Psychotherapie, Universitätsklinikum Frankfurt amMain, Frankfurt am Main, Germanye-mail: [email protected]

© Springer Nature Switzerland AG 2020P. Riederer, G. Laux et al. (eds.), NeuroPsychopharmacotherapy,https://doi.org/10.1007/978-3-319-56015-1_117-1

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Maintenance Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39Bipolar II Disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40Effects on Mixed States . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40Effects on Rapid Cycling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40Breastfeeding Period . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41

AbstractMood-stabilizing medication is widely used in treating bipolar disorder. How-ever, not for every phase of bipolar disorder, there is sufficient and recentevidence supporting the use of mood-stabilizing medication. Especially in bipolardepression and mixed episodes, published studies are still sparse. The same is truefor potential treatment differences between bipolar I and bipolar II subtypes. Wereviewed the most recent available guidelines on the treatment of bipolar disorderas well as the published clinical studies and report the evidence that is at hand forseveral mood stabilizers in the treatment of different phases and subtypes ofbipolar disorder. Additionally, more women suffering from bipolar disorders wishto become pregnant and breastfeed their children. As in this area, there are norandomized controlled trials for ethical reasons; we shortly summarized theevidence that is at hand with a focus on risk for malformation and lactationfrom register and cohort studies, case series, and a few controlled studies.

Introduction

Writing a chapter on mood stabilizers, first a definition of this term and of its use inthis chapter has to be made, as the term is seen by some authors as “underdefined”(Ketter 2018) and its use as “inconsistent” (Yatham et al. 2018) in literature andclinical practice.

In the before-cited article, Ketter advocates the definition of the term moodstabilizer as “any treatment that is effective in any phase of bipolar disorder butnot active at dopamine receptors” (thus excluding antipsychotics). In this chapter wewill use a broader definition for the term and will also report on certain second-generation antipsychotics that have been found – in varying degrees – to be effectivein treating as well acute bipolar depression and acute mania as also to be of benefit inmaintenance treatment of bipolar disorder and are also included in most of theexisting guidelines on bipolar disorders.

For this chapter we will thus – referring to Ketter – broaden the definition of theterm mood stabilizers as any pharmacological treatment that is effective in any stateof bipolar disorder and will try to give an overview of pharmacological agents whichmatch this definition. We will thus in this chapter consider neither first-generationantipsychotics nor antidepressants. As for the latter, their elevated risk of possiblyinducing (hypo)mania – at least when given as monotherapy – could be shown in

2 J. Gfesser and S. Kittel-Schneider

numerous studies, for example, in a large Swedish registry study of 3240 patients(Viktorin et al. 2014), and has been concluded in systematic literature reviews (e.g.,Pacchiarotti et al. 2013).

Also, there is good evidence that first-generation antipsychotics can worsen orinduce depressive symptoms and episodes in patients with bipolar disorder (Wu et al.2016; Fountoulakis et al. 2017). It is for these reasons that these substance classes donot meet our above set definition criteria for mood stabilizers.

With a lifetime prevalence of at least 1%, bipolar disorder is a common diseasewith a chronic course. In many patients it can take a disabling development, makingit the 16th and the 4th leading cause of years lived with disability (YLD) in generaland in patients aged 10–24 years, respectively (Ferrari et al. 2016; Gore et al. 2011).

It is therefore crucial to start an effective and evidence-based treatment thatpossibly covers all phases of bipolar disorder as early as possible in the course ofthe condition.

Because of its phasic character, the treatment of bipolar disorder is challengingsince as mentioned above medication used in distinct phases of the illness can have anegative effect on the other polarity or for maintenance treatment.

Furthermore, bipolar disorder is not a homogenous entity but comprises a rangeof diagnostic subgroups which is also taken into account by the latest edition of theDiagnostic and Statistical Manual of Mental Disorders (DSM-5) differentiatingbetween bipolar I and bipolar II disorders and introducing certain specifiers to beable to more precisely describe the individual presentation of the bipolar syndromein each patient (American Psychiatric Association 2013).

We will take this into account trying to give advice and present evidence(if available) for particularities in certain subcategories and specifiers.

Thus, each medication treated in this chapter will be presented in regard to itsefficacy in treating acute mania and acute depression as well as in maintenancetreatment. For each drug particularities in bipolar II disorder (if any) will beilluminated just as its potential specific effect on mixed states as well as rapidcycling (considering the respective specifiers in DSM-5). Existing guidelines onthe treatment of bipolar disorders as well as published studies are reviewed in thischapter to give a summary of the evidence of mood stabilizers in bipolar disorder.

By providing a brief advice on the peripartal use (that means the use of themedication in pregnancy and breastfeeding period) of each pharmaceutical agent,we will also take into consideration the peripartum onset specifier in DSM-5.Furthermore, an increasing number of women diagnosed with bipolar disorderwish to get pregnant. In some agents, embryotoxic risks are described; however,the relapse risk especially in the postpartum period without a mood stabilizer is veryhigh (about 70% vs. 30%) if the mood-stabilizing medication had been continuedduring pregnancy and delivery (Wesseloo et al. 2017a), so that the decision for oragainst continuing the medication should be discussed individually. Additionally,experiencing mood episodes in pregnancy and breastfeeding period is known to havenegative impacts on the mother-child relationship and interaction and can lead tolong-term negative impact on child development (Suri et al. 2014). When psycho-pharmacological medication is given in the third trimester and during delivery, there

Guidelines on Mood Stabilizers 3

is an increased risk of the so-called neonatal abstinence syndrome (NAS), whichfeatures can be vigilance dysregulation, tachypnea, tachycardia, hypoglycemia,increased arousal, and feeding problems. This is described in about 20–30% of theexposed children; however, NAS symptoms associated with mood-stabilizing drugsare mostly self-limiting and very rarely require symptomatic therapy (Convertinoet al. 2016). Also potential negative effects on pregnancy and birth complicationshave been described like higher risk for gestational diabetes, preterm birth, andhigher and lower birth weight (Scrandis 2017). However, those data are still incon-sistent, and it is hard to disentangle the effect of the medication from the effect of thedisorder itself in the available studies; therefore, we only focused on malformationrisk and report on short-term breastfeeding outcomes.

Guidelines on Bipolar Disorder

There are several national and international guidelines for the treatment of bipolardisorder in which pharmacological and non-pharmacological treatments for thedifferent episodes of bipolar disorder over the life span are described. We reviewedthose guidelines regarding the mood stabilizer therapy and reviewed the underlyingclinical studies for this chapter. The most recently updated guidelines available areguidelines for the biological treatment of bipolar disorders of the World Federationof Societies of Biological Psychiatry (WFSBP) (Grunze et al. 2018); evidence-basedguidelines for treating bipolar disorder from the British Association for Psychophar-macology (Goodwin et al. 2016); guidelines for the management of bipolar disorderin children, adolescents, and adults of the National Institute for Health and CareExcellence; Canadian Network for Mood and Anxiety Treatments (CANMAT) andInternational Society for Bipolar Disorders (ISBD) collaborative update ofCANMAT guidelines for the management of patients with bipolar disorder: updatedin 2018 (Yatham et al. 2018); and the German S3 guidelines for bipolar disorders(Bauer 2012).

Mood Stabilizers Sorted by Substance Class

Lithium

Since its (re-)introduction into modern psychiatry in 1949 by John Cade and itsapproval by the Food and Drug Administration (FDA) for treatment of mania in the1970s, lithium salts are the longest used and probable best studied mood-stabilizingagents and still seen by many authors and societies as gold standard in the treatmentof bipolar disorder.

Acute Bipolar DepressionThere is not much data in literature supporting the efficacy of lithium monotherapyin treating acute bipolar depression. To our knowledge there is only one relatively


recent double-blind, placebo-controlled study which did not find a superioritycompared to placebo (and quetiapine) in the treatment of acute bipolar depression,i.e., in Montgomery-Åsberg Depression Scale (MADRS) response and remissionrates, Hamilton Depression Rating Scale (HDRS), Clinical Global Impressions-Bipolar-Severity (CGI-BP-S) of Illness and Change, and Hamilton Anxiety RatingScale (HARS) (Young et al. 2010). It is also concluded in two meta-analysescomparing drug treatments for bipolar depression that the use of lithium mono-therapy in bipolar depression lacks sufficient evidence and requires more adequatetesting (Selle et al. 2014; Taylor et al. 2014). Nevertheless, lithium is stillrecommended as the first-line treatment for acute bipolar depression by nationaland international guidelines, for example, by the Royal Australian and New ZealandCollege of Psychiatrists clinical practice guidelines for mood disorders or theCanadian Network for Mood and Anxiety Treatments (CANMAT) and InternationalSociety for Bipolar Disorders (ISBD) 2018 guidelines for the management ofpatients with bipolar disorder (Malhi et al. 2015; Yatham et al. 2018) the authorsof the latter arguing with positive results in older and smaller studies and possiblytoo low serum lithium levels (with a mean of 0.61 mEq/L) in the aforementionednegative study.

Acute ManiaIn a meta-analysis from 2011 comprising seven studies (with 1366 patients in total)comparing lithium to placebo, lithium was significantly more effective than placeboin treating acute mania but turned out to be significantly less effective than haloper-idol and (but not significantly) less effective than certain second-generation antipsy-chotics (asenapine, quetiapine, olanzapine, and risperidone) in acute (3-week)treatment of mania concerning mean change scores in the Young Mania RatingScale (YMRS) (Cipriani et al. 2011). Another meta-analysis from 2015 confirmedthe findings concerning lithium’s significant superiority over placebo regarding theimprovement in manic symptom ratings, whereas a significant superiority of anyother tested drug (including haloperidol) over lithium was not reported (Yildiz et al.2015). According to those studies, lithium is a well-tested agent with very goodevidence for its effectiveness in treating acute mania which is also reflected by itsrecommendation by national and international guidelines as a first-line treatment ofacute mania in bipolar disorder (e.g., Malhi et al. 2015; Yatham et al. 2018;Fountoulakis et al. 2017; Pfennig et al. 2012; American Psychiatric Association2002; Goodwin et al. 2016).There is positive evidence regarding the superiority of acombination therapy of lithium with second-generation antipsychotics over mono-therapy in therapy-refractory manic patients from a relatively recent meta-analysis(Ogawa et al. 2014).

Maintenance TreatmentIn a meta-analysis on pharmacological maintenance treatment of bipolar disorderfrom 2014 comprising 21 randomized controlled trials with at least 12 weeks offollow-up comparing lithium with other drugs or placebo, lithium proved to be


significantly superior to placebo in preventing any recurrent mood episode (depres-sive, manic, hypomanic, or mixed) (Miura et al. 2014).

In another recent meta-analysis from 2014 focusing on the role of lithium in theprevention of mood episodes comprising seven randomized controlled trials (RCTs)(with a total of 1580 participants) comparing lithium with placebo and another sevenRCTs comparing lithium with anticonvulsants (carbamazepine, lamotrigine, andvalproate) all with at least 3 months of follow-up reported lithium to be significantlymore effective than placebo in the prevention of overall mood episodes and superiorto anticonvulsants preventing manic episodes.

The authors of both meta-analyses highlighted and promoted lithium’s status as avery valuable first-line treatment option underlining its consistent evidence and itsbroad treatment spectrum. This is concordant with high level of recommendation innational and international treatment guidelines on bipolar disorders (e.g., Malhi et al.2015; Yatham et al. 2018; Fountoulakis et al. 2017; Pfennig et al. 2012; AmericanPsychiatric Association 2002; Goodwin et al. 2016).

Bipolar II DisorderIn the meta-analyses presented above, a useful differentiation between bipolar I andbipolar II disorder could not be made, due to a minor proportion of bipolar II patientsincluded in the studies. There are – to our knowledge – no placebo-controlled RCTsexploring the effectiveness of lithium monotherapy in bipolar II depression. Apartfrom this, evidence is inconsistent: In a recent randomized double-blind (but notplacebo controlled) comparison study on 142 patients with bipolar II depressionover 16 weeks, comparing sertraline monotherapy, lithium monotherapy, and lithium+ sertraline combination therapy (with regard to switch rates), lithium monotherapyshowed similar treatment response rates as sertraline monotherapy (Altshuler et al.2017), whereas in a double blind but not placebo-controlled RCT comparing lithiummonotherapy to venlafaxine monotherapy in bipolar II major depressive episode(also with regard to switch risk), lithium was significantly less effective thanvenlafaxine concerning treatment response (Amsterdam et al. 2016). In a compari-son study of lithium and lamotrigine in bipolar II depression, both patient groupsshowed significant improvement in depressive symptoms (Suppes et al. 2008).

There are – to our knowledge – no placebo-controlled RCTs investigating theeffectiveness of lithium in hypomania. Also, apart from this, there is insufficientevidence in general for this indication.

Concerning maintenance treatment, the – to our knowledge – latest placebo-controlled RCT in bipolar II patients dates from 1982. In this study lithium wassignificantly more effective than placebo in preventing depressive and hypomanicrelapses during an average period of 11 months of follow-up. In a recent study,lithium was as effective as quetiapine in preventing relapse in bipolar II patients(Nierenberg et al. 2016). In a retrospective long-term longitudinal study, lithium wasconcluded to be more effective in maintenance treatment in bipolar II than in bipolarI patients with a focus on episode frequency and “time ill”.


Mixed StatesPrevious early studies suggested that patients with mixed episodes show poorerlithium response (Prien et al. 1988) and seem to respond better to valproate (Swannet al. 1997), but there is no prospective randomized controlled trial to confirm thosefindings. Regarding current data an evidence-based statement on the specific efficacyof lithium in bipolar mixed states cannot be made.

Rapid CyclingIn a review from 2005, the authors conclude similar efficacy between lithium andvalproate in the long-term treatment of rapid-cycling bipolar disorder (Calabreseet al. 2005). Also, in a systematic review from 2013, the authors conclude compa-rable efficacy of lithium, valproate, and certain second-generation antipsychotics butat the same time stressing the fact of too little evidence in this field to come to clearrecommendations or to prefer one treatment option over another (Fouontoulakiset al. 2013). Further studies are needed to investigate this subject.

Lithium in PregnancyFormer studies and the “lithium-baby register” reported a significant increase ofsevere cardiac malformation (among others Ebstein anomaly) associated with lith-ium medication (Schou et al. 1975). However, recent studies could show that there isonly a small increase in cardiac malformation associated with lithium exposure, andthe prevalence of severe cardiac defects like the Ebstein anomaly most likely is dueto other risk factors (Boyle et al. 2017; Diav-Citrin et al. 2014). Lithium levelsshould be measured very regularly in pregnancy because on the one hand higher riskof malformation might be associated with higher serum concentrations and, on theother hand, lithium levels decrease during pregnancy and increase again afterdelivery (Wesseloo et al. 2017b; Patorno et al. 2017c). However, the relapse in thepostpartum period without a mood stabilizer is very high (about 70% vs. 30% if themood-stabilizing medication had been continued during pregnancy and delivery), sothat the decision for or against continuing the medication should be discussedindividually (Wesseloo et al. 2017a).

Lithium in Breastfeeding PeriodThere are very few studies, mostly case reports, on use of lithium in lactatingmothers. However, a recent review summarized that infant/maternal serum lithiumconcentration ratios were calculated between 0.17 and 0.58 in the existing studies.There were no severe adverse effects reported in the exposed children (Uguz andSharma 2016). Breastfeeding in lithium-treated women in principle seems to bepossible; however, the lithium serum levels of the child as well as renal and thyroidfunction need to be measured regularly.

ConclusionLithium is a well-studied and effective treatment in bipolar disorder with goodacceptability and adequate tolerability and should be regarded as a first-line


treatment especially in patients with a mania-accentuated course. Its particular effectin bipolar II disorder as well as in rapid-cycling conditions and the treatment ofmixed states need to be further studied as evidence is scarce. In therapy-refractorymanic patients, combination therapy with a second-generation antipsychotic is agood option. Additionally, it has to be mentioned that there are patients that respondvery well to lithium treatment, whereas in other patients it is not effective. Thesedifferences in lithium responders and non-responders are very probable due togenetic reasons (probable influencing signal transduction and excitability on thelevel of single neurons) as they appear to be a familial trait. Clinically, lithiumresponders seem to be characterized by the presence of typical/classical features ofbipolar disorder. Several hypothesis-driven as well as hypothesis-free genome-wideassociation studies reported genetic variants associated with lithium response; how-ever, those studies need replication in independent samples before a clinical genetictest for lithium response can be developed.

Anticonvulsants

Since the approval by the US Food and Drug Administration (FDA) of valproate inthe indication for mania in 1995 anticonvulsant (and in particular valproate, carba-mazepine (CBZ) (FDA approval 2004), and lamotrigine (FDA approval 2003)) havebeen widely used and studied in the treatment of bipolar disorders (Lopéz-Muñozet al. 2018). Other anticonvulsants such as gabapentin, pregabalin, and topiramatehave also been claimed to be effective in the treatment of bipolar disorder but stay, tothis point, off-label treatments in most countries.

Valproate

Acute Bipolar DepressionIn a meta-analysis the efficacy of valproate (VPA, valproic acid) in the treatment ofbipolar depression was studied. VPA showed effectiveness measures equal to treat-ment with serotonin reuptake inhibitors (SSRI) concerning depressive symptoms inbipolar depression, only being inferior to olanzapine + fluoxetine and olanzapinemonotherapy (Taylor et al. 2014).

In a second meta-analysis from 2014, four RCTs comparing valproate to placebowere analyzed, and valproate proved to be effective in the treatment of bipolardepression in comparison to placebo and only inferior to a combination therapy ofolanzapine and fluoxetine in pooled analysis. But also, the limitations of thesefindings have been stressed out. In the case of valproate, two of the four analyzedplacebo-controlled RCTs presented negative findings regarding the effectiveness ofvalproate in acute bipolar depression (Selle et al. 2014). Due to this inconsistentevidence, valproate is not seen as a first-line treatment in most guidelines and has noofficial approval in the treatment of bipolar depression in most countries.


Acute ManiaIn a meta-analysis from 2011 comprising ten studies comparing valproate to otherantimanic drugs or placebo, valproate was significantly more effective than placeboin treating acute mania but was found being significantly less effective than certainantipsychotics (haloperidol, risperidone, and olanzapine) (Cipriani et al. 2011). Thelatest meta-analysis from 2015 confirmed the results of valproate being significantlymore effective than placebo in treating acute mania and reported only risperidonebeing significantly superior over valproate in this indication (Yildiz et al. 2015).

According to this, valproate has a high level of positive evidence in the treatmentof acute mania making it a first-line treatment for this indication which is alsoreflected by its recommendation by national and international guidelines (e.g.,Malhi et al. 2015; Yatham et al. 2018; Fountoulakis et al. 2017; Pfennig et al.2012; American Psychiatric Association 2002; Goodwin et al. 2016).

There is positive evidence regarding the superiority of a combination therapy ofvalproate with second-generation antipsychotics over monotherapy in therapy-refractory manic patients from a relatively recent meta-analysis (Ogawa et al. 2014).

Maintenance TreatmentIn a meta-analysis from 2014 investigating the effectiveness of several pharmaco-logical agents in maintenance treatment of bipolar disorder comprising four ran-domized controlled trials with at least 12 weeks of follow-up comparing valproatewith other drugs or placebo, valproate proved to be efficient in preventing anyrecurrent mood episode (depressive, manic, hypomanic, or mixed) (Miura et al.2014). As a limitation to these conclusions, it has to be mentioned that there is onlyone study comparing valproate to placebo (with lithium as active control). In thisstudy valproate did not prove more effective than placebo in bipolar maintenancetreatment. But as the same was the case for lithium (Bowden et al. 2000) and thelatter having proven evidence for its effectiveness in maintenance treatment inseveral studies before, the mentioned study is considered a failed study by someauthors (e.g., Fountoulakis et al. 2017; Yatham et al. 2018). In a randomized open-label trial from 2010, lithium plus valproate as well as lithium monotherapy wasmore likely to prevent relapse than was valproate monotherapy (Geddes et al. 2010).Also, in a Cochrane review from 2013, the authors conclude that there is limitedevidence for the efficacy of valproate in the long-term treatment of bipolar disorder(Cipriani et al. 2013). Despite those findings, valproate is still recommended as afirst-line maintenance treatment in certain guidelines on bipolar disorders (e.g.,Yatham et al. 2018), the authors arguing with its wide use in clinical practice,especially in patients having been treated with valproate in their acute episode ofmania and with a favorable cohort study (Hayes et al. 2016), while others consid-ering it only as a second- or third-line treatment for this indication (e.g., Fountoulakiset al. 2017).


Bipolar II DisorderThere is no sufficient data studying the specific role of valproate in bipolar IIdepression. In a placebo-controlled RCT from 2011 on valproate treatment inbipolar I as well as bipolar II depression, valproate was not superior to placebo inthe bipolar II subgroup (Muzina et al. 2011).

In the only placebo-controlled RCT of valproate therapy in hypomania, patientstreated with valproate proved to have a significantly higher rate of reduction in meantotal YMRS scores than patients receiving placebo (McElroy et al. 2010). Being theonly study and having some limitations, such as relatively small sample sizes, furtherevidence has still to be created in this field.

There is no sufficient evidence concerning aspects of maintenance treatmentwith valproate specific to bipolar II disorder as in the vast majority of studies alsocontaining bipolar II patients, their sample size was insufficient for separateanalyses.

Mixed StatesMost studies compared the effect of valproate versus lithium in groups of manic andmixed patients together. Valproate, as well as lithium, significantly improved ManiaRating Scale (MRS) scores compared with placebo in manic and mixed patients(Bowden et al. 1994). Overall, valproate seems to be more effective than lithium inacute mixed episodes; however, prospective randomized controlled trials to confirmthose findings are lacking (for a review see Fountoulakis et al. (2012)). In a recentsystematic review, the authors conclude on the efficacy of valproate in the preventionof new mixed episodes but also stressing out the current inadequate amount of datain this research field (Verdolini et al. 2018).

Rapid CyclingIn a review from 2005, the authors concluded that there is similar efficacy ofvalproate and lithium in the long-term treatment of rapid-cycling bipolar disorder(Calabrese et al. 2005). Also, in a systematic review from 2013, the authors suggestcomparable efficacy of valproate, lithium, and certain second-generation antipsy-chotics in the treatment of bipolar mixed states but at the same time stressing out thefact of too little evidence in this field to come to clear recommendations or to preferone treatment option over another (Fouontoulakis et al. 2013). Further studies areneeded to investigate this subject.

Valproate in PregnancyValproate is known to cause lower IQ levels in exposed children as well as about10% malformation, especially spinal malformation (Petersen et al. 2017). It has beenshown to have the most negative impact on neurodevelopment in children exposedduring pregnancy in comparison to other anticonvulsant drugs (Veroniki et al. 2017).Therefore, valproate should not be prescribed to bipolar women in childbearing age.And if for any reason a woman is taking valproate as a mood stabilizer and wishes toget pregnant, then the medication should be changed in advance to, for example,


quetiapine. However, if a woman gets pregnant when taking valproate, still it shouldnot be a general reason for terminating the pregnancy.

Valproate in Breastfeeding PeriodThere is very few data available on valproate treatment in lactation. The breastfedinfant VPA levels reported in a recent review ranged between 1.5% and 6% of themother’s serum levels. Only one of the nine published infants showed clinicalsymptoms (thrombocytopenic purpura and anemia) (Uguz and Sharma 2016).

ConclusionValproate is a well-studied agent in bipolar disorder with good acceptability andtolerability. Best evidence exists for its efficacy in treating acute manic episodes,where it should be regarded as a first-line treatment. In therapy-refractory manicpatients, combination therapy with a second-generation antipsychotic is a goodoption. Weaker and less consistent evidence exists for its efficacy in treating acutebipolar depression and in maintenance therapy where other agents should be pre-ferred in first line. The use of valproate is not recommended in women of childbear-ing age due to its teratogenic risks.

Carbamazepine and Oxcarbazepine

Because of their strong similarity, oxcarbazepine being a keto derivative of carba-mazepine (Glauser 2001), both substances are discussed together in this section.

Acute Bipolar DepressionIn a meta-analysis on the comparative efficacy and acceptability of drug treatmentsfor bipolar depression, carbamazepine was not included at all in the analysis (Tayloret al. 2014). In a second meta-analysis from 2014, carbamazepine was included butonly contributing to the analysis with one placebo-controlled RCT (Selle et al. 2014)in which efficacy in the treatment of acute bipolar depression could been shown(Zhang et al. 2007) leading the authors of the meta-analysis to the conclusion thatcarbamazepine appears to be promising but requires more studies (Selle et al. 2014).There is – to our knowledge – no sufficient data regarding the use of oxcarbazepinein bipolar depression.

Acute ManiaIn a meta-analysis from 2011 comprising eight studies comparing valproate to otherantimanic drugs or placebo, carbamazepine proved to be significantly more effectivethan placebo in treating acute mania. Oxcarbazepine was not considered by thismeta-analysis due to the lack of studies (Cipriani et al. 2011). Also, in a meta-analysis from 2015, it was concluded that there is good evidence for the efficacy ofcarbamazepine in acute mania. The same study reported lack of efficacy ofoxcarbazepine in the treatment of acute mania in their analysis (Yildiz et al. 2015).In a systematic Cochrane database review from 2011, the authors lament the


insufficient number of adequate trials on oxcarbazepine in the treatment of acuteaffective episodes in bipolar disorder, which has not improved by now.

Maintenance TreatmentAccording to a meta-analysis from 2014 analyzing the effectiveness of severalpharmacological agents in maintenance treatment of bipolar disorder, carbamazepinewas not more effective than placebo concerning maintenance treatment of bipolardisorder (Miura et al. 2014). However, there is just one, small placebo-controlledRCT from 1981 in which no superiority over placebo could be shown but not leastdue to lack of power (Okuma et al. 1981), thus making it problematic to conclude alack of efficiency of carbamazepine in maintenance treatment of bipolar disorderfrom this study. There are a certain number of studies comparing carbamazepine tolithium in bipolar maintenance therapy – the most recent dating from 1997 to 2000(Greil et al. 1997; Kleindienst and Greil 2000) – showing a comparable grade ofefficacy between the two substances with an overall tendency of lithium beingsuperior to carbamazepine but with the tendency of carbamazepine being moreefficient in a subgroup of patients with nonclassical features of the disorder(Kleindienst and Greil 2000). Furthermore, there are studies – although with certainlimitations regarding sample size and statistical power – suggesting improvedoutcome in certain measures (YMRS, HDRS-21, MADRS, CGI-S and CGI-I)when adding carbamazepine or oxcarbazepine to lithium, oxcarbazepine beingmore effective than carbamazepine (Juruena et al. 2009; Vieta et al. 2008), butthese findings need further study and confirmation.

Bipolar II DisorderThere is no sufficient data concerning the specific efficacy of carbamazepine oroxcarbazepine in bipolar II depression or hypomania. Regarding maintenancetreatment – as mentioned above – there is evidence from one study that carbamaz-epine was at least as efficient as, and in tendency superior to, treatment with lithiumin maintenance treatment of a subgroup of patients with bipolar II disorder or bipolardisorder not otherwise specified (Kleindienst and Greil 2000).

Mixed StatesWeisler et al. could show a significant superiority of carbamazepine in bipolar mixedepisodes on depressive as well as manic symptoms (as measured by HDRS andYMRS scales) in two placebo-controlled RCTs and a post hoc pooled analysis of thetwo studies which were conducted on manic and mixed patients together (Weisleret al. 2004, 2005, 2006). Studies including mixed patients exclusively are lacking.Also, there is no sufficient data on the role of oxcarbazepine in this indication.

Rapid CyclingThere is no sufficient data to emphasize the specific efficacy of carbamazepine oroxcarbazepine monotherapy in rapid-cycling bipolar disorder. From the results of aRCT from 1997 comparing lithium monotherapy with carbamazepine monotherapyand lithium + carbamazepine combination therapy, the authors conclude that there


might be significantly better response rates of the combination therapy compared tomonotherapy (Denicoff et al. 1997). Sufficient data on the role of oxcarbazepine inrapid-cycling bipolar disorder does not exist.

Carbamazepine and Oxcarbazepine in PregnancyCarbamazepine is reported to have an increased risk of neural tube deficits (up to1%), craniofacial defects (up to 11%), and developmental delays in the exposedchildren (up to 20%). Therefore, even if the risk of major congenital malformation isless than in valproate use, carbamazepine is not recommended in childbearingwomen (Andrade 2018; Tomson et al. 2018). Oxcarbazepine seems to have a riskof malformation which lies between 2% and 3% and therefore not higher than inunexposed population. However, before considering oxcarbazepine safe in preg-nancy, more data also from bipolar women should be analyzed (Tomson et al. 2018).

Carbamazepine and Oxcarbazepine in Breastfeeding PeriodFor CBZ there is some data from case reports or case series available which hints atno adverse events in the breastfed children caused by CBZ. The infant-mother serumratios varied widely between 0.0 and 2.6. In conclusion it seems possible to continueCBZ while lactating. For oxcarbazepine there are only two cases reported with noadverse effects on the children (Uguz and Sharma 2016).

ConclusionCarbamazepine (CBZ) is an adequately studied agent with good acceptability andtolerability. Best evidence exists for its efficacy in treating acute manic episodes. Forother indications evidence is much more scarce and inconsistent, but it seems thatcarbamazepine has a certain efficacy in the maintenance treatment of bipolar disor-der and could have a positive effect in patients with bipolar II disorder as well as withrapid cycling and mixed features which needs further studying. Because of therelatively scarce and inconsistent evidence along with its pharmacokinetic interac-tion potential as CBZ is a very potent cytochrome P450 isoform 3A4 (CYP3A4)inducer (Oscarson et al. 2006), carbamazepine should be considered rather as asecond- or third-line treatment in bipolar disorder.

Lamotrigine

Acute Bipolar DepressionThe two latest meta-analyses examining the efficacy of lamotrigine (LTG) in thetreatment of acute bipolar depression were published in 2014. One study – analyzingfive RCTs comparing lamotrigine to placebo and two others comparing lamotrigineto other agents (including a total number of 1625 participants) – comes to theconclusion, though stating the significant superiority of lamotrigine to placebo inmeasures of depression scale change, that lamotrigine should perhaps not be used intreating acute bipolar depression because its relatively high risk of inducing a switchinto mania also revealed in the said analysis. Additionally, LTG was shown to be


relatively inferior to other studied agents in its antidepressant impact (Taylor et al.2014). Also, the second meta-analysis concludes on a relatively weak efficacy andinconsistent evidence of lamotrigine and also commenting on the difficulty of itsapplication in acute illness phases because of the need for slow increase of dosage(Selle et al. 2014). Nevertheless, more recent guidelines on the treatment of bipolardisorder recommend its use in bipolar depression, in one case underlining at thesame time the need for installation of an additional agent to prevent manic episodesbecause of the assumed lack of efficacy of lamotrigine in this indication (Malhi et al.2015; Yatham et al. 2018; Fountoulakis et al. 2017; Pfennig et al. 2012; AmericanPsychiatric Association 2002; Goodwin et al. 2016). There is certain evidence thatLTG could be used effectively as an adjunctive treatment in bipolar depression as ithas, for example, been proven in placebo-controlled RCTs for combination withquetiapine (Geddes et al. 2016) as well as with lithium.

Acute ManiaThere is relatively robust negative evidence concerning the effectiveness oflamotrigine in acute mania as, for example, concluded in two meta-analyses explor-ing the efficacy of certain (potentially) antimanic drugs (Cipriani et al. 2011; Yildizet al. 2015).

Maintenance TreatmentBest evidence exists for the effectiveness of lamotrigine in the prevention ofdepressive episodes in bipolar disorder (Miuara et al. 2014). Although havingbeen proven to be significantly more effective in preventing any mood episode(Miura et al. 2014), its specific effectiveness in preventing manic episodes is lessconsistent, and there is evidence that other agents are superior to lamotrigine in thisindication (Miura et al. 2014; Bowden et al. 2003; Calabrese et al. 2003) which iswhy it should not primarily be used in patients with a predominant manic polarity.

Bipolar II DisorderIn a meta-analysis from 2011 focusing on the pharmacotherapy of acute bipolar IIdepression, it was concluded that there is inconsistent support for the effectivenessof lamotrigine in this indication warranting further research but not ruling out thepossibility of its effectiveness. There is no sufficient data exploring the use oflamotrigine in hypomania. There is certain evidence from a placebo-controlledRCT that lamotrigine could be effective in the maintenance treatment of rapidcycling in bipolar II patients (Calabrese et al. 2000). In a prospective naturalisticopen-label study from 2017, lamotrigine was associated with a significantly longertime to recurrence/relapse of any mood episode in bipolar II than in bipolar Ipatients. Apart from that, no sufficient data concerning the specific efficacy oflamotrigine in bipolar II maintenance treatment does exist.

Mixed StatesThere is no sufficient data concerning the effectiveness of lamotrigine in patientswith a current mixed episode or concerning its specific efficacy in preventing one.


Rapid CyclingThere is certain evidence that lamotrigine could have a positive effect on rapidcycling – possibly especially in bipolar II disorder as already presented above – asdescribed in a systematic review on the topic from 2013 (Fountoulakis et al. 2013).In a meta-analysis from 2003 comparing lamotrigine with lithium and other anti-convulsants, a significant superiority of any treatment could not be found; however,there was a tendency toward inferiority of lamotrigine compared to other analyzedagents (Tondo et al. 2003).

Lamotrigine in PregnancyLTG has been shown to have only a small increase in malformation in some studies(Dolk et al. 2016; Patorno et al. 2017b), whereas in other studies, no evidence ofincreased malformations could be found (Tomson et al. 2018). The concentration ofLTG seems to be the same in the blood of the mother and in the cord blood. It isimportant to know that the LTG clearance increases in pregnancy because this isestrogen-mediated. After 3–4 weeks after delivery, LTG blood concentration willincrease again (Clark et al. Am, J. Psychiatry, 2013). There are no negative effects oncognitive or psychomotor development reported in the children; however, a recentstudy suggested that the risk of autism spectrum disorders could be increased inLTG-exposed children, but this finding warrants replication with a suitable studydesign (Veroniki et al. 2017).

Lamotrigine in Breastfeeding PeriodLTG can be measured in the breast milk. It has been reported that breastfed childrenhave up to 30% of the maternal serum levels in their blood. However, there wereonly few adverse effects seen in breastfed children while their mothers were takinglamotrigine; Uguz and Sharma reported only 3.27% adverse effects in their reviewcontaining data on 122 infants (Uguz and Sharma 2016), and those were self-limiting and not clearly caused by the LTG exposure.

ConclusionLamotrigine is an overall well-studied therapeutic agent with generally very goodtolerability and acceptability (irrespective of the rare occurrence of severe dermato-logic adverse events which can be diminished by very slow dosage increase over4–6 weeks). Evidence for its efficacy in bipolar depression is inconsistent, reflectedby different recommendations in different guidelines. Therefore, other substancesshould be preferred in this indication, but it should be considered in combinationtreatment because lamotrigine could be valuable as adjunctive treatment togetherwith other agents, but further evidence is needed. Lamotrigine is not effective in thetreatment of acute mania and should not be used in this indication.

It is a very good option for maintenance treatment in patients with a primarilydepressive polarity and, also regarding its generally very good tolerability, could beused in this indication as a first-line treatment, which is also recommended by certainmore recent guidelines (Malhi et al. 2015; Yatham et al. 2018; Goodwin et al. 2016).


Possibly, lamotrigine has a specifically positive effect on bipolar II disorder and alsoits rapid-cycling variant, but further evidence is needed.

Gabapentin

Acute Bipolar DepressionIn two relatively recent meta-analyses from 2014 regarding the treatment of acutebipolar depression, gabapentin was not included in the analyses (Taylor et al. 2014;Selle et al. 2014). In a placebo-controlled RCT in refractory mood disorders (includ-ing unipolar and bipolar patients), gabapentin was not superior to placebo in terms ofresponse rates (Frye et al. 2000). In general, evidence is insufficient concerning theefficacy of gabapentin in the treatment of acute bipolar depression.

Acute ManiaIn a meta-analysis from 2011, gabapentin was found to be significantly less effectivethan placebo and (together with topiramate) significantly less effective than all otherantimanic drugs included in the analysis (Cipriani et al. 2011). In a second meta-analysis from 2015, gabapentin was not included; hence, evidence is scarce, andfurther studies are needed to evaluate its role in treating acute mania (Yildiz et al.2015).

Maintenance TreatmentIn the most recent meta-analysis on maintenance treatment in bipolar disorder from2014, gabapentin was not included in the analysis (Miura et al. 2014). In a smallplacebo-controlled RCT, gabapentin – as adjunctive treatment to other mood-stabilizing treatment (lithium, valproate, carbamazepine, or a combination of thementioned substances) – was shown to have a certain efficacy in the long-termoutcome of bipolar disorder, without being able, though, to show its acute efficacyand additionally limited by a rather small sample size of only 13 patients in thetreatment arm (Vieta et al. 2006).

There is no sufficient evidence to evaluate gabapentin’s particularities in bipolarII disorder nor its effect on mixed states and rapid cycling.

Gabapentin in PregnancyThere are very few data on pregnancy outcomes after gabapentin exposure. It issuggested that gabapentin is not associated with a significant elevated risk of majorcongenital malformation (Andrade 2018).

Gabapentin in Breastfeeding PeriodThere are only few case reports and case series available; however, there were noadverse short-term effects in the exposed children (Ohman et al. 2005; Kristensenet al. 2006).


ConclusionAs evidence is scarce, clear recommendations on the use of gabapentin cannot begiven. Gabapentin should not be used in treating acute mania because of negativeevidence regarding this indication. Encouraging findings in case reports and smallopen-label studies concerning the effectiveness of gabapentin in maintenance ordepression treatment could not be confirmed by larger RCTs to this point. There islimited evidence that gabapentin could have a positive effect as an adjunctivetreatment in the long-term course in bipolar patients and can – in this indication –be used as a second- or rather third-line treatment. Gabapentin should not be used asa first-line treatment in any indication in bipolar disorder.

Pregabalin

Acute Bipolar DepressionIn two relatively recent meta-analyses from 2014 concerning the treatment of acutebipolar depression, pregabalin was not included in the analyses (Taylor et al. 2014;Selle et al. 2014). In an open-label study from 2013 studying pregabalin as an acuteand maintenance adjunctive treatment in patients with treatment-resistant bipolardisorder, it appeared to have mood-stabilizing and antidepressant properties inaddition to antimanic effects (Schaffer et al. 2013). Further evidence is needed toinvestigate this subject.

Acute ManiaIn two relatively recent meta-analyses from 2011 and 2015 concerning the treatmentof acute mania, pregabalin was not included in the analyses (Cipriani et al. 2011;Yildiz et al. 2015). As described above, in an open-label study from 2013, pre-gabalin, as an acute and maintenance adjunctive treatment in patients with treatment-resistant bipolar disorder, had also antimanic effects (Schaffer et al. 2013), butfurther evidence is needed to investigate this subject.

Maintenance TreatmentIn the most recent meta-analysis on maintenance treatment in bipolar disorder from2014, pregabalin was not included in the analysis (Miura et al. 2014). As statedabove, pregabalin seemed to have certain mood-stabilizing qualities (Schaffer et al.2013) but far from being supported by sufficient evidence.

There is no sufficient evidence to evaluate the particularities of pregabalin inbipolar II disorder nor its effect on mixed states and rapid cycling.

Pregabalin in PregnancyA very recent cohort study could not confirm the previously suggested teratogeniceffect of pregabalin in first-trimester pregnancy (Patorno et al. 2017a; Winterfeldet al. 2016). However, before pregabalin should be considered safe in early preg-nancy, larger studies need to be conducted.


Pregabalin in Breastfeeding PeriodThere is not enough data on pregabalin in breastfeeding period to give any recom-mendation up to date.

ConclusionEvidence for the effectiveness of pregabalin in bipolar disorder is insufficient.Therefore, at this point of time, pregabalin cannot be recommended as a treatmentoption in bipolar disorder. In comorbid anxiety disorders, it could be a good optionbecause of its potentially lower switch risk compared to antidepressants, assumed byseveral recent guidelines on the treatment of bipolar disorders (Yatham et al. 2018;Fountoulakis et al. 2017; Malhi et al. 2015), all stressing the hypothetical nature ofthis consideration, as for lack of data concerning this issue.

Topiramate

Acute Bipolar DepressionIn two relatively recent meta-analyses from 2014 concerning the treatment of acutebipolar depression, topiramate was not included in the analyses (Taylor et al. 2014;Selle et al. 2014). In a comparative single-blind study without placebo control,topiramate was effective in reducing depressive symptoms when added as adjunctivetreatment to existing mood stabilizer therapy, and its effect was comparable tobupropion treatment (McIntyre et al. 2002). Apart from this, evidence is insufficient.

Acute ManiaIn a meta-analysis from 2011, topiramate was found to be significantly less effectivethan placebo and (together with gabapentin) significantly less effective than all otherantimanic drugs included in the analysis (Cipriani et al. 2011). The same wasreported in another meta-analysis from 2015 (Yildiz et al. 2015); thus, there isquite robust negative evidence concerning the effectiveness of topiramate in treatingacute mania.

Maintenance TreatmentIn the most recent meta-analysis on maintenance treatment in bipolar disorder from2014, topiramate was not included in the analysis (Miura et al. 2014). As no recentevidence has been created since, data concerning this indication is insufficient.

There is no sufficient evidence to evaluate particularities in bipolar II disorderwhen treated with topiramate nor its effect on mixed states and rapid cycling.

Topiramate in PregnancyTopiramate has been shown to be associated with a higher risk of malformation thanlamotrigine and levetiracetam and therefore should be avoided in pregnancy whenpossible (Andrade 2018).


Topiramate in Breastfeeding PeriodOnly case reports are available, which suggest an extensive transfer into the breastmilk; however, no adverse short-term effects were reported in the children (Ohmanet al. 2002; Gentile 2009).

ConclusionLevel of evidence investigating the use of topiramate in bipolar disorder is insuffi-cient. It should not be used in acute mania, as there is negative evidence concerningits efficacy in this indication, nor can it be recommended as monotherapy in the othermentioned indications. Topiramate could have a value as adjunctive treatment optionnot least in bipolar patients with comorbid obsessive-compulsive disorder where itspositive effect on OCD symptoms as an adjunctive treatment could be shown in asmall RCT (Saharain et al. 2014) but also in treatment-resistant depression. Further-more, topiramate could be of benefit in bipolar patients with comorbid obesity as itcould be shown – in an RCT actually focusing on its antimanic efficacy – tosignificantly reduce body weight relative to placebo without worsening depressiveor manic symptoms (Chengappa et al. 2006).

Second-Generation Antipsychotics

Since the approval of several second-generation antipsychotics (SGAs) by the FDAin the early 2000s (olanzapine in 2000, risperidone in 2003, quetiapine, ziprasidone,and aripiprazole in 2004), atypical antipsychotics have had great success in treatingdifferent forms and phases of bipolar disorder and are widely clinically used whichled to the approval of the already approved substances in broader indications inbipolar disorder as well as to the approval of further and newer substances morerecently, the latest being the approval by the FDA of cariprazine in bipolar disorderin 2015 (Lopéz-Muñoz et al. 2018).

Quetiapine

Acute Bipolar DepressionTwo meta-analyses dating from 2014 comparing different drug treatments forbipolar depression conclude that quetiapine is effective in treating acute bipolardepression, one coming to the conclusion that quetiapine (together with combinationof olanzapine + fluoxetine) with a high grade of evidence (the meta-analysiscomprising six studies with a total number of 3896 participants) had the best balanceof efficacy and safety also with respect to switch risk in treating bipolar depression(Taylor et al. 2014), and the other also ranked quetiapine under the four mosteffective agents, though also referring to its possible negative long-term effectswith regard to its strong association with weight gain and development of metabolicsyndrome (Selle et al. 2014).


Also, a recent meta-analysis focusing only on existing studies of quetiapine’sefficacy in bipolar depression reports its efficacy and superiority over lithium andparoxetine in treating bipolar depression (Datto et al. 2016). The good base ofevidence in this indication is reflected by its recommendation in guidelines onbipolar disorder as a first-line treatment and its broad approval by national regulatoryauthorities (e.g., Malhi et al. 2015; Yatham et al. 2018; Fountoulakis et al. 2017;Pfennig et al. 2012; American Psychiatric Association 2002; Goodwin et al. 2016).

Acute ManiaIn a meta-analysis from 2011 comprising seven studies comparing quetiapine toother antimanic drugs or placebo, quetiapine was significantly more effective thanplacebo in treating acute mania and also was being one of the three most favorabledrugs in terms of acceptability (Cipriani et al. 2011). These findings were essentiallyconfirmed in a more recent meta-analysis from 2015 (Yildiz et al. 2015). It could beshown in a relatively recent double-blind RCT that the combination of quetiapineand lithium is significantly more effective than the combination of quetiapine andplacebo (Bourin et al. 2014) which goes in line with earlier RCTs that found theadd-on of quetiapine to monotherapy with lithium or valproate is significantly moreeffective in acute mania compared to the add-on of placebo (Sachs et al. 2004;Yatham et al. 2007).

According to this data, quetiapine has a high level of positive evidence as mono-as well as combination therapy in the treatment of acute mania, making it a first-linetreatment for this indication which is also recommended by guidelines on bipolardisorders (e.g., Malhi et al. 2015; Yatham et al. 2018; Fountoulakis et al. 2017;Pfennig et al. 2012; American Psychiatric Association 2002; Goodwin et al. 2016).

Maintenance TreatmentA meta-analysis from 2014 found quetiapine to be one of the most effectivetreatments in prevention of both manic and depressive relapse or recurrence, butalso underlining the need for cautious interpretation of study results because of therelatively high proportion of studies with enrichment design, still giving a recom-mendation for its use in maintenance treatment in bipolar disorder (Miura et al. 2014)which goes in line with recommendations of guidelines and national drug approvalsin particular if used as maintenance treatment in patients where quetiapine wasefficient in the respective acute mood episode (e.g., Malhi et al. 2015; Yathamet al. 2018; Fountoulakis et al. 2017; Pfennig et al. 2012; American PsychiatricAssociation 2002; Goodwin et al. 2016).

There is good evidence that combination treatment of quetiapine as add-on toeither lithium or valproate is significantly more effective than placebo in mainte-nance treatment of bipolar disorder as stated in a post hoc analysis of two largeplacebo-controlled RCTs (Suppes et al. 2013).

Bipolar II DisorderIn a recent post hoc pooled analysis of five placebo- controlled RCTs of quetiapine inbipolar depression focusing on the differences in its effectiveness between bipolar I


and bipolar II patients, the authors conclude that despite an initially slower treatmentresponse, after 8 weeks of treatment, improvement of depressive symptoms wassimilar in patients with bipolar I and bipolar II depression (Datto et al. 2016).

Data concerning the effectiveness of quetiapine in hypomania is less consistent.Two relatively small placebo-controlled RCTs exist on the topic. One is investigatingthe effect of adjunctive quetiapine in bipolar II patients experiencing hypomaniawith mixed features at the time of inclusion, and whereas depressive and overallsymptoms improved significantly compared to placebo, hypomanic symptoms didnot (Suppes et al. 2013). The other study, also including a relatively high proportionof patients with mixed features, reported significant improvement of global bipolarsymptoms as well as manic symptoms as measured by the CGI-BP, but only amarginal improvement of hypomanic symptoms as measured by the YMRS inbipolar II patients when quetiapine monotherapy is administered compared toplacebo (McElroy et al. 2010).

Concerning maintenance treatment, in the large-scale placebo-controlled RCTEMBOLDEN study, it was shown that in bipolar II patients with a recent depressiveindex episode, further treatment with quetiapine monotherapy significantly loweredthe risk for recurrence of overall mood events compared to placebo (Young et al.2014).

Mixed StatesThe above-presented studies on hypomania suggested that quetiapine is at leastpartially effective in bipolar II patients with mixed features (Suppes et al. 2013;McElroy et al. 2014), but in general, there is no sufficient evidence concerningquetiapine’s specific role in mixed states, whereby it seems that combination therapywith quetiapine as adjunction to either valproate or lithium is significantly moreeffective than adjunction of placebo regarding time to recurrence of mood events inpatients with an index mixed episode.

Rapid CyclingIn a relatively recent systematic review from 2013 about treatment of rapid-cyclingbipolar disorder, the authors concluded that quetiapine is effective in the treatment ofacute episodes in patients with rapid cycling and that it appears promising also formaintenance treatment in this indication. But the limitations of nearly all reviewedstudies in this indication and the need for further investigation were also pointed out(Fountoulakis et al. 2013).

Quetiapine in PregnancyQuetiapine seems to be a safe option in pregnancy as there is no association with anincreased risk of malformation (Cohen et al. 2018). The blood levels of quetiapinetend to decrease in pregnancy and increase again after delivery. This has to be takenaccount, and depending on the psychopathology of the mother, the dosage mightneed modification during the course of the pregnancy (Uguz 2017).


Quetiapine in Breastfeeding PeriodQuetiapine can only be measured in very low concentration in breast milk. Nonegative effects in breastfed children have been published so far. Quetiapine shouldbe considered as the first option in breastfeeding among the mood stabilizers(Pacchiarotti et al. 2016).

ConclusionQuetiapine is a well-studied and very versatile pharmacotherapeutic agent disposingover proven efficacy in all three indications of bipolar disorder. It has a goodtolerability and acceptability, although in long-term treatment, attention has to bepaid on its possible metabolic side effects. Quetiapine can be recommended as a first-line treatment in all three phases of bipolar disorder although its effect on certainsubgroups, e.g., patients with rapid cycling, needs further study, which is also truefor its specific effect on bipolar II disorder, whereby, compared to other substances,there is relatively reasonable evidence for its efficacy also in this indication. More-over, quetiapine has proven to have additional efficacy as a combination andadjunctive treatment (best evidence exists for combination with lithium or valproate)in various phases of bipolar disorder. Furthermore, quetiapine seems to be a safeoption in pregnancy and breastfeeding period.

Aripiprazole

Acute Bipolar DepressionTwo meta-analyses focusing on the treatment of acute bipolar depression presentnegative evidence concerning the effectiveness of aripiprazole in treating bipolardepression concluding that it should not be used in this indication (Taylor et al. 2014;Selle et al. 2014). There is certain evidence from two open-label studies thataripiprazole could be effective as an adjunctive treatment in bipolar depression(Dunn et al. 2008; McElroy et al. 2007), but placebo-controlled RCTs concerningthis issue do still not exist.

Acute ManiaIn a meta-analysis from 2011 considering seven studies comparing aripiprazole toother antimanic drugs or placebo, aripiprazole proved significantly more effectivethan placebo in treating acute mania with a good efficacy/acceptability ratio(Cipriani et al. 2011). These findings were confirmed by a more recent meta-analysisfrom 2015 (Yildiz et al. 2015). Aripiprazole monotherapy is widely recommended asa first-line treatment by multiple guidelines and has wide approval from nationalauthorities in treating acute mania (e.g., Malhi et al. 2015; Yatham et al. 2018;Fountoulakis et al. 2017; Pfennig et al. 2012; American Psychiatric Association2002; Goodwin et al. 2016).

In an RCT from 2008, it could be shown that the addition of aripiprazole totreatment with either valproate or lithium in (partially) nonresponsive patients with


acute mania leads to significant improvement of manic symptoms compared toaddition of placebo (Vieta et al. 2008).

Maintenance TreatmentIn the latest meta-analysis on the topic, aripiprazole was not considered to be moreeffective than placebo in reducing risk for relapse or recurrence of any mood episode(Miura et al. 2014). However, it has to be mentioned that there was only one RCTincluded in the analysis and that the original study – that was conducted on patientswith a recent manic index episode – reported on its significantly higher efficacy inpreventing any mood episode as well as manic episodes compared to placebo withthe limitation that it did not prove more effective than placebo in preventingdepressive episodes, though (Keck et al. 2006, 2007). This evidence could beconfirmed in a recent RCT studying the efficacy of long-acting injectablearipiprazole as maintenance treatment in bipolar patients with an index manicepisode. Aripiprazole proved to be significantly more effective than placebo inpreventing any mood episode with predominant effect on manic episodes (Calabreseet al. 2017). Moreover, aripiprazole proved significantly more effective than placeboin preventing relapse to any mood episode as an addition to an existing treatmentwith lithium or valproate in patients with previously inadequate response to moodstabilizer monotherapy.

Bipolar II DisorderThere is no sufficient data concerning the use of aripiprazole in bipolar II depression,neither has aripiprazole been sufficiently studied regarding its specific effect onhypomania and maintenance treatment in bipolar II disorder.

Mixed StatesIn a meta-analysis on the efficacy of SGAs in acute mixed episodes, the authorsconclude that aripiprazole appears to be effective in treating manic symptoms inmixed states, albeit data deriving solely from post hoc analyses of studies investi-gating both manic and mixed patients. Prospective studies exclusively investigatingpatients with mixed states are lacking.

Rapid CyclingThere is no sufficient evidence concerning the effectiveness of aripiprazole in thisindication which is also stated by the authors of a meta-analysis on the issue at thesame time remarking that aripiprazole appears to be promising in maintenancetreatment of rapid-cycling patients, but that further evidence is needed (Fountoulakiset al. 2013).

Aripiprazole in PregnancyInitial data from animal studies hinted at teratogenic effects; however, in humanpatients, no evidence for an increased risk of malformation has been found, and thedata available are large enough up to date that aripiprazole can be considered as


being not associated with an increased risk of major malformation (Huybrechts et al.2016; Damkier and Videbech 2018).

Aripiprazole in Breastfeeding PeriodFrom the scarce data available, aripiprazole seems to be safe in breastfeedingregarding short-term effects, but the evidence still is too sparse to give generalrecommendation (Uguz 2016).

ConclusionAripiprazole is an overall well-studied agent with good tolerability and acceptability.At this point of time, it cannot be recommended for treating acute bipolar depressionas there is negative evidence for its efficacy. In acute mania though, it proved to beefficacious and can and should be used as a first-line treatment also considering itsgood tolerability and acceptability. Its role in maintenance treatment is less consis-tent. Aripiprazole can be used as maintenance treatment in patients with an indexmanic episode and with predominant manic polarity. There is insufficient negativeevidence for its efficacy in preventing depressive episodes; thus, it should not beused as maintenance monotherapy in patients with an index depressive episode or apredominant depressive polarity. Furthermore, there is evidence for its efficacy asadd-on treatment to lithium or valproate in acute mania as well as in maintenancetreatment.

Olanzapine

Acute Bipolar DepressionIn a meta-analysis from 2014, the combination therapy olanzapine + fluoxetine(in some countries marketed as a combination product, e.g., SYMBYAX™ in theUSA) was recommended as the first-line treatment for bipolar depression havingperformed best in primary and secondary outcomes in the analysis, but alsorecommending olanzapine monotherapy as alternative first-line treatment based onthree placebo-controlled RCTs with a total number of 1329 participants where itproved to be significantly more efficacious than placebo in depression scale changeand response rates (Taylor et al. 2014). Another meta-analysis from 2014 was moreconservative in its conclusions. The authors rated olanzapine + fluoxetine as themost effective treatment in bipolar depression but also stated that a high number ofanalyzed treatments including olanzapine monotherapy, even though proving to besignificantly more effective than placebo, showed only moderate effect sizes andunfavorable values of number needed to treat (NNT = 11 in the case of olanzapine).The authors underline the need for more research in this field (Selle et al. 2014). Aseparate post hoc pooled analysis of the two existing placebo-controlled RCTs ofolanzapine’s efficacy in acute bipolar depression concluded on the significant supe-riority of olanzapine monotherapy in reducing depressive core symptoms comparedto placebo (Tohen et al. 2013).


Acute ManiaThere is robust evidence for the efficacy of olanzapine in acute mania. In a meta-analysis from 2011 comprising 17 studies comparing olanzapine to other antimanicdrugs or placebo, olanzapine proved to be significantly more effective than placeboin treating acute mania, ranking among the most effective treatments, at the sametime having a very favorable efficacy/acceptability ratio compared to most othertested agents (Cipriani et al. 2011). These findings where basically confirmed byanother meta-analysis from 2015 (Yildiz et al. 2015) which underlines olanzapine’srole as a first-line treatment in acute mania as widely approved and recommendedtreatment by both national authorities and guidelines (e.g., Malhi et al. 2015; Yathamet al. 2018; Fountoulakis et al. 2017; Pfennig et al. 2012; American PsychiatricAssociation 2002; Goodwin et al. 2016).

Moreover, combination respectively augmentation therapy of olanzapine togetherwith lithium or valproate proved significant superior effectiveness in reducing manicsymptoms compared to the respective monotherapy with lithium or valproate aspresented in a meta-analysis on the issue (Ogawa et al. 2014).

Maintenance TreatmentAmeta-analysis on pharmacological maintenance treatment of bipolar disorder from2014 analyzed three RCTs comparing olanzapine with other drugs or placebo, theincluded studies disposing of enrichment design. It was concluded that olanzapinewas superior to placebo in preventing relapse or recurrence of any mood episode, butit did not prevent depressive relapse or recurrence. However, in separate analyses itproved significantly superior to placebo in preventing manic episodes (Miura et al.2014).

Bipolar II DisorderThere is no sufficient evidence to evaluate olanzapine’s specific role in treatingbipolar II disorder.

Mixed StatesIn a meta-analysis on the efficacy of SGAs in acute mixed episodes, olanzapine wasrated to be significantly more effective in treating acute mixed episodes than placebobut also underlining the scarce evidence concerning this issue and the fact thatavailable data for olanzapine monotherapy are only being captured by post hocanalyses of studies investigating both manic and mixed patients.

Concerning combination and add-on treatment with olanzapine in a prospectiveRCT exclusively investigating mixed patients, it could be shown that adjunctiveolanzapine was significantly superior to the adjunction of placebo in patients with sofar inadequate response to valproate in acute mixed states (Houston et al. 2009). Inan RCT regarding maintenance treatment of patients with an index mixed episode,olanzapine proved significantly more effective than placebo in regard to incidence ofand time to relapse (Tohen et al. 2009).


Effects on Rapid CyclingIn a relatively recent systematic review from 2013 analyzing the evidenceconcerning treatment of rapid-cycling bipolar disorder, the authors come to theconclusion that olanzapine has an equal antimanic efficacy in rapid and non-rapidcyclers, with even certain evidence existing, that it develops its antimanic effectearlier in rapid than in non-rapid cyclers (Fountoulakis et al. 2013).

Olanzapine in PregnancyNo increased risk of malformation due to olanzapine treatment during early preg-nancy has been shown. Pregnancy-related diabetes mellitus seems to be higher inolanzapine-treated women; however, data are inconsistent (Huybrechts et al. 2016;Damkier and Videbech 2018).

Olanzapine in Breastfeeding PeriodOlanzapine is among the primarily recommended SGAs in breastfeeding periodbecause it is the substance with the most published data, and no severe adverseeffects have been reported in the breastfed children (Uguz 2016).

ConclusionOlanzapine seems to be effective in acute bipolar depression, but apparently withonly moderate effect size, which is why it is rather recommended as a second- not afirst-line treatment in this indication. Olanzapine is an effective, well-tolerated, andwell-accepted treatment in acute mania and should be used as a first-line treatment inthis indication. Olanzapine seems to be effective in maintenance treatment inpatients with an index manic episode that responded to olanzapine treatment andshould only be used as a maintenance treatment in those patients and in patients withpredominant manic polarity as there is insufficient evidence concerning its efficacyin preventing depressive episodes and in maintenance therapy in patients with adepressive index episode in general. There is first and promising evidence thatolanzapine could play a beneficial role in treating rapid-cycling and mixed episodes,but further studies are needed. Whereas it disposes of a good tolerability andacceptability in the short-term treatment, the adverse effects on patients’ glucoseand lipid metabolism have to be considered in long-term treatment.

Risperidone and Paliperidone

Because of their strong similarity, paliperidone being the primary active metaboliteof risperidone, and the fact that paliperidone is often used as a long-acting injectabletreatment variant after an oral treatment with risperidone had been established, bothsubstances are discussed together in this section.


Acute Bipolar DepressionTwo meta-analyses regarding the treatment of acute bipolar depression both con-clude on the lack of efficacy and the lack of evidence concerning risperidone intreating acute bipolar depression. Paliperidone was not even included in the analyses(Taylor et al. 2014; Selle et al. 2014).

Acute ManiaTwo meta-analyses from 2011 and 2015 both came to the conclusion that there is asignificantly superior efficacy of risperidone when compared to placebo and, more-over, on the fact that risperidone has proved significantly superior to other antimanicagents (as, e.g., aripiprazole and valproate) as concluded in one of the meta-analyses(Yildiz et al. 2015). Together with olanzapine, risperidone was rated superior to otherdrugs regarding both efficacy and acceptability (Cipriani et al. 2011). One meta-analysis that treated paliperidone and risperidone together for primary analyses andonly separating them for secondary analysis did not lead to substantially differentresults as stated by the authors (Cipriani et al. 2011). The other meta-analysisinvestigated paliperidone as a separate drug showing significant superiority overplacebo but a tendency to be inferior than risperidone in its antimanic efficacy(Yildiz et al. 2015) which was in principle confirmed by the other meta-analysisby the authors remarking that the joint effect of both agents was based mainly on theeffectiveness of risperidone rather than paliperidone (Cipriani et al. 2011). In a meta-analysis on combination therapy in acute mania, it was concluded that risperidonebut not paliperidone showed significantly higher efficacy in combination withlithium or valproate compared to the respective monotherapy, a combination withrisperidone even leading to significantly reduced drop-out rates for any reasoncompared to monotherapy (Ogawa et al. 2014).

Maintenance TreatmentIn a meta-analysis on maintenance treatment of bipolar disorder, two RCTs (bothwith enrichment design) were included both investigating the long-acting injectablevariant of risperidone in maintenance treatment and patients with a current depres-sive episode. The authors of the meta-analysis suggest that risperidone has asignificant superiority over placebo in terms of prevention of any mood and manicepisodes but not depressive episodes (Miura et al. 2014).

In the same meta-analysis, paliperidone was not significantly superior to placeboin preventing any relapse or recurrence of mood episode. Data was derived from onesingle RCT using an enrichment design and investigating overall 766 recently manicor mixed patients. The authors of the study – unlike the authors of the above-citedmeta-analysis – came to the conclusion that in patients treated with paliperidone’slong-acting injectable variant compared to placebo, there is a significantly delayedtime to recurrence of any mood symptoms as well as manic symptoms. Paliperidonewas not superior to placebo in delaying time to recurrence of depressive symptoms(Berwaerts et al. 2012).


Bipolar II DisorderThere is no sufficient data concerning the use of risperidone and paliperidone inbipolar II depression, neither have both substances been sufficiently studiedregarding their specific effect on hypomania andmaintenance treatment in bipolarII disorder. It exists a small open-label study of risperidone suggesting its efficacy intreating and preventing hypomania (Vieta et al. 2001), but further evidence fromlarger placebo-controlled RCTs would be needed to confirm these findings.

Mixed StatesIn one of the studies investigating risperidone’s efficacy in mania, risperidone wassuperior to placebo measured by YMRS scores in the treatment of both manic andmixed bipolar patients. But there were only 12 mixed patients included in the citedstudy, so to make a statement on the specific effect of risperidone in mixed states isdifficult. A study investigating risperidone’s therapeutic efficacy exclusively inpatients with a current mixed episode does not exist. The same applies forpaliperidone, whereby in the studies proving its efficacy in acute mania and main-tenance treatment, a greater number of mixed patients were included compared to therisperidone studies, and it was concluded by the authors that the agent is alsoefficient in treating acute mixed states (Berwaerts et al. 2012; Vieta et al. 2010) aswell as preventing another mixed episode.

Rapid CyclingThere is insufficient evidence concerning the role of either risperidone orpaliperidone in treating rapid-cycling bipolar disorder.

Risperidone and Paliperidone in PregnancyHuybrechts and colleagues reported a small but significant risk for all malformations(RR 1.26, 95% KI 1.02–1.56) and cardiac malformation (RR 1.26, 95% KI0.88–1.81) (Huybrechts et al. 2016) for risperidone. However, this risk is verysmall, and it is not clear whether it is truly causally associated with risperidone.Still, if possible, olanzapine or quetiapine should be prescribed in early pregnancybecause those medications were not associated with a significant risk ofmalformations. No data are available for paliperidone.

Risperidone and Paliperidone in Breastfeeding PeriodTransfer from risperidone into breast milk is low, and there are no reports on seriousadverse effects in exposed children (Uguz 2016). No data are available forpaliperidone.

ConclusionNeither risperidone nor paliperidone can be recommended as treatment of depressiveepisodes in bipolar disorder. Risperidone is an effective, well-tolerated, and well-accepted treatment in acute mania and should be used as a first-line treatment in thisindication. Paliperidone is also effective in treating acute mania, but as there is


certain evidence for its inferiority to risperidone in this indication both in terms ofefficacy and acceptability, risperidone should be preferred over paliperidone intreating acute mania.

There is certain evidence in the effectiveness of risperidone in preventing moodepisodes in patients with former response to risperidone in the acute episode. Asthere is negative evidence for its efficacy in prevention of depressive relapse orrecurrence, it should – as a monotherapy – only be used in patients with a predom-inant manic polarity. Evidence for paliperidone in maintenance treatment is evenscarce, and thus it should not be used as a first-line monotherapy in maintenancetreatment of bipolar disorder.

The specific effectiveness of risperidone and paliperidone in bipolar II as well asin rapid cycling and patients with mixed symptomatology is not sufficiently studied,whereas for the latter indication, there is certain evidence for both substances (butmore so for paliperidone) to be of benefit.

Ziprasidone

Acute Bipolar DepressionTwo meta-analyses concerning the treatment of acute bipolar depression presentnegative evidence regarding the effectiveness of ziprasidone in treating bipolardepression concluding that it should not be used as monotherapy in this indication(Taylor et al. 2014; Selle et al. 2014). Moreover, in an RCT on 298 patients studyingthe effectiveness of ziprasidone as adjunctive treatment to either lithium, valproate,or lamotrigine in acute bipolar depression, it did not prove more effective thanplacebo in terms of improving depressive symptoms as measured by the MADRS(Sachs et al. 2011).

Acute ManiaIn a meta-analysis from 2011 comprising six studies comparing ziprasidone to otherantimanic drugs or placebo, ziprasidone was significantly more effective thanplacebo in treating acute mania but being among the least effective agents analyzedand thus being evaluated as disposing of a less beneficial efficacy/acceptability ratiothan other antimanic drugs. Therefore, ziprasidone is not considered as a first-linechoice when other treatment options are available (Cipriani et al. 2011). Thesefindings were essentially confirmed in a more recent meta-analysis from 2015(Yildiz et al. 2015).

Adjunctive treatment with ziprasidone in addition to lithium or valproate did notprove to be more efficient than placebo in an RCT on 680 patients with an acutemanic or mixed episode (Sachs et al. 2012).

Maintenance TreatmentIn the most recent meta-analysis on maintenance treatment in bipolar disorder from2014, ziprasidone was not included in the analysis (Miura et al. 2014). A placebo-controlled RCT on ziprasidone monotherapy in maintenance treatment of bipolar


disorder does not exist, but it could be shown in an RCT on 240 patients investigat-ing ziprasidone as adjunctive treatment to lithium or valproate that it was signifi-cantly more effective than placebo in preventing any mood episode in patients with amanic index episode being generally well tolerated (Bowden et al. 2010).

Bipolar II DisorderThere is one small 8-week open-label trial on 30 patients with acute and majorbipolar II depression in which the authors report significant improvement indepression rating scales in patients treated with ziprasidone monotherapy (Liebowitzet al. 2009), but, to date, a placebo-controlled RCT concerning this subject, whichwould be needed to confirm and further investigate these promising findings, doesnot exist. Additionally, there is a small placebo-controlled RCT on mixed depressivestates in patients with either MDD or bipolar II disorder. In this study ziprasidoneproved to be significantly superior to placebo in treating mixed depressive symptomswith a reported pronounced effect in the bipolar II patient subgroup (Patkar et al.2012). There is no sufficient data concerning the specific efficacy of ziprasidone inpure hypomania neither examining its role in maintenance treatment of bipolar IIdisorder.

Mixed StatesAs described above in the paragraph on bipolar II disorder, ziprasidone significantlyimproved mixed symptoms in patients with MDD and even more so in mixeddepressive episodes in bipolar II patients compared to placebo (Patkar et al. 2012).In a placebo-controlled RCT on patients with an acute manic or mixed episodeincluding 80 patients with a current mixed episode, it was concluded that ziprasidonewas significantly superior to placebo in symptom reduction in both subgroupsshowing a comparable improvement in Mania Rating (MRS) and Clinical GlobalImpression (CGI) Scale (Keck et al. 2003) suggesting effectiveness of ziprasidone inmixed patients without separately investigating its efficacy in this subgroup, whichmeans that further studies are needed not least to also investigate the effect ondepressive symptoms of mixed states.

In a long-term open-label trial in manic and mixed patients having responded toziprasidone with 19 mixed patients included in the sample, the authors reportsustained and comparable symptom improvements in both manic and mixed patientsubgroups (Keck et al. 2009).

Effects on Rapid CyclingThere is no sufficient evidence concerning the specific role of ziprasidone in treatingrapid-cycling bipolar disorder.

Ziprasidone in PregnancyThere is not enough human data to estimate the safety profile of ziprasidone inpregnancy; however, it does not seem to be associated with a significant increasedrisk of major malformation (Damkier and Videbech 2018).


Ziprasidone in Breastfeeding PeriodThere are very few case reports published; there were no adverse short-term effectsin the exposed children; however, more data are needed to give recommendation(Uguz 2016).

ConclusionZiprasidone has not been found to be effective in the treatment of bipolar depression.Being proven effective in acute mania, but disposing of a less beneficial efficacy/acceptability ratio than other antimanic drugs, ziprasidone is not recommended as afirst-line treatment in acute mania but is an option as a second-line treatment inpatients not responsive to first-line agents. There is no sufficient data on its possibleefficacy in maintenance treatment as a monotherapy, whereby it did not proveadditionally effective in combination therapy with lithium or valproate in thisindication. There is promising data regarding ziprasidone being beneficial in bipolarII depression and in bipolar II mixed depressive states as well as in bipolar I mixedmania. In these globally understudied patient subgroups, ziprasidone has a compa-rably good evidence base and should definitely be considered as a treatment option.Ziprasidone is mostly well tolerated. It disposes of a lower risk of weight gain but ahigher risk of QT prolongation compared to other SGAs (Orsolini et al. 2016).

Asenapine

Acute Bipolar DepressionIn two relatively recent meta-analyses from 2014 concerning the treatment of acutebipolar depression, asenapine was not included in the analyses, though beingincluded in the comprehensive literature research preceding the analyses in at leastone of the studies (Taylor et al. 2014; Selle et al. 2014). Also since 2014, nosufficient evidence has been produced to support asenapine’s efficacy in treatingacute bipolar depression.

Acute ManiaIn a meta-analysis from 2011 comprising two studies comparing asenapine to otherantimanic drugs or placebo, asenapine was significantly more effective than placeboin treating acute mania but being rated as having a less beneficial efficacy/accept-ability ratio than other antimanic drugs (Cipriani et al. 2011). These findings wereessentially confirmed in a more recent meta-analysis from 2015 (Yildiz et al. 2015).In the meantime, one additional RCT has been published confirming its efficacy intreating acute manic or mixed episodes with moderate effect sizes (Landbloom et al.2016).

Maintenance TreatmentIn the most recent meta-analysis on maintenance treatment in bipolar disorder from2014, asenapine was not included in the analysis (Miura et al. 2014). There is one


very recent placebo-controlled RCT with enrichment design on 253 patients with amanic or mixed index episode. In this study asenapine proved to be significantlysuperior to placebo in preventing any mood episode. It could also be shown in posthoc analyses that asenapine significantly prolonged time to recurrence of eithermanic or depressive episodes compared to placebo.

Bipolar II DisorderThere is no sufficient data concerning the use of asenapine in bipolar II depression,neither has asenapine been sufficiently studied regarding its specific effect onhypomania and maintenance treatment in bipolar II disorder.

Mixed StatesIn a pooled post hoc analysis of two placebo-controlled RCTs concerning theefficacy of asenapine in acute manic or mixed episodes, the authors analyzedasenapine’s effect on depressive symptoms in these patients concluding thatasenapine showed significant superiority over placebo in reducing symptoms inmanic and mixed patients experiencing relevant depressive symptoms at baseline(Szegedi et al. 2011). Those results suggest that asenapine is efficient in bothpolarities of bipolar disorder, which is additionally supported by two other morerecent post hoc analyses of asenapine studies with a similar approach (McIntyre et al.2013; Berk et al. 2015). In a more recent RCT, asenapine proved partially effective inboth manic and mixed episodes, significantly improving mania and depression asmeasured by the mean change from baseline in YMRS and MADRS total score,whereas it did not prove more efficacious than placebo concerning YMRS 50%responders at day 21 (Landbloom et al. 2016). Prospective and separately conductedRCTs exclusively on mixed patients are lacking.

Rapid CyclingThere is insufficient evidence concerning the efficacy of asenapine in treating rapid-cycling bipolar disorder.

Asenapine in PregnancyThere are no human data available on outcomes in pregnancy.

Asenapine in Breastfeeding PeriodThere are no published data on the use of asenapine in breastfeeding.

ConclusionConsidering the evidence to date, asenapine does not play a role in the treatment ofbipolar depression. Asenapine is an effective agent in acute mania but tends todispose of a less beneficial efficacy/acceptability ratio than other antimanic drugs(e.g., risperidone, olanzapine, and quetiapine) which should therefore be preferredover asenapine as the first-line treatment of acute mania. On the other hand,asenapine seems to have a beneficial effect on mixed states – and in these also onthe depressive component of mixed states (a subject generally understudied) – and


can be considered as a first-line treatment option in this indication which goes in linewith recommendations of recent guidelines (Fountoulakis et al. 2017; Yatham et al.2018).

There is also recent evidence that asenapine is effective in maintenance treatmentof patients with an index manic or mixed episode which responded to asenapine andcan thus be used in this indication. Asenapine disposes of a good tolerability andacceptability in both short- and longer-term treatments with a relatively low risk ofweight gain and extrapyramidal motor symptoms (EPS), though there seems to be acertain association with QT prolongation and arrhythmia (Orsolini et al. 2016).

Lurasidone

Acute Bipolar DepressionRegarding two relatively recent meta-analyses from 2014, lurasidone was consid-ered significantly more effective than placebo in treating acute bipolar depression,ranking under the four most effective options of analyzed treatments in bothexaminations. But as data was derived from only one placebo-controlled RCT(Loebel et al. 2014), the authors also underline the need for future studies confirmingand further investigating lurasidone’s role in treating bipolar depression (Taylor et al.2014; Selle et al. 2014). Lurasidone was found significantly more effective thanplacebo in improving depressive symptoms when added to lithium or valproate asadjunctive treatment, the combination therapy, in general, being well tolerated(Loebel et al. 2014).

Acute ManiaHaving been approved for the treatment of bipolar depression by the FDA in 2013, ina meta-analysis from 2015 concerning the treatment of acute mania, lurasidone wasnot included in the analyses (Yildiz et al. 2015), already indicating lack of sufficientevidence concerning this subject which is still the case to date.

Maintenance TreatmentLurasidone was not considered in the most recent meta-analysis from 2014 on thesubject (Miura et al. 2014). In a recent placebo-controlled RCT on 496 patients whoresponded to a lurasidone + lithium or valproate combination therapy in the acuteepisode, the same combination therapy did not prove significantly superior tocombination of lithium or valproate and placebo in preventing any mood episodeover a period of 28 weeks in the whole patient group even though there was a trendfor doing so. But in the same study, lurasidone adjunctive therapy proved to besignificantly superior to that of placebo in preventing any mood episode in thesubgroup of patients with a depressive index episode (Calabrese et al. 2017).


Bipolar II DisorderThere is no sufficient data concerning the use of lurasidone in bipolar II depression,neither has lurasidone been sufficiently studied regarding its specific effect onhypomania and maintenance treatment in bipolar II disorder.

Mixed StatesConcerning lurasidone’s effect on mixed states, the only evidence from a prospectiveplacebo-controlled RCT derives from a trial of its role in patients with majordepressive disorder (MDD) with mixed features in which lurasidone showed to besignificantly improving depressive, hypomanic, and global symptoms in thesepatients compared to placebo (Suppes et al. 2016). In a post hoc analysis of thesame study, the authors further reported the significant efficacy of lurasidone intreating the subgroup of patients with mild and moderate to severe anxiety. Acomparable prospective study was not conducted to date with bipolar patients forwhich evidence solely derives from a post hoc analysis from 2015 (the original studydating from 2009 investigating the effect of lurasidone in treating bipolar depres-sion). Out of this analysis, the superiority of lurasidone over placebo in reducingdepressive symptoms in depressed bipolar patients with mixed features was con-cluded (McIntyre et al. 2015).

Rapid CyclingThe specific effectivity of lurasidone in rapid-cycling bipolar disorder is not suffi-ciently researched.

Lurasidone in PregnancyThere is no human data on the safety in pregnancy up to date.

Lurasidone in Breastfeeding PeriodThere is no published data on lurasidone in breastfeeding mothers and children.

ConclusionConsidering the evidence to date, lurasidone does not play a role in the treatment ofacute mania and should not be used in this indication. There is positive evidence forthe efficacy in treating bipolar depression as monotherapy where it can and should beused as a first-line treatment, which goes in line with recommendations from recentguidelines (Yatham et al. 2018; Founoukoulakis et al. 2017).

Also, it exists positive evidence for its efficacy as adjunctive treatment in thisindication. To date there is insufficient evidence concerning lurasidone’s role inmaintenance therapy in general with certain evidence that it could be beneficial asmaintenance treatment in patients with a depressive index episode. In these patientlurasidone can be considered still as a promising second-line treatment option, thesame being true for patients in mixed states with a marked depressive component, inwhich lurasidone seems to play a beneficial role. Lurasidone could furthermore befavorable in the treatment of an additional anxious component, but here further


evidence is needed. There is preliminary evidence that lurasidone could be useful asan add-on treatment in euthymic bipolar patients reducing cognitive impairment(Yatham et al. 2017), but further study is needed.

Lurasidone is a generally a well-tolerated and well-accepted agent with relativelylow sedative side effects, minimal metabolic effects, good cardiac safety profile, buta relatively high risk for EPS (Orsolini et al. 2016).

Cariprazine

Acute Bipolar DepressionIn two relatively recent meta-analyses from 2014 concerning the treatment of acutebipolar depression, cariprazine was not included in the analyses (Taylor et al. 2014;Selle et al. 2014) mainly due to its novelty being first approved as a medicaltreatment only in 2015.

In the meantime, it exists a large RCT in which cariprazine showed significantlysuperior to placebo in improving depressive and general symptoms as measured byMADRS and CGI-S scores in patients with bipolar depression over an 8-weekobservation period (Durgam et al. 2016).

Acute ManiaHaving been approved for the treatment of mania by the FDA in 2015, in a meta-analysis also dating from 2015 including four placebo-controlled RCTs with a totalof 1198 investigated patients, cariprazine proved to be significantly superior toplacebo in treating acute mania, ranking under the five most effective agents butalso showing relatively high all-cause discontinuation rates compared to placebo(Yildiz et al. 2015). Since then, two more RCTs not included in the meta-analysishave confirmed these findings (Sachs et al. 2015; Durgam et al. 2015) furtherunderlining the efficacy of cariprazine in treating acute mania.

Maintenance TreatmentCariprazine was not considered in the most recent meta-analysis from 2014 on thesubject of maintenance treatment of bipolar disorder (Miura et al. 2014). To ourknowledge no sufficient evidence concerning cariprazine’s role in maintenancetreatment of bipolar disorder has been generated since. A recently initiatedplacebo-controlled RCT Phase III study on over 800 patients investigating thissubject (identification number NCT03573297) is still in the recruiting phase (NIH,US National Library of Medicine 2018).

Bipolar II DisorderThere is no sufficient data concerning the use of cariprazine in bipolar II depres-sion, neither has cariprazine been sufficiently studied regarding its specific effect onhypomania and maintenance treatment in bipolar II disorder.


Mixed StatesIn two post hoc analyses by the same authors including the three most recentplacebo-controlled RCTs on the efficacy of cariprazine in acute mania (Sachs et al.2015; Durgam et al. 2015; Calabrese et al. 2015), the effect of cariprazine in differentsubgroups was examined. The authors conclude that in cited studies including145 mixed patients (14%) all together in both treatment arms, cariprazine provedsignificantly more effective than placebo in treating manic symptoms, which means,in return, that these studies do not allow a statement on the effect of cariprazine ondepressive symptoms in mixed states.

Effects on Rapid CyclingThere is no evidence supporting the efficacy of cariprazine in treating rapid-cyclingbipolar disorder.

Cariprazine in PregnancyThere are no human data on cariprazine in pregnancy.

Cariprazine in Breastfeeding PeriodNo information is available on the use of cariprazine during breastfeeding.

ConclusionThe most consistent evidence for cariprazine exists for the treatment of acute maniawhere it ranked under the most effective agent in the meta-analyses and can thus berecommended as a first-line treatment option in this indication being also effective inmixed manic states. Evidence for its efficacy in bipolar depression is less consistentwith one large placebo-controlled RCT proving its efficacy but a smaller previousone not finding a significant efficacy in treating bipolar I depression, making it rathera second-line – and in most countries probable off-label – treatment in this indica-tion. Sufficient evidence for its role in maintenance treatment does not exist to date.Cariprazine is a generally well-tolerated and well-accepted agent with a somewhatelevated risk of developing EPS relative to other SGAs (Orsolini et al. 2016).

Clozapine

Acute Bipolar DepressionIn two relatively recent meta-analyses from 2014 concerning the treatment of acutebipolar depression, clozapine was not included in the analyses (Taylor et al. 2014;Selle et al. 2014). Also, there is no sufficient evidence concerning clozapine’sefficacy in treating bipolar depression.

Acute ManiaIn two relatively recent meta-analyses from 2011 and 2015 concerning the treatmentof acute mania, clozapine was not included in the analyses (Cipriani et al. 2011;


Yildiz et al. 2015). There are no placebo-controlled RCTs investigating clozapine’seffectiveness in treating acute mania, but some older and smaller open-label studiesconcerning clozapine’s effect in otherwise therapy-refractory manic and manicpsychotic patients suggest a certain effectiveness in this subgroup (e.g., Greenet al. 2000; Kimmel et al. 1994).

Maintenance TreatmentAs it is the case concerning acute manic or depressive episodes, clozapine is notincluded in the most recent meta-analysis on maintenance treatment in bipolardisorder (Miura et al. 2014) due to lack of placebo-controlled RCTs on the subject.There is certain evidence from a 1-year follow-up open-label study comparingadjunctive clozapine treatment with treatment as usual in 38 patients withtreatment-resistant bipolar disorder which means there is persistence of symptomsdespite adequate treatment with two out of three (lithium, valproate, carbamazepine)mood stabilizers and – if psychotic symptoms – despite treatment with a typicalantipsychotic. The authors of the study report a significant clinical improvement asmeasured by several rating scales and reflected in a significantly decreased totalmedication use in the patient group treated with clozapine (Suppes et al. 1999)suggesting that clozapine can play a beneficial although still not sufficiently studiedrole in maintenance treatment in the subgroup of otherwise therapy-refractorypatients.

Bipolar II DisorderThere is no sufficient data concerning the use of clozapine in bipolar II depression,neither has clozapine been sufficiently studied regarding its specific effect onhypomania and maintenance treatment in bipolar II disorder.

Effects on Mixed StatesEvidence on the possible effectiveness of clozapine in mixed bipolar patients is veryscarce. It exists a publication from 1992 describing, in a case series, severalotherwise therapy-refractory patients with marked mixed symptoms with a goodresponse to clozapine treatment also in the longer term (Suppes et al. 1992).

Effects on Rapid CyclingThe specific effectiveness of clozapine in rapid-cycling bipolar disorder is unknown.

Clozapine in PregnancyFrom the available data, it does not seem that clozapine is associated with anincreased risk of major congenital malformation. It has been suspected that clozapineleads to increased birth weight in the newborns and has a greater risk for more severeneonatal abstinence syndrome. But the data are too few to draw valid conclusions(Damkier and Videbech 2018). However, other medications that have more favor-able safety profiles should be preferred in pregnancy.


Clozapine in Breastfeeding PeriodSerious adverse effects have been reported in breastfed children exposed to cloza-pine: agranulocytosis, drowsiness, and delayed onset of speech. There are only smallnumbers of reports, but other second-generation antipsychotics do not seem to haveserious adverse effects, so clozapine in breastfeeding should be avoided (Uguz2016).

ConclusionClozapine is not relevant in treating bipolar disorder but relevant in therapy-refractory patients as a third-line mono- or combination therapy considering rela-tively scarce evidence and safety and tolerability issues.

General Conclusion and Recommendation

As it was presented, the therapeutic agents dealt with in this chapter are all poten-tially useful as mood stabilizers in the sense of the introduction, which means beingeffective in any state of bipolar disorder. As it could be shown, they do have variousdegrees of scientific evidence in doing so. There is a wide range between theparticular above-presented substances with, for example, an agent like quetiapine,on the one hand, disposing over consistent evidence for its effectiveness in manicand depressive states as well as in maintenance treatment, whereas on the other hand,for an agent like clozapine, there is only marginal evidence of its efficacy, and thisalso only in particular subgroup of otherwise therapy-refractory patients. Further-more, it could be shown that the fact of insufficient evidence is globally true for thetreatment of particular subgroups of bipolar patients such as those with a rapid-cycling course or generally for patients with bipolar II disorder. Certainly, and evenmore so with having in mind the fact of partially insufficient evidence, it isrecommended for all patients to always take into account their individual course ofillness which means to gain an as clear as possible understanding of effectivenessand tolerability of specific medication in prior episodes, the predominant polarity,(psychiatric) comorbidities, and of course individual tolerability and safety issues(e.g., to maybe not treat an already overweight and diabetic patient with olanzapineor quetiapine when there are other alternatives with comparable efficacy).

Nevertheless, we will, in the following, deliver a short general conclusion ofeffective medication in different phases and patient subgroups, to give readers a shortoverview of the above-presented content.

Acute Bipolar Depression

The best and at the same time most recent evidence exists for the efficacy ofquetiapine. Lurasidone and cariprazine also proved efficient in recent RCTs (thoughdata for both deriving from only one study, respectively). Olanzapine monotherapy


proved to be efficient but with only moderate effect sizes. Lurasidone provedadditionally effective as an adjunctive treatment to lithium in bipolar depression.Evidence for lithium and valproate is, though at least partially positive, less consis-tent and partially outdated, but both substances stay as possible treatment choices.Evidence for lamotrigine and carbamazepine is, though as well partially positive, tooinconsistent to recommend their use in acute bipolar depression.

There is certain evidence that topiramate could be effective as an adjunctivetreatment in bipolar depression.

There is negative or insufficient evidence for oxcarbazepine, gabapentin, pre-gabalin, aripiprazole, risperidone, paliperidone, ziprasidone, asenapine, cariprazine,and clozapine and their use in bipolar depression.

Acute Mania

Good evidence for their efficacy in acute mania exists for several substances,whereby most evidence and longest clinical experience exist for lithium andvalproate. Several SGAs are also efficient in treating acute mania, the most effectivebeing risperidone, quetiapine, olanzapine, and cariprazine, naturally having advan-tages in treating mania with psychotic features, but carbamazepine, paliperidone,aripiprazole, ziprasidone and asenapine are proved to be less effective. Clozapineshould only be used in patients with therapy-refractory mania.

There is negative or insufficient evidence for lamotrigine, oxcarbazepine,gabapentin, pregabalin, and topiramate as well as for lurasidone.

Maintenance Treatment

Very good scientific evidence and at the same time the most clinical experience existfor lithium, which can still be considered as gold standard in this indication.

There is very good evidence for the efficacy of quetiapine in maintenancetreatment, making it a versatile first-line treatment in this indication, above all, ifthe patient was successfully treated with the substance in the prior acute episode.

Olanzapine, aripiprazole, asenapine, risperidone, and paliperidone are a goodoption for maintenance treatment of patients with a predominant manic polarityhaving been successfully treated with the respective substance in the acute episode.

On the other hand, lamotrigine is a first-line option in patients with a predominantdepressive polarity.

Less consistent evidence and a lesser degree of recommendation exist for main-tenance treatment with valproate, which is still widely used, but should, by now, beconsidered more of a second-line treatment in this indication. Carbamazepine can beconsidered as a second- to third-line treatment. Clozapine should only be used as athird-line treatment in otherwise therapy-refractory patients.

There is negative or insufficient evidence for oxcarbazepine, gabapentin, pre-gabalin, and topiramate as well as for lurasidone, ziprasidone, and cariprazine.


Bipolar II Disorder

Evidence being generally scarce concerning this issue best scientific support existsfor quetiapine’s efficacy in treating bipolar II patients in all three phases. There areseveral substances, for which exist hints in the literature on their potentially bene-ficial effect on bipolar II disorder, all deriving from smaller studies with a relativelylow degree of evidence, requiring further investigation. These substances are lithiumfor bipolar II depression, valproate for hypomania, carbamazepine for bipolar IImaintenance treatment, lamotrigine for bipolar II depression and maintenance treat-ment, risperidone for hypomania, and ziprasidone for bipolar II depression.

Effects on Mixed States

Concerning this issue, too, only a low degree of scientific evidence exists for somesubstances potentially being of benefit in the treatment of mixed states, but requiringfurther studies, these substances being valproate, carbamazepine, quetiapine,olanzapine, and ziprasidone as well as aripiprazole (mania in mixed states), risper-idone and paliperidone (mania in mixed states), cariprazine (mania in mixed states),asenapine (depression in mixed states), and lurasidone (depression in mixed states).

Effects on Rapid Cycling

Concerning grade of evidence, the same applies as for bipolar II disorder and mixedstates substances of a certain interest being lithium, valproate, lamotrigine,quetiapine, and olanzapine.

Pregnancy

Olanzapine and quetiapine are considered the safest options regarding use in earlypregnancy from the second-generation antipsychotics. The anticonvulsant drugs aremore or less associated with increased risk of malformation and negative neurodeve-lopmental outcome on the children; however, lamotrigine seems to be the anticon-vulsant which can be considered during pregnancy. Lithium is much less associatedwith cardiac malformation than previously thought, and therefore pregnancy underlithium medication can be considered weighing the individual risk/benefit for eachpatient. Valproate and carbamazepine should not be prescribed to women in child-bearing age unless there are no other alternatives due to their relatively highembryotoxic potentials.


Breastfeeding Period

Olanzapine and quetiapine seem to be the safest and best studied mood-stabilizingmedication in lactation. However, also for the anticonvulsants lamotrigine andvalproate, no severe adverse short-term effects were reported in breastfed babies.Also lithium medication could possibly be used in breastfeeding women; however,the children then need to be monitored closely. Long-term outcomes of exposedchildren in pregnancy and breastfeeding are still understudied; however, for lithiumand most of the second-generation antipsychotics as well as lamotrigine, there seemto be no negative long-term effects.

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guidelines on mood stabilizers...effects on rapid cycling ..... 40 pregnancy ..... 40 breastfeeding...

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