Guias psiquiatria biologica depresion aguda.pdf

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The World Journal of Biological Psychiatry, 2010; 11: 81109

Correspondence: Prof. Dr. Heinz Grunze, Institute of Neuroscience, Division of Psychiatry, RVI, Newcastle University, Newcastle upon Tyne NE1 4LP, UK.Tel:44 191 282 5765. Fax: 44 191 222 6162. E-mail: [email protected]

(Received and 14 December; accepted 14 December 2009)

ISSN 1562-2975 print/ISSN 1814-1412 online 2010 Informa UK Ltd. (Informa Healthcare, Taylor & Francis AS)DOI: 10.3109/15622970903555881

GUIDELINES

The World Federation of Societies of Biological Psychiatry (WFSBP)Guidelines for the Biological Treatment of Bipolar Disorders: Update

2010 on the treatment of acute bipolar depression

HEINZ GRUNZE1,2, EDUARD VIETA3, GUY M. GOODWIN4, CHARLES BOWDEN5,RASMUS W. LICHT6, HANS-JRGEN MLLER2, SIEGFRIED KASPER7& WFSBP TaskForce On Treatment Guidelines For Bipolar Disorders

1Newcastle University, Institute of Neuroscience, Newcastle upon Tyne, UK, 2Department of Psychiatry, Ludwig-Maximilians-

University, Munich, Germany, 3Bipolar Disorders Programme, Institute of Neuroscience, Hospital Clinic, University of Barcelona,

IDIBAPS, CIBERSAM, Barcelona, Catalonia, Spain, 4Department of Psychiatry, University of Oxford, Warneford Hospital,Oxford, UK,5Department of Psychiatry, University of Texas Health Science Center, San Antonio, TX, USA, 6Mood Disorders

Research Unit, Aarhus University Hospital, Risskov, Denmark, and 7Department of Psychiatry and Psychotherapy, Medical

University of Vienna, Vienna, Austria

AbstractObjectives. These guidelines are based on a first edition that was published in 2002, and have been edited and updated withthe available scientific evidence until September 2009. Their purpose is to supply a systematic overview of all scientificevidence pertaining to the treatment of acute bipolar depression in adults.Methods. The data used for these guidelines havebeen extracted from a MEDLINE and EMBASE search, from the clinical trial database clinicaltrials.gov, from recent pro-ceedings of key conferences, and from various national and international treatment guidelines. Their scientific rigor wascategorised into six levels of evidence (AF). As these guidelines are intended for clinical use, the scientific evidence was

finally assigned different grades of recommendation to ensure practicability. Results. We identified 10 pharmacologicalmonotherapies or combination treatments with at least limited positive evidence for efficacy in bipolar depression, severalof them still experimental and backed up only by a single study. Only one medication was considered to be sufficientlystudied to merit full positive evidence. Conclusions. Although major advances have been made since the first edition of thisguideline in 2002, there are many areas which still need more intense research to optimize treatment. The majority oftreatment recommendations is still based on limited data and leaves considerable areas of uncertainty.

Key words: Bipolar disorder, depression, acute treatment, evidence-based guidelines, pharmacotherapy, antipsychotics,antidepressants, mood stabiliser, electroconvulsive therapy, psychotherapy

Abbreviations

BDI, Beck Depression Inventory; CBT, cognitivebehavioural therapy; CE, category of evidence; CGI,Clinical Global Impression; DSM, Diagnostic andStatistical Manual; ECT, electroconvulsive ther-apy; FEWP, free and easy wanderer plus; HAMD,Hamilton Rating Scale for Depression; ICD, Inter-national Classification of Diseases; IDS, Inventory ofDepressive Symptoms; ISBD, International Society

for Bipolar Disorder; MADRS, MontgomeryAsbergDepression Rating Scale; MES, BechRafael-sen Melancholia Scale; MDE, major depressiveepisode; NNH, Number-needed-to-harm; OFC,olanzapinefluoxetine combination; PCOS, poly-cystic ovary syndrome; RCT, randomized con-trolled trial; RG, recommendation grade; rTMS,repetitive transcranial magnetic stimulation;STEP-BD, Systematic Treatment Enhancement


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recoverers (Judd et al. 2008). This may add to theutmost importance of full remission as the ultimatetreatment goal in bipolar depression, with a fullreturn to normal levels of psychosocial functioning.

Further goals of treatment in bipolar depressionare to diminish the risk of suicidal acts and avoidsubsequent episodes. Out of all psychiatric disorders,

bipolar disorders (both I and II) carry the highestrisk of suicide (or suicidal behaviours in its broadersense)(Rihmer 2005).

Diagnosis of bipolar depression

The diagnostic criteria, both in DSM-IV (AmericanPsychiatric Association 1994) and ICD-10 (WorldHealth Organization 1992), for a major depressiveepisode (MDE) as part of bipolar disorder are notdifferent from those for MDE in unipolar depres-sion. Some symptoms as leaden paralysis, hyper-somnia or increased appetite have been reported tobe more frequent in bipolar depression (Akiskalet al. 1983; Mitchell and Malhi 2004; Perlis et al.2006; Goodwin and Jamison 2007). Other variablessuch as earlier onset of illness or family history ofbipolar disorder may point towards an underlyingbipolar course (Winokur et al. 1993), and also somebiological variables may show subtle differences(Yatham et al. 1997). Looking at differing symp-tomatology in two large study cohorts of unipolarand bipolar depressed patients, Perlis et al. (2006)identified eight individual symptom items on the

Montgomerysberg Depression Rating Scale(MADRS) and the Hamilton Anxiety Rating Scale:inner tension, pessimistic thoughts, suicidal thoughtsand fear were more frequent symptoms in bipolarsubjects, whereas apparent sadness, reduced sleepand cognitive and several somatic symptoms of anx-iety were more frequent in unipolars. A proposedprobabilistic approach to distinguish betweenunipolar and bipolar depression in a person with amajor depressive episode and no clear prior manic,hypomanic or mixed episode had been put forwardby the International Society of Bipolar DisorderGuidelines Taskforce on Bipolar Depression, sum-

marizing the so far available evidence (Table I;Mitchell et al. 2008). However, the presence orabsence of any of these characteristics would notcontribute to diagnostic certainty in the individualcase. In addition, a substantial proportion of patientsconsidered as unipolar depressive for decades even-tually experience a hypomanic manic or mixed epi-sode (Angst 2006).

Careful questioning for past mania and hypoma-nia among those who present with major depressiveepisode is of utmost importance. While the bipolar

Program for Bipolar Disorder; TEAS, treatmentemergent affective switch; VNS, vagus nerve stim-ulation; WFSBP, World Federation of Societies ofBiological Psychiatry; YMRS, Young Mania RatingScale.

Preface and disclosure statement

This practice guideline for the biological, mainlypharmacological treatment of acute bipolar depressionwas developed by an international Task Force of theWorld Federation of Societies of Biological Psychia-try (WFSBP) and is part of a series covering theacute treatment of mania, bipolar depression andmaintenance treatment of bipolar disorder. Thepreparation of these guidelines has not been finan-cially supported by any commercial organization.

This guideline has mainly been developed bypsychiatrists and psychotherapists who are in active

clinical practice. Experts of the task force wereselected according to their expertise and with theaim to cover a multitude of different cultures.

In addition, some contributors are primarilyinvolved in research or other academic endeavours.It is possible that through such activities some con-tributors have received income related to medicinesdiscussed in this guideline.

Some drugs recommended in the present guide-line may not be available in all countries, andapproved doses may vary.

Introduction

Although mania is considered as the hallmark ofbipolar disorder, major depressive episodes anddepressive symptoms place an even more significantburden onto bipolar patients (Judd et al. 2002;Goodwin and Jamison 2007). Traditionally, bipolardepression is considered to be more refractory thanunipolar depression (Kupfer et al. 2000), with lessfavourable response to treatments, and the perceivedrisk of treatment emergent affective switches (TEAS;Tohen et al. 2009). It poses an important challengefor clinicians, since data suggest that bipolar patients

once diagnosed spend about three-fold more timebeing depressed than manic or hypomanic, in addi-tion to a considerable time with subthreshold depres-sion (Kupka et al. 2007). Even subsyndromaldepression is characterised by a significant loss offunctionality (Altshuler et al. 2006; Marangell et al.2008) and is associated with an increased risk ofrelapse into major affective episodes. Thus, patientsrecovering, but still having residual affective symp-toms, experience subsequent major affective epi-sodes more than three times faster than asymptomatic


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WFSBP Guidelines for the biological treatment of bipolar depression 83

et al. 2002), the available evidence for differentmedications in bipolar depression has markedlyincreased, and differences are being proposed. Somecaution is needed, since simply to show efficacy ineither unipolar or particularly bipolar groups can-not prove specificity. Indeed, unless equal effort ismade to study both unipolar and bipolar patientgroups, the claim for efficacy in one (and not theother) could be pseudo-specific. Moreover, the mostobvious difference between the conditions lies in thepotential for TEAS for patients with a bipolar illnesshistory, rather than differential presentation of the

depressed state per se.

Methods

The main focus of this guideline is on pharmaco-logical treatments and while best practice regardingother physical treatments and psychotherapy will besummarised briefly, an evidence based review ofthese modalities is beyond the scope of the presentpaper. Although the authors are aware that bipolardisorder is a changeable condition which also showscommon overlap of the different poles of mood (i.e.

mixed mania and mixed depression), the guidelinesare initially divided into the classical categories ofacute treatments for bipolar depression and maniaand prophylaxis. This article will concentrate on thetreatment of bipolar depression in adults as there is,despite the clear clinical need (Leverich et al. 2007),unfortunately a paucity of evidence for the treatmentin children and adolescents. Due both to the lack ofclear-cut and universally accepted diagnostic crite-ria, and the lack of controlled evidence for treatment,these guidelines will not cover depressive mixed

nature of major depressive episode is evident foreverybody if the patient has had a past manic epi-sode, health professionals are usually less sensitizedfor detecting past spontaneous hypomania and pasttreatment-associated hypomania. A family historyof bipolar disorder, early age of onset (Benazzi andAkiskal 2008) and agitated unipolar major depres-sion (Akiskal et al. 2005) and other soft signs ofbipolar spectrum disorder also deserve close atten-tion (Ghaemi et al. 2002).

Patients with those indicators of possible bipolar-ity are not only particularly vulnerable for affective

switches when depressed, but might also be moreprone to antidepressant resistance (ODonovan et al.2008). In this follow-up study, almost all antidepres-sant resistant depressives (and those who becomesuicidal during antidepressant monotherapy) werefound among the pre-bipolar depressives, as com-pared to pure unipolar depressives. Similar findingswere published by Woo et al. (2008).

Potentially insufficient treatment with antide-pressant monotherapy in these cases might result inworsening both the short and long-term outcomeincluding suicidal behaviours as a consequence ofworsening of depression (Rihmer and Akiskal 2006).

In light of these it is not surprising that particularlyjuvenile depressives have been found to be vulnera-ble for antidepressant-induced suicidality, sinceearly age of onset is among the best indicators ofbipolarity in major depression.

Until recently, it has been widely assumed thatevidence from the treatment of unipolar depressioncan be extrapolated to the bipolar syndrome. This hasseemed justified by an acute symptomatology that isvirtually undistinguishable. However, since the firstedition of this guideline came out in 2002 (Grunze

Table I. A proposed probabilistic approach to distinguish between a major depressive episode in unipolar vs. bipolar depression(Mitchell et al. 2008).

The greater likelihood of the diagnosis of Bipolar I depression shouldbe considered if 5 of the following features are presenta

The greater likelihood of the diagnosis ofUnipolar Depressionshould be considered if4 of the following features are presenta

Symptomatology and mental state signs

Hypersomnia and or increased daytime napping Initial insomnia reduced sleep

Hyperphagia and or increased weight Appetite and or weight lossOther atypical depressive symptoms such as leaden paralysis

Psychomotor retardation Normal or increased activity levels

Psychotic features and or pathological guilt Somatic complaints

Lability of mood manic symptoms

Course of illness

Early onset of first depression (25 years)a Later onset of first depression (25 years)a

Multiple prior episodes of depression (5 episodes)a Long duration of current episode (6 months)a

Family history

Positive family history of bipolar disorder Negative family history of bipolar disorder

aConfirmation of the specific numbers to be used requires further study and consideration.


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states. There is no clear consensus where the dividingline runs between what some conceptionalize asbipolar mixed depressive state and others as unipolaragitated depression, especially when it comes to theimportance of elated mood and motor activity (Majet al. 2003; Benazzi 2004a,b; Akiskal et al. 2005;Benazzi and Akiskal 2006). However, clinicians

should be aware that patients with potentially manicsymptoms while depressed constitute a differentchallenge (Goldberg et al. 2009b), and some medi-cations, e.g., antidepressants, are believed to requirecaution (Goldberg et al. 2007).

We are also not able to differentiate on an evi-dence base between the treatment of bipolar depres-sion with or without psychotic symptoms.Unfortunately, there are no controlled studies pro-viding guidance on the drug treatment of bipolardepression with accompanying psychotic symptoms.

The methods of retrieving and reviewing the evi-dence base and coming up with an recommendationare identical to those described in the WFSBP guide-line for acute mania (Grunze et al. 2009). For thosereaders who are not familiar with the mania guide-line, we will summarize the methods in the followingparagraphs.

The data used for these guidelines have beenextracted from a MEDLINE and EMBASE search,the Science Citation Index at Web of Science (ISI)and a check of the Cochrane library for recentmetaanalyses (all until September 2009), and fromrecent proceedings of key conferences. To ensurecomprehensiveness of data, we also consulted vari-

ous national and international treatment guidelines,consensus statements and comprehensive reviews(Zarin et al. 2002; Licht et al. 2003; Royal Australianand New Zealand College of Psychiatrists Clini-cal Practice Guidelines Team for Bipolar Disorder2004; National Collaborating Centre for MentalHealth 2006; Yatham et al. 2006; Sartorius et al.2007; Fountoulakis et al. 2008; Goodwin et al. 2008;

Jon et al. 2008; Kasper et al. 2008; Nolen et al. 2008).Afew additional trials were found by hand-searchingin text books. In addition, www.clinicaltrials.gov wasaccessed to check for unpublished studies.

The results of metanalyses have been used as a

secondary source of evidence in the absence of con-clusive studies or in the case of conflicting evidence.Metaanalyses often compile different drugs into onegroup, although the individual agents may be quiteheterogeneous in their mode of action. In addition,they may have a number of methodological short-comings, which can make their conclusions less reli-able than those of the original studies (Anderson2000; Bandelow et al. 2008). For bipolar depression,there are few metaanalyses available (e.g., Gijsmanet al. 2004) and results and conclusions may be

confounded by methodological issues (Fetter andAskland 2005; Ghaemi and Goodwin 2005;Hirschfeld et al. 2005). Metaanalysis may pick upweak signals and magnify them to significance, e.g.,in the case of lamotrigine (Geddes et al. 2009); how-ever, statistical significance should not be unthink-ingly equated to clinical significance ( the latter being

also true for individual studies). In general, metaanal-yses of negative primary data might identify a smalleffect size benefit as significant because of the powerof Fisherian statistics.

In order to achieve uniform and, in the opinionof this taskforce, appropriate ranking of evidence weadopted the same hierarchy of evidence based rigorand level of recommendation as recently used inother WFSBP guidelines (Bandelow et al. 2008;Grunze et al. 2009) (see Table II). Depending on thenumber of positive trials and the absence or presenceof negative evidence, different categories of evidencefor efficacy can be assigned. Ideally, a drug musthave shown its efficacy in double-blind placebo-con-trolled studies in order to be recommended withsubstantial confidence (categories of evidence (CE)A or B, recommendation grades 13); however, asdetailed later, these strict criteria may be not suitablein bipolar depression due to a lack of conclusive evi-dence. A distinction was also made between lack ofevidence (i.e. studies proving efficacy or non-effi-cacy do not exist) and negative evidence (i.e. themajority of controlled studies shows non-superiorityto placebo or inferiority to a comparator drug). Whenthere is lack of evidence, a drug with a potentially

positive mechanism of action could still reasonablybe tried in a patient unresponsive to standard treat-ment. Recommendations were then derived from thecategory of evidence for efficacy (CE) and fromadditional aspects as safety, tolerability and interac-tion potential. The grades of recommendation do notfully resemble what is generally understood as effec-tiveness. Clinical effectiveness is composed of effi-cacy, safety/tolerability and treatment adherence andpersistence (Lieberman et al. 2005). As we do nothave reliable data on treatment adherence for mostof the medications dealt with in this chapter, anystatement on clinical effectiveness must be partially

based on assumptions.The recommendation grades (RG) can generally

be viewed as steps: Step 1 would be a prescriptionof a medication with RG 1. When this treatment fails,all other Grade 1 options should ideally be tried firstbefore switching to treatments with RG 2, then 3, 4and 5. In some cases, e.g., the combination of an RG1 and an RG 2 option can preferentially be triedinstead of combining two RG 1 options, e.g., withsome augmentation strategies. In the case of bipolardepression, the primary treatment may still be a


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Table II. Categories of evidence (CE) and recommendation grades (RG).

Category ofEvidence Description

A Full Evidence From Controlled Studies

is based on:2 or more double-blind, parallel-group, randomized controlled studies (RCTs) showing superiority to placebo (orin the case of psychotherapy studies, superiority to a psychological placebo in a study with adequate blinding)

and1 or more positive RCT showing superiority to or equivalent efficacy compared with established comparatortreatment in a three-arm study with placebo control or in a well-powered non-inferiority trial (only required ifsuch a standard treatment exists)In the case of existing negative studies (studies showing non-superiority to placebo or inferiority to comparatortreatment), these must be outweighed by at least 2 more positive studies or a metaanalysis of all available studiesshowing superiority to placebo and non-inferiority to an established comparator treatment.Studies must fulfill established methodological standards.The decision is based on the primary efficacy measure.

B Limited Positive Evidence From Controlled Studies

is based on:1 or more RCTs showing superiority to placebo (or in the case of psychotherapy studies, superiority to apsychological placebo)ora randomized controlled comparison with a standard treatment without placebo control with a sample sizesufficient for a non-inferiority trial

andIn the case of existing negative studies (studies showing non-superiority to placebo or inferiority to comparatortreatment), these must be outweighed by at least 1 more positive study or a metaanalysis of all available studiesshowing superiority to placebo or at least one more randomized controlled comparison showing non-inferiority toan established comparator treatment.

C Evidence from Uncontrolled Studies or Case Reports/Expert Opinion

C1 Uncontrolled Studies

is based on:1 or more positive naturalistic open studies (with a minimum of 5 evaluable patients)ora comparison with a reference drug with a sample size insufficient for a non-inferiority trialandno negative controlled studies exist

C2 Case Reports

is based on:1 or more positive case reportsandno negative controlled studies exist

C3 Based on the opinion of experts in the field or clinical experience

D Inconsistent Results

Positive RCTs are outweighed by an approximately equal number of negative studies

E Negative Evidence

The majority of RCTs studies or exploratory studies shows non-superiority to placebo (or in the case ofpsychotherapy studies, superiority to a psychological placebo) or inferiority to comparator treatment

F Lack of Evidence

Adequate studies proving efficacy or non-efficacy are lacking.

Recommendation

Grade (RG) Based on:1 Category A evidence and good risk-benefit ratio

2 Category A evidence and moderate risk-benefit ratio

3 Category B evidence

4 Category C evidence

5 Category D evidence

medication with a RG as low as 5 as the RG 1 and2 choices are rather limited and may not suit everypatient. In addition, unequal quality of studies may

substantially impact on CE and derived RG andeven appear contradictory to clinical experience (seeparagraph on valproate).


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recent trials choose the MontgomeryAsberg Depres-sion rating scale (MADRS; Montgomery and Asberg1979). There are subtle differences between thesescales, and neither seems to adequately pick upsymptoms more frequent in bipolar depression thanunipolar depression such as hypersomnia, moodlability and psychomotor disturbances. Other, less

frequently used scales in bipolar depression trialsinclude the Inventory of Depressive Symptoms (IDS,(Rush et al. 1986), the self-rated Beck DepressionInventory (BDI; Beck et al. 1961) and the BechRafaelsen Melancholia Scale (MES) (Bech 2002).An issue, which is often not considered is whetherthe available rating scales fulfil the criteria of unidi-mensionality by item response theory analysis (Lichtet al. 2005). Among the rating scales, the MES is theonly scale that has been shown to fulfil such criteria.This heterogeneity of scales for the primary out-comes may have such an impact that it determineswhether a study has a positive or failed outcome,e.g., as seen in one study with lamotrigine (Calabreseet al. 1999a). Future studies may, subject toregulatory authorities acceptance, use more specificscales as the Bipolar Depression Rating Scale (Berket al. 2007).

The task force is aware of several inherent limita-tions of these guidelines. When taking negative evi-dence into consideration, we rely on their publicationor their presentation or the willingness of studysponsors to supply this information. Thus, this infor-mation may not always be complete and may biasevidence of efficacy in favour of a drug where access

to such information is limited. This potential bias hasbeen minimized as much as possible by checking thewww.clinicaltrials.gov data base; however, this doesnot work for older studies conducted prior to theimplementation of this website. Another method-ological limitation is sponsor bias (Lexchin et al.2003; Perlis et al. 2005; Heres et al. 2006; Lexchinand Light 2006) inherent in many single studies onwhich the guidelines are based. Also, all recommen-dations are formulated by experts who may try theirbest to be objective but are still subject to their indi-vidual pre-determined attitudes and views for oragainst particular choices. Therefore, no review of

evidence and guideline can in itself provide anunchallengeable recommendation but it can directreaders to the original publications and, by this,enhance their own knowledge base and anchor theirtreatment decisions more securely.

Finally, the value of any guideline is defined bythe limitations of evidence. It is a particular addi-tional problem that placebo trials in depressionhave become harder to conduct, and that thosethat have been conducted relatively recently tend tohave higher placebo response rates. The necessary

A general problem when reviewing trials is thequestion of adequate dosing of medication. For sev-eral medications, a doseresponse relationship isknown, especially from studies in unipolar depres-sion. Established drugs which are used as internalcomparators in sponsored three-arm studies mightbe underdosed as it is not in the interest of the spon-

sor that they came out as superior to the drug underinvestigation. Using this, although controlled, evi-dence could induce an unfair bias against establishedmedication, as it might be the case with the twoEMBOLDEN studies using paroxetine (Younget al. 2008) and lithium (McElroy et al. 2008),respectively, as comparators.

The WFSBP guideline series, including the bipo-lar guidelines, review acute and long-term treatmentissues separately. They do not take into account long-term efficacy when addressing short-term treatment.This approach may be suitable for acute medicalconditions, but the WFSBP Bipolar task force stillfeels uncertain whether an episode based approachis really the best way for a disorder which is almostcharacterised by the chronicity of its symptoms. Thisdilemma is most obvious in the case of lithium:Acute treatment data are not convincing enough fora higher category of evidence than D, however,when long-term considerations, including suiciderisk, are taken into account lithium would clearly fallinto a higher category (Mller-Oerlinghausen et al.2006; Young and Newham 2006).

We have not considered the direct or indirectcosts of treatments as these vary substantially across

different health care systems. Additionally, some ofthe drugs recommended in this guideline may not(or not yet) have received approval for the treatmentof bipolar depression in every country, especially ifthey have been developed lately. As approval bynational regulatory authorities is also dependent ona variety of factors, including the sponsors commer-cial interest (or lack thereof) this guideline is exclu-sively based on the available evidence, not marketingauthorisation.

Most RCTs in acute bipolar depression have aduration of 68 weeks, and only more recently havedouble-blind extension periods been added to the

protocols. Thus, with the relative paucity of data, theclinically important question of maintenance ofeffect could not be considered as a core criterion forefficacy, but may become a supportive argumentwhen a choice between similar effective medicationshas to be made.

Another unsolved issue is the choice of the appro-priate rating scale for depression (Mller 2009)Whereas older studies usually applied the HamiltonRating scale for Depression (HAMD; Hamilton1967), either in its 17- or 21-item versions, more


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available (Vieta 2008) and, until recently, the lack ofsensible alternatives (Ghaemi et al. 2006a).

Having a thorough review of previous treatmentmodalities in depression, if there were any, is essen-tial before initiating new treatment. Previous responseto a medication appears to be one of the strongestpredictor for treatment success. In addition, some

medications may be ruled out due to previous non-response or tolerability problems.

The use of lithium rests on old unconvincingtrials of small scale and idiosyncratic design(Bhagwagar and Goodwin 2002). The latest con-trolled evidence in a large cohort study could notshow separation of low-serum level lithium fromplacebo (Young et al. 2008) (CE D, RG 5).Nevertheless, a generally recommended approach ina patient with bipolar depression who is already ontreatment with lithium is to increase the dosage tothe maximum tolerated level while remaining withinthe established therapeutic range. This recommen-dation is indirectly derived from post-hoc analysis ofstudy results (Nemeroff et al. 2001), but mainlybased on clinical experience and is in part a varianton watchful waiting (CE C3, RG 4). On the otherhand, this strategy is to some extend contradicted bya recent analysis suggesting that high lithium serumlevels are associated with an increased rate of relapseinto bipolar depression (Severus et al. 2009).

Maximizing the benefit from a single medicationreduces potential adding up of side effects whenmedications are combined, and makes it easier todetermine the effectiveness of that medication. Only

a few studies have examined the role of combinationpharmacotherapy when monotherapy is unsuccess-ful. Based on the results of one such study (van derLoos et al. 2009) lamotrigine might be initiatedwhen lithium optimisation is unsuccessful (CE B,RG 3). Other options with lower grades of evidenceinclude the addition of an atypical antipsychotic tolithium or some augmentation strategies.

The use of anticonvulsants also remains animportant option, which will be reviewed in detailbelow.

Since the previous version of this guideline in2002, two atypical antipsychotics have emerged as

new treatment options in bipolar depression. Basedon the findings of large, multicentre, placebo-con-trolled clinical trials, the initial approach to the phar-macotherapy of bipolar depression (either bipolar Ior bipolar II) could be to initiate quetiapine mono-therapy (Calabrese et al. 2005; Thase et al. 2006;McElroy et al. 2008; Young et al. 2008) (CE A, RG1)for untreated patients or to add quetiapine to ongo-ing treatment (CE C1, RG4) (Sokolski and Denson2003; Suppes et al. 2007) using either the immedi-ate-release or extended-release formulation.

resources to do them properly can only come froman industry which has had little incentive to studybipolar depression until recently. In addition, one ofthe most important clinical questions that cannotbe sufficiently answered in an evidence-based way iswhat to do when any first step treatment fails, whichhappens in a significant number of cases. Some stud-

ies, as the Systematic Treatment Enhancement Pro-gram for Bipolar Disorder (STEP-BD; Sachs et al.2003) tried to develop such algorithms, but resultsare not conclusive and cannot cover the large vari-ety of treatment options (Nierenberg et al. 2006). Inparticular, there are no systematic studies in bipo-lar depression that can guide the clinician when toswitch medication. In the absence of other, morespecific evidence, the task force suggests consid-ering 4-week intervals for the different treatmentsteps. With the current level of knowledge we canonly provide suggestive guidelines and not rigorousalgorithms.

Once a draft of this guideline had been preparedby the Secretary and the principal authors it was sentout to the 53 members of the WFSBP Task Force onTreatment Guidelines for Bipolar Disorders for crit-ical review and addition of remarks about specifictreatment peculiarities in their respective countries.A second draft, revised according to the respectiverecommendations, was then distributed for finalapproval to all task force members and, in addition,to the presidents of the 63 national member societiesof the WFSBP.

The acute treatment of bipolar depression

Overview

When initiating treatment for bipolar depression,some general principles apply as outlined in theCanadian Guidelines (Yatham et al. 2006) and itsmost recent update (Yatham et al. 2009):

assess safety/functioningestablish treatment settingrule out medical causesdiscontinue caffeine, alcohol and illicit sub-stances

consider behavioural strategies/rhythms, psy-choeducation

The Canadian guidelines also recommend as abasic principle to discontinue antidepressants; how-ever, the role of antidepressants in the treatment ofbipolar depression remains controversial and willbe discussed in more detail in the related chapter.Clinically, the use of antidepressants especially incombination treatment remains common, perhapsreflecting this ongoing controversy, the limited data


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detected between unipolar and bipolar depressedpatients. Other open studies are also in line withsimilar antidepressant efficacy of antidepressants inunipolar and bipolar depressed patients (for a review,see Grunze (2006).

There is a large body of controlled clinical stud-ies that support the efficacy of the different available

antidepressants in treating symptoms of unipolardepression (Sartorius et al. 2007). However, this isunfortunately only true for unipolar depression.Bipolarity has regrettably been an exclusion criterionin most antidepressant trials of the last two decades(Mller et al. 2006).

More recent, some doubts have been raised aboutthe efficacy of antidepressants in milder forms ofunipolar depression, as well as in adolescents. Theissue of severity is important in establishing or clar-ifying the size of the effect of antidepressants (Kirschet al. 2008, see also McAllister-Williams 2008;Mller 2008). The study by Bridge et al. (Bridgeet al. 2009) in children reinforces this, as does themetaanalysis of lamotrigine (Geddes et al. 2009)(see chapter on lamotrigine). Unfortunately, thenumber of study subjects in most trials with antide-pressants is too small to allow for separate responderanalysis depending on severity of depression.

Overall, the controlled evidence for antidepres-sant efficacy of antidepressants as a group of medica-tion in bipolar depression is inconclusive (Vieta,2008). The available evidence is detailed below, andthe deduced CE and RG gradings for antidepres-sants in monotherapy and as part of a combination

treatment are given in Table III.Several small controlled studies support the useof deprenyl (Mendlewicz and Youdim 1980), tranyl-cypromine (Himmelhoch et al. 1982; Nolen et al.2007), imipramine and fluoxetine (Cohn et al. 1989).Together with a study examining the effect of olan-zapinefluoxetine combination (OFC)(Tohen et al.2003), these studies except the one by Nolen et al.(2007) have also been subject to a metaanalysisshowing beneficial effects of antidepressants as agroup in bipolar depression (Gijsman et al. 2004);however, the conclusions of this metaanalysis (whichfocussed on short-term exposure) have been criti-

cised for not recognizing the perceived long-termharms of antidepressant use (Fetter and Askland2005; Ghaemi and Goodwin 2005; Hirschfeld et al.2005). The particular problem has been the inade-quate size and small number of monotherapy trialsin bipolar depression. Such trials may be negativewhen considered alone and positive when part of anattempt to synthesize all the available data. It iswidely agreed that the evidence is inadequate, andinterpretation is accordingly subject to fewer con-straints than if the evidence was very clear.

Olanzapine, although mildly effective on its own,is another option especially when given in combi-nation with fluoxetine (OFC). This combination hasbeen approved and marketed as fixed dose tablets inthe US. Its efficacy is supported by one placebo-controlled trial (Tohen et al. 2003) and one head-to-head comparison to lamotrigine (Brown et al. 2006)

(CE B, RG 3). However, interpretation of the latterstudy is difficult as it remains doubtful whether lam-otrigine can be considered as a standard comparatorfor bipolar depression, given its relative small effectsize.

Of the different non-medication treatments, ECTis also a reasonable choice (CE C1, RG4) particularlyin patients with very severe depression, severe suiciderisk, catatonic features, or psychosis (Valenti et al.2007). ECT may also be used for severe depressionduring pregnancy. Repetitive transcranial magneticstimulation (rTMS)(Nahas et al. 2003) and vagusnerve stimulation (VNS) (Goodnick et al. 2001) has,to date, shown only modest benefits (CE F).

Certain psychotherapy modalities may also behelpful as adjuncts to pharmacotherapy (Vieta 2005).Results of the Systematic Treatment Evaluation Pro-gram for Bipolar Disorder study indicate that inter-personal and social rhythms therapy, CBT, andfamily-focused therapy may also speed recoverywhen added to pharmacotherapy during depressiveepisodes in patients with either bipolar I or bipolarII disorder (Miklowitz and Otto 2007; Miklowitzet al. 2007) (CE A, RG 1).

In conclusion, there is no choice of first step in

treating bipolar depression that shows unequivocalbenefits. We are obliged to review the options as justthat, without an overwhelming preference for anysingle treatment based on careful comparisons ofhead to head efficacy and acceptability.

Antidepressants

Efficacy.Antidepressants are frequently used in bipo-lar depression (Simon et al. 2004), at least as part ofcombination treatment, and the severity of depressiveburden is correlated with the use of antidepressantsas part of complex combination treatment (Gold-

berg et al. 2009a). Open studies suggest that whatis true about efficacy for acute treatment of unipolardepression seems very likely to be true also for bipo-lar depression. Some evidence for comparable effi-cacy of tricyclics in unipolar and bipolar depressedpatients is provided by a large retrospective analysisof 2032 inpatients recruited in the years 19801992at the Department of Psychiatry of the Universityof Munich (Mller et al. 2001). When the routinelyrecorded clinician rating scales and the length of stayin hospital were compared, no difference could be


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Table III. Categories of evidence (CE) and grade of recommendation (RG) for pharmacological and physical treatments used in acuteBipolar I depression (in alphabetical order within one category of evidence)

MedicationCategory of

Evidence (CE)Recommendation

Grade (RG) Critical references and commentsDose ranges or maximum

dosages used in studies

Monotherapies

Quetiapine A 1 (Young et al. 2008; McElroy et al. 2008;Suppes 2008; Thase et al. 2006; Calabreseet al. 2005)

300600 mg

Fluoxetine1 B 3 (Cohn et al. 1989; Tohen et al. 2003) Noincreased rate of TEAS with accompanyingantimanic drug, but unclear in monotherapy

2050 mg

Lamotrigine B 3 (Calabrese et al. 2008; Brown et al. 2008;Geddes et al. 2009; Frye et al. 2000; vander Loos et al. 2009)

50200 mg

Olanzapine B 3 (Tohen et al. 2003) 520 mg

Valproate B 3 (Davis et al. 2005; Ghaemi et al. 2007;Sachs et al. 2002)

Serum level 7090 mg/l

Carbamazepine D 5 (Ballenger 1988; Small 1990; Zhang et al.2007)

6001200 mg (serum level415 mg/l)

Lithium D2 5 (Young et al. 2008; Zornberg and Pope1993)

6001200 mg (serum level0.81.3 mEq/l. In thenegative study, mean serumlevels were 0.61 mEq/l

Paroxetine E3 (McElroy et al. 2008) 20 mg

Aripiprazole E (Thase et al. 2008) 1530 mg

Ziprasidone E (Sachs et al. 2009) 80160 mg

Combination and augmentation treatments

OFC B 3 (Tohen et al. 2003; Brown et al. 2006) 612 mg olanzapine and2550mg fluoxetine

Lamotrigine lithium

B 3 (van der Loos et al. 2009) Lamotrigine: Up to 200 mg/d

Modafinil ongoing

treatment

B 3 (Frye et al. 2007) Modafinil: 100200 mg

N-acetylcysteine lithium orValproate

B 3 (Berk et al. 2008) N-acetylcysteine: 2 g

FEWPcarbamazepine

B 3 (Zhang et al. 2007) FEWP: 36 g/d

Sertraline lithiumor valproate

C1 4 (Leverich et al. 2006) Sertraline: 50 200 mg

Tranylcypromineongoing treatment

C1 4 (Himmelhoch et al. 1991; Nolen et al.2007)

Tranylcypromine up to100 mg

Venlafaxine lithiumor valproate

C1 4 (Post et al. 2006; Vieta et al. 2002)and evidence from Bipolar II (Amsterdam1998; Amsterdam and Garcia-Espana

2000); may bear increased risk of TEASin Bipolar I

Venlafaxine up to 375 mg/d

L-Thyroxine ongoing treatment

C1 4 (Bauer et al. 1998; Bauer et al. 2005) L-Thyroxine: Up to450 mcg

Topiramate lithiumor valproate

C1 4 (McIntyre et al. 2002) Topiramate: 50300 mg

Zonisamidelithiumor valproate

C1 4 (McElroy et al. 2005; Baldassano et al.2004; Wilson and Findling 2007; Ghaemi etal. 2006b)

Zonisamide: 100500 mg

Imipraminelithium

D 5 (Nemeroff et al. 2001; Cohn et al. 1989;Silverstone 2001)

Imipramine: 50150 mg

(Continued)


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90 H. Grunze et al.

Table III. (Continued)

MedicationCategory of

Evidence (CE)Recommendation

Grade (RG) Critical references and commentsDose ranges or maximum

dosages used in studies

Inositollithium orvalproate

D 5 (Evins et al. 2006; Nierenberg et al. 2006) Inositol: up to 22 g

Omega 3 fatty acidslithium or

valproate

D 5 (Frangou et al. 2006; Keck et al. 2006) EPA: 18 g

Paroxetine lithiumor valproate

D 5 (Nemeroff et al. 2001; Sachs et al. 2007;Vieta et al. 2002; Young et al. 2000)

Paroxetine: 2050 mg(Nemeroff et al. 2001)

Bupropionlithiumor valproate

D 5 (McIntyre et al. 2002; Sachs et al. 1994;Sachs et al. 2007; Leverich et al. 2006)

Bupropion: 100450 mg

Gabapentinongoing treatment

D 5 (Frye et al. 2000; Carta et al. 2003) Gabapentin: up to 4800 mg

Physical treatments

Sleep deprivation ongoing treatment

C1 4 (Riemann et al. 2002; Wu et al. 2009)

ECTongoingtreatment

C1 4 (Silverstone and Silverstone 2004)

rTMS

ongoingtreatment E (Nahas et al. 2003)

VNSongoingtreatment

F (Rush et al. 2000; Daban et al. 2008)

The use of imipramine has not been supportedby a failed add-on study to lithium when lithium

levels are higher; however, with lower lithium levelsimipramine may add some benefit (Nemeroff et al.2001). Paroxetine has shown no benefit in the treat-ment of bipolar depression when compared to pla-cebo in one monotherapy study (McElroy et al.2008), conflicting results in two placebo-controlledadd-on studies to lithium (Nemeroff et al. 2001;Sachs et al. 2007), where in one study (Nemeroffet al. 2001) paroxetine was superior to placebo insubjects with lower lithium levels, and potential effi-cacy in two add-on comparator studies (Young et al.2000; Vieta et al. 2002). The situation is similar withbupropion: limited evidence exists from small, dou-

ble-blind comparator studies against desimipramine(Sachs et al. 1994) and topiramate (McIntyre et al.2002), but in a larger placebo-controlled add-onstudy to mood stabilizer it could not provide anyadditional benefit (Sachs et al. 2007). Citalopramappeared effective in a small comparative study(Schaffer et al. 2006), but the choice of the com-parator (lamotrigine, see related chapter) makes thestudy finally inconclusive. One large blinded studydid find that a subset of patients benefited from addi-tion of sertraline, bupropion or venlafaxine, but the

absence of a placebo comparator means that theextent of benefit cannot be finally estimated (Post

et al. 2003; Leverich et al. 2006).Probably the best positive evidence exists for flu-oxetine. Besides the smaller studies mentioned, flu-oxetine was also effective in a placebo-controlledstudy by Cohn et al. (1989). This study alone maynot merit a high ranking of fluoxetine monotherapy,as 22 of the 89 patients in this study had concomitantlithium which, on the other hand, has no signal forefficacy in a recent monotherapy study (McElroyet al. 2008). The strongest evidence comes fromanother study: fluoxetine add-on to olanzapine wassignificantly more effective than olanzapine mono-therapy and than placebo in a sufficiently powered

study (Tohen et al. 2003) maintaining this efficacywithout increased rates of treatment emergent affec-tive switches (TEAS) during a 24-week open labelextension (Corya et al. 2006). Also, during the acutephase, the risk of TEAS into mania or hypomaniawas not increased in subjects treated with the com-bination of fluoxetine and olanzapine as compared tothose treated with placebo (Keck et al. 2005).

The two most recent studies, which are alsoprobably those studies with the most elaborate meth-odology and sufficient number of subjects, did not

1 When olanzapine monotherapy is considered as the placebo condition in the study by Tohen et al. (2003).2 The D rating is mainly triggered by the study of Young et al. (2008) where lithium plasma levels were relatively low. In the case of

pre-existing lithium treatment, antidepressive response may be achieved by dosage increase towards high plasma levels (Nemeroffet al. 2001) (CE B, RG 3)

3 In the study by Altshuler et al. (2009) paroxetine was used in a potentially less effective dose of 20 mg/day.


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weaker antidepressants. In this analysis, it appearsthat escitalopram, venlafaxine, sertraline and mir-tazapine are among those with a relatively strongeraction, whereas in another analysis, again venlafaxineand escitalopram, but also clomipramine were judgedsuperior to other antidepressants (Montgomery et al.2007). Unfortunately, none of them has been tested

in bipolar depression in placebo-controlled designs.For two of them, venlafaxine and sertraline, there areless rigorous data in bipolar disorder suggestive ofefficacy (Post et al. 2006). But given the large varietyof depressive manifestations, it would be somehownave to assume that each given antidepressant showssimilar efficacy in all conditions (Ayuso-Gutierrez2005). Therefore, it may be more appropriate in thefuture not to look at antidepressants as a group buton the individual agents (and their dosing) whenmaking statements on efficacy and TEAS rates inbipolar patients.

Evidence on how to proceed if antidepressantacute treatment is effective is also conflicting. Sev-eral observational studies suggesting increased moodinstability with long-term antidepressants may bebiased by the fact that in clinical settings the moreseverely ill patients are more likely to be treatedwith antidepressants (Goldberg et al. 2009a). Open(Altshuler et al. 2003a) and controlled (Altshuleret al. 2009) data of the Stanley Foundation BipolarNetwork (SFBN) would favour continuation of anti-depressants in selected patients. In both studies, therisk of a depressive relapse appears significantly lowerin patients continuing the antidepressant compared

to those discontinuing after remission, with no statis-tically significant difference for breakthrough manicepisodes. However, these patients may not be repre-sentative in several aspects. A metaanalysis publishedprior to the controlled study of the SFBN could notestablish a benefit from antidepressant continuation(Ghaemi et al. 2008b); however, it was dominatedby older studies of the tricyclic impiramine and evenshort-term data suggest higher risks of switch withtricyclic antidepressants. Looking only into studieswhich combined imipramine with lithium, no addi-tional risk of TEAS could be observed. In summary,it may again be crucial to look into the individual

patients history to establish whether he or she seemsto be at elevated risk of TEAS and whether he or shepreviously responded well on antidepressants.

Safety, tolerability and practicability.From the safetyand side effect profiles, the newer generation antide-pressants are believed to be better tolerated bypatients, and are less toxic when taken in overdose(Lader 1996; Barbey and Roose 1998; Frey et al.2000; Peretti et al. 2000; see also Sartorius et al.

establish efficacy for antidepressants in bipolardepression. Paroxetine was used as an internal com-parator in a study designed to prove the efficacy ofquetiapine in bipolar depression. Paroxetine mono-therapy was not superior to placebo after 8 weeks inany depression-related outcome, only in improvingsymptoms of anxiety (McElroy et al. 2008). One

criticism of this study is what is considered as a rel-atively low dose of paroxetine (20 mg/day), whereasclinically effective doses in unipolar depression arein the range of 30-40 mg/day (Dunner and Dunbar1992; Mller et al. 1993).

Paroxetine (2040 mg, mean dose 30 mg) andbupropion (150300 mg, mean dose 300 mg) werealso investigated as adjunctive treatment to moodstabilizer in depressed Bipolar I and II patients. Thisstudy was part of the STEP-BD program (Sachset al. 2003). For the primary outcome, durable recov-ery as defined as at least eight consecutive weeks ofeuthymia (with no more than two depressive or twomanic symptoms), there was no statistical significantdifference between lithium or valproate placeboand lithium or valproate antidepressant. Althoughthe chosen outcome criterion may be very meaning-ful from the clinical perspective, it is unclear howsensitive it may be, and it makes difficult to comparethis trial to those with a classical outcome, e.g.,reduction of a given depression rating scale. More-over, both the allowed additional use of antipsychot-ics and psychotherapy which the majority of patientsreceived may have contributed to reduce the abilityto detect additional effects of antidepressant therapy.

Finally, at randomisation, patients had already beentreated within the framework of the STEP-BD foraround half a year on average, and presumably asubstantial number of patients may have shown non-response to other antidepressants before randomisa-tion. As a matter of fact, an unknown number ofpatients in this trial still were still using their previousantidepressant during the first 2 weeks of the dou-ble-blind phase with an antidepressant or placebo(there was no wash-out). Therefore, the design of theSTEP-BD study does not allow a firm conclusionabout antidepressants in bipolar depression.

What can we conclude from these latest stud-

ies? What we can say with some confidence is thatparoxetine (20 mg/day) alone (McElroy et al. 2008)has failed to show efficacy in a controlled bipolardepression trial. Add-on paroxetine (2040 mg/day)and or bupropion (150300 mg/day) to mood sta-bilizers (Sachs et al. 2007) also failed to show effec-tiveness; however, there are several methodologicalconcerns about this study. But interestingly, parox-etine and bupropion appear in a recent metaanalysisof 12 newer antidepressants in unipolar depression(Cipriani et al. 2009) to belong to the group of


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92 H. Grunze et al.

between antidepressant use and switch events, and theevidence from observational studies and retrospectiveself-reports is divergent (Leverich et al. 2006; Carlsonet al. 2007; Truman et al. 2007). This may, in part, bedue to the fact that there are so far no operationalizedcriteria for switches, especially the time criterion (howlong after beginning/discontinuation of treatment

does an affective switch count as treatment emer-gent?) remains vague and differs between studies. Itis just recently that a task force of the ISBD has putforward a suggested definition of switch, irrespectivelyits relation to treatment, hence it needs validation inprospective trials: a switch (i.e. the appearance of anepisode of the opposite pole directly from/after theindex episode) would be defined as occurring up to 8weeks after remission (Tohen et al. 2009). The defini-tion of TEAS itself remains controversial, with manystudies requiring high thresholds such as needing tomeet full syndromal criteria for mania, and clinicallysignificant but lower thresholds are not explored inmany studies.

Two recent reviews have very diligently lookedinto this and other methodological problems whenconsidering a switch as caused by treatment or asbeing part of the natural course of the illness (Grunze2008b; Licht et al. 2008). Similar arguments havealso been outlined by Angst and Gamma (2002).Also, only cases with switch events are reported lead-ing to a publication bias. In addition, all studiesreporting on switches do not only have a uniformdefinition of a switch, and also calculate switch rateson an intent-to-treat basis, including non-responders

in the analysis. Assuming that antidepressants areefficacious at least in a subgroup of patients, thisclearly favours placebo treated patients because onlypatients who respond can switch, but not those whoremain depressed. Finally, placebo treated patientsmay drop out of trials earlier due to inefficacy andthus have a shorter observational period and smallerchance to develop a switch as part of the naturalcourse of bipolar disorder.

The natural risk of a switch into mania duringrecovery from a bipolar depression has been esti-mated to be between 4 and 8% (Bunney et al. 1972;Angst 1985), and mood stabiliser monotherapy show

either similar rates of switches or appear to be pre-ventive, especially lithium (Calabrese et al. 1999b).Bipolar I patients appear to be more prone to switchevents into manic/hypomanic states than Bipolar IIpatients (Bond et al. 2008). Monotherapy with someantidepressants, especially tricyclics, without anaccompanying mood stabiliser, however, may beassociated with an increased rate of TEAS (Lewisand Winokur 1982; Wehr and Goodwin 1987),although the causal relation is impossible to establishin observational studies. When newer antidepressants

2007). It has to be added, however, that a Cochranelibrary metaanalysis established only a tendency, butno significant advantage for SSRI compared to TCAwhen looking at dropout rates in clinical trials inunipolar patients (Barbui et al. 2000). Adherence totreatment is often a highly critical issue, particularlyin bipolar patients (Colom et al. 2000), so even a

trend of better tolerability might favour the use ofthe new generation antidepressants unless othereffectiveness issues do not contradict it.

A warning concerning the use of antidepressantsespecially in children and adolescents but also in allage groups has been issued by the FDA (FDA Pub-lic Health Advisory 2004). This was due to emergingdata suggesting a possible link between suicidality(thinking and behaviour but not completed suicide)and antidepressant use. Both a more thorough viewon the available evidence (Moller et al. 2008) andnewer, larger population-based studies seem not tosupport this claim (Simon et al. 2006), and as a mat-ter of fact, suicide rates have increased in adolescentswith a drop in antidepressant use (Gibbons et al.2007). As far as bipolar patients are concerned, datafrom the large STEP-BD program do not suggestany increased suicidality when treated with antide-pressants (Bauer et al., 2006).

Treatment emergent affective switches (TEAS).Althoughthis chapter gives some general thoughts about theassociation of antidepressants with TEAS, weighingrisks and benefits in the single patient still remains

a highly important clinical task. On the one hand,manic episodes can be devastating for the patientand his occupational and family life. On the otherhand, insufficient treatment of depression mayseverely reduce the patients functional capacitiesand put them at an increased risk of suicide.

As a matter of fact, the direct transition of depres-sion into hypomania/mania without a symptom-freeinterval (switch) was fundamental for the definitionof the folie double forme proposed by Baillargerin 1854 in Paris; the switch was interpreted as a reac-tion to the preceding depression, emphasizing thatswitching is part of the bipolar course of illness

(Pichot 1995) at a time long before the first antide-pressant entered the market. Instability of mood is akey feature of bipolar disorder, and any tamperingwith a scarcely stable system may produce unpredict-able effects. For example, there is also some evidencethat the withdrawal of antidepressants might also pro-voke manic episodes (Andrade 2004).

However, more concerns are clearly associatedwith the introduction of antidepressants into a treat-ment regimen. A recent systematic review (Visser andVan der Mast 2005) found no strong association


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placebo suggest that lithium is superior to placeboin treating bipolar depression (Zornberg and Pope1993). However, most of these trials are method-ologically questionable (Grunze 2003) and morerecently lithium could not demonstrate clear-cutefficacy in the methodologically most advancedstudy to date in bipolar depression (Young et al.

2008). In this study, lithium served as an internalcomparator in a study investigating the efficacy ofquetiapine versus placebo. At study end (week 8)there was only a non-significant trend of separationfrom placebo for lithium. However, lithium plasmalevels in this study were rather low (mean 0.61mEq/l). In addition, the reported time to onset ofantidepressant action of lithium is 68 weeks, whichis slower than that observed for other antidepressantinterventions (Zornberg and Pope 1993). This mayalso explain the failure of lithium in the Young et al.study, as there was a non-significant tendency forseparation of lithium from placebo just towardsstudy end at week 8. It remains speculative whethera significant outcome may have been achieved withhigher lithium levels and/or longer study duration.

The strength of the antidepressant effect oflithium monotherapy compared to that of otheragents also remains rather unclear. Five rather smalldouble-blind trials have been documented (for areview, see Adli et al. (1998). In particular, we arenot aware of published controlled trials in bipo-lar patients comparing the antidepressant efficacyof lithium with that of antidepressants of the newgeneration head to head. The previously mentioned

study of Young et al. (2008) was not designed andpowered to allow comparison for superiority ornon-inferiority between quetiapine and lithium, andwe are not aware of such a post-hoc analysis.

Lithium is frequently used as an augmentationstrategy in refractory unipolar depression (Crossleyand Bauer 2007). However, data for lithium aug-mentation in in bipolar depression are scarce andrestricted to open studies (Altshuler et al. 2003b).When some antidepressants are combined with lith-ium, their efficacy may be greater than in mono-therapy (Gyulai et al. 2003; see also following sectionon valproate).

Safety, tolerability and practicability.Similar to its usein acute mania, the usefulness of lithium in acutebipolar depression may be limited by a slow onset ofaction and the need for regular plasma level checksto avoid toxicity, as well as by its side effect profileand contraindications (Fountoulakis et al, 2008).Although not absolutely contraindicated, lithium israrely suitable in certain medical conditions, whichtherefore should be excluded before treatment

are used, the switch risk may not be much differentfrom the natural switch risk (Peet 1994). The lateststudies (Sachs et al. 2007; McElroy et al. 2008) didnot find increased switch rates either with paroxetinemonotherapy or paroxetine or bupropion in combi-nation with a mood stabilizer. The switch risk witholder TCAs may also be sufficiently controlled with

the addition of an antimanic agent (Boerlin et al.1998), although this cannot totally eliminate the riskof TEAS (Quitkin et al. 1981; Bottlender et al. 1998).However, available data consistently support the lowrisk of TEAS with the combination of an antidepres-sant with an antimanic medication (Grunze 2008a).TEAS may occur especially when there are concom-itant manic symptoms (Goldberg et al., 2007). Manicsymptoms, especially increased motor activity,speech, and languagethought disorder whiledepressed have been shown to be predictive for anincreased risk of TEAS with antidepressants (Fryeet al. 2009).

Recommendations.It is virtually impossible to give arecommendation for antidepressants as a groupgiven the diversity of agents, their dosing, observedoutcomes and trial quality. In addition, many dataare from combination treatments with antimanicagents, and it is hard to predict the individual con-tribution of medications and potentiating effectsnaturally not seen in monotherapy. The main indica-tion for antidepressants in bipolar depression comesfrom extrapolation of the strong unipolar data, giventhe absence of proven differences in the underlyingbiology of bipolar and unipolar depressed states. Thismay change in the future with emerging data on bio-logical differences, e.g., BDNF serum levels (Fer-nandes et al. 2009). The task force is aware that thegrading of antidepressants as given in Table III issubject to many limitations and thus should be onlya preliminary guide for the reader. As to the TEASinto mania with antidepressant use, all the largerstudies suggest that this risk is quite modest, at leastwhen combined with a mood-stabilizing medication,and seem to be generally lower in Bipolar II than inBipolar I patients (Bond et al. 2008). Actually, as

reviewed above there is evidence suggesting thatwhen an antidepressant is combined with a mood-stabilizer, there is seemingly no increased risk ofTEAS in the sense of full syndromal switches.

Lithium

Efficacy. There is very limited evidence that lithiummay be more effective in bipolar compared to uni-polar depression (Goodwin et al. 1972; Baron et al.1975). Eight of nine small double-blind trials versus


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94 H. Grunze et al.

been fully published; thus, the methodological accu-racy of the unpublished studies (Sachs et al. 2002;Muzina et al. 2008) is difficult to assess.

Some more indirect evidence also comes from amaintenance study comparing valproate, lithium andplacebo for 1 year (Bowden et al. 2000). This hasbeen the only maintenance study to date that allowed

treatment of breakthrough depression with an anti-depressant (either sertraline or paroxetine). Valproateor lithium plus a selective serotonin-reuptake inhib-itor (SSRI) provided longer time in study withoutdiscontinuation for depression than did placebo plusa SSRI. Fewer patients discontinued prematurelyamong valproate plus SSRI-treated patients thanamong placebo-treated patients (Gyulai et al. 2003).These results indirectly suggest that the combinationof valproate and an SSRI in acute bipolar depressionis more effective than SSRI monotherapy.

Safety, tolerability and practicability.The tolerability ofvalproate appears fair across trials. Gastointestinaldiscomfort, sedation and tremor are in most trialsmore regularly seen with valproate. For rare, butsevere complications such as thrombocytopenia,hepatic failure, pancreatitis or hyperammonaemiccoma and precaution measures we refer to the per-tinent reviews (e.g., Bowden and Singh 2005). Whenvalproate is started during acute bipolar depression,it is mostly not meant as the primary antidepressiveagent, but as an augmentation and antimanic cover.This implies that valproate may be continued forquite a considerable time which may require addi-tional precautions, e.g., the use in females of childbearing age (polycystic ovary syndrome (PCOS),teratogenicity). Neurocognitive effects in neonatesmean it is now strongly contra-indicated in womenof child bearing potential (Meador et al. 2009).

Recommendation. Three out of four small sized, butplacebo-controlled studies support antidepressantefficacy of valproate in acute bipolar depression.Thus, the CE is B and the RG 3; however, inspecial groups as women of child bearing age val-proate cannot be recommended due to safety issues.

This graduation of evidence and recommenda-tion grade for valproate strictly follows the pre-setcriteria. The positioning of valproate as an RG 3,especially when contrasting this to the RG for lith-ium, has evoked some controversial discussion withinthe task force. Clinical experience does not seem toreflect a better efficacy of valproate monotherapythan for monotherapy with lithium. As a conse-quence for this guideline, the task force agreed notto restrict first line treatment to a RG 1-3, but feelsthat in individual patients also a RG as low as 5

initiation, e.g., renal problems or thyroid dysfunction.In these instances, regular medical checkups aremandatory. These limitations have been dealt moreextensively in textbooks (Goodwin and Jamison2007) and reviews (McIntyre et al. 2001). A sloweronset of action of lithium, relative to the investiga-tional drug, has been suggested as decisive for inferior

outcome in the study by Young et al. (2008)Lithium has only limited sedating effects, although

these may actually be desirable in patients withsevere depression and suicidal impulses. Antisuicidaleffects of lithium have been pointed out by recentsystematic reviews (Baldessarini et al. 2003; Baldessariniet al. 2006; Mller-Oerlinghausen et al. 2006); however,the putative antisuicidal effect of lithium is thought tobe not acute but develops over time.

Recommendation.Based on the available studies, lith-ium monotherapy falls into CE for acute antidepres-

sive efficacy D, and the RG is 5. A positiveimpression from individually less compelling studiesis currently contradicted by a well conducted, nega-tive, large randomized study (Young et al. 2008). Ifconsiderations of maintenance treatment or suicidalrisks play an additional role at the time of acute treat-ment initiation, lithium should, however, still be con-sidered as part of a combination or augmentationtreatment approach (see also Methods section).

Valproate

Efficacy. This guideline uses valproate as commongeneric name for the different preparations tested inbipolar disorder, e.g., valproic acid, sodium valproate,divalproate, divalproex sodium, and valpromide. Asfar as pharmacokinetics and pharmacodynamics areconcerned, only valproic acid finally reaches andpenetrates the blood-brain barrier. Although tolera-bility is enhanced with extended release prepara-tions, the difference does not warrant groupingvalproic acid derivatives as different medications.

Initially, an open study by Lambert showed aresponse in only 24% of 103 depressed bipolarpatients (Lambert 1984). This 24% response rate

is probably not different from an expected placeboresponse. More recently, however, limited evidencefor an acute antidepressant effect of valproate has builtup. Three out of four small, but placebo-controlledstudies show superiority of valproate over placebo(Davis et al. 2005; Ghaemi et al. 2007; Muzina et al.2008), the fourth displayed a clear trend, probablymissing significance due to lack of power (Sachs et al.2002). Numbers in these trials were small, the larg-est one included 54 subjects (Muzina et al. 2008).Unfortunately, only two out of the four studies have


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Recommendation. The evidence base for carbam-azepine as monotherapy of acute bipolar depres-sion is not convincing (CE D, RG 5), although itmay be helpful to prevent TEAS. Two small trialsincluding a placebo condition gave contradictoryresults, one placebo-controlled study showedimprovement in the CGI at week 12 (endpoint).

With complex combination treatment, the RG forcarbamazepine may even be lower due to its highinteraction potential.

Lamotrigine

Efficacy. Of all anticonvulsants used in bipolar disor-der, lamotrigine has the largest portfolio of method-ologically well-designed studies in bipolar depression.Numerous early open studies have been conducted(Calabrese et al. 1998) suggesting already that lam-otrigine may be more effective in patients with a pre-

dominantly depressive polarity (Colom et al. 2006).The first placebo-controlled study was published in2000 (Frye et al. 2000) showing significant improve-ment of treatment refractory depression with lam-otrigine when compared to placebo or gabapentin.This study applied a cross-over design which raisesmethodological concerns, and included both unipolarand bipolar patients. Since the mid of the 1990s, fivecontrolled, parallel-group monotherapy studies (Cala-brese et al. 2008) and one add-on study to lithium(van der Loos et al. 2009) have looked more system-atically at the efficacy of lamotrigine in acute bipolardepression. Results from the first double-blind, pla-

cebo-controlled clinical trial (Calabrese et al. 1999a)seemed to confirm its efficacy in bipolar depressionat doses of 200 mg daily. However, improvement inthe HAMD, which was the primary outcome, was notsignificant. In the following, there have been fouradditional negative trials of lamotrigine in bipolardepression. Results of these trials have not been pub-lished until recently (Calabrese et al. 2008) which hasraised questions as to the extent that publication biascan contribute to widespread use of a medicationdespite the presence of negative evidence (Ghaemiet al. 2008a). With all monotherapy trials being neg-ative for their primary outcome, several drug licens-ing authorities did not consider the lamotrigine datastrong enough to merit an acute bipolar depressionlicense. A recent individual patient data metanalysis(Geddes et al. 2009) has shed additional light onthese studies. Overall, there was a modest, but sig-nificant aggregate effect for lamotrigine. However,more importantly, those patients with higher baselineHAM-D scores showed an interaction (P0.04) bybaseline severity of depression: lamotrigine was supe-rior to placebo in people with HRSD score 24(RR1.47, 95% CI 1.161.87, P0.001) but not in

may justify first line use of a medication (e.g., in thecase of previous good response in acute and/or long-term treatment) (see Figure 1). The task force alsofeels that it would be highly desirable to conduct wellpowered, high quality studies of valproate in bipolardepression in the future to achieve a more reliableranking of the evidence.

Carbamazepine

Efficacy. Similar to valproate, carbamazepine hasbeen much less studied in the treatment of acutebipolar depression than in mania and prophylaxis(Grunze 2006). The majority of studies are, again,in mixed unipolar and bipolar depressed patients.Some trials suggested moderate efficacy (Ballengerand Post 1980; Neumann et al. 1984; Matkowskiand Rybakowski 1992; Dilsaver et al. 1996) includ-ing one small placebo-controlled cross-over trial(Ballenger 1988) but others did not replicate this

(Small 1990). However, a more recent double-blind,placebo-controlled study showed a significant effectof carbamazepine in a Chinese population at week12 (endpoint) in the CGI, but not in the HAMDand MADRS (Zhang et al. 2007). When carbam-azepine was combined with the herbal remedy Freeand easy wanderer plus (FEWP) a significantimprovement compared to placebo was observed forall three outcomes. Unfortunately, the article doesnot clarify which of the three scales was chosen asthe primary outcome, so the evidence remains incon-sistent for carbamazepine monotherapy.

Safety, tolerability and practicability. Common sideeffects of carbamazepine include oversedation andblurred vision, especially with high dosages and rapidtitration. Rare, but potentially severe side effectsinclude allergic reactions, lupus erythematosus,agranulocytosis and hyponatremia. Detailed infor-mation on the tolerability and safety profile of car-bamazepine is available in recent reviews (Grunzeand Walden 2002; Gajwani et al. 2005). In addition,carbamazepine is associated with an increased riskof birth defects (Morrow et al. 2006). The mainshortcoming in routine use of carbamazepine, how-

ever, is its manifold interactions with other psycho-tropic medication, including several antipsychotics,antidepressants and anticonvulsants (Spina et al.1996). If a patient has already received carbam-azepine as a prophylactic treatment and has so farresponded well to it, continuation of this treatmentmay be justified. Otherwise, if prophylactic treat-ment is about to be commenced other treatmentoptions with less interaction potential such as lith-ium, valproate, lamotrigine or some atypicalantipsychotics should be considered.


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96 H. Grunze et al.

Starting medication:Choose treatment with a RG 1-5 medication, considering:

. Symptoms of depression and severity

. Previous experience and patients preference

. Evidence for efficacy as maintenance treatment if appropriate

. Suicidality, modifying medical factors and specific safety profile

. Route and ease of administration

. Tolerability and efficacy in continuation therapy if indicated

Partial response after 4 weeks: Continue on this

medication, optimize dosage, consider additional

psychotherapy

Full response after 4 weeks: Continue on

medication until full remission has been achieved

or beyond, if maintenance treatment is indicated

If no further improvement is observed over the

next 4 weeks, consider add-on treatment with

another recommended medication or augmentation

strategies

No response after 4 weeks: switch to another

recommended medication or consider

combination, consider additional psychotherapy

If still unresponsive after 4 weeks: Consider

augmentation treatments

If no or insufficient response:

Exchange one medication (the potentially

less effective for the actual symptoms) of

the combined treatment against another

medication with highest possible CE

If insufficient or no response:

. Exchange one medication againstanother medication including

lower CE if appropriate or

. In severe depression: consider

ECT

Level 1

Level 2

Level 3

Level 4

Level 5

Figure 1. Treatment algorithm as suggested by the WFSBP taskforce. This algorithm applies to bipolar I depression of initially moderateseverity, and may vary in mild or severe depression. CE: category of evidence; RG: recommendation grade (see Tables II and III).

people with HRSD score or24 (RR1.07, 95%CI 0.901.27, P0.445) which might reflect an effectalso seen in several antidepressant trials. The result inhigher baseline scorers is comparable to that seen

with quetiapine. Whether such patients better reflectreal world patients is an important question. LowerHRSD scores in these trials were associated with highplacebo arm recovery rates.


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small number this finding was not significant (Nolenet al. 2007).

Safety, tolerability and practicability. The major con-cern with lamotrigine is the risk of serious rash, whichappears in very rare cases (three per thousand), as

opposed to benign rash (10% of patients), which canbe prevented by gradually tapering the daily dosage.Cases of severe exfoliative dermatitis and lethal Ste-venJohnson syndrome have been described as con-sequence of an allergic reaction (Bowden et al. 2004).It is recommended that clinicians strictly adhere tothe producers recommended tapering scheme. Inpatients on concomitant valproate or carbamazepine,the tapering scheme has to be adapted since valproatelowers and carbamazepine increases the metabolismof lamotrigine (Hurley 2002).

Lamotrigine does not appear to possess anti-manic properties, since both double-blind clinical

trials which focused on this aspect have been nega-tive (Grunze et al. 2009). The rate of TEAS in con-trolled studies with lamotrigine was not differentfrom placebo, possibly meaning that lamotriginemay not favour switches, but is also not especiallyprotective against treatment emergent mania. Effectsagainst mania were smaller than against depressionin the relapse prevention studies (Goodwin et al.2004).

Recommendation.For lamotrigine monotherapy, theCE would be strictly speaking E with negative

controlled studies outweighing positive studies.4The effect size of lamotrigine seems to be too smallto separate from placebo in five sponsored PhaseIII studies, and only a metaanalysis of these indi-vidual studies with large numbers can detect asmall, but significant signal triggered by the moreseverely ill patients (Geddes et al. 2009). Negativeresults of the individual trials may be due to patientselection, and if you do not have assay sensitivityin clinical trials the outcome reflects more a prop-erty of the patients than the drug. However, thetask force takes into account that lamotrigine hasshown efficacy in more severely (Geddes et al.

2009) (see above) and treatment refractorydepressed patients (Nierenberg et al. 2006; Fryeet al. 2000). A CE of E would also mean thatlamotrigine monotherapy cannot be recommended

As noticed previously, these secondary analysesmay support the drug and cast at the same timedoubt on the subjects included in the monotherapystudies.

This would fit with controlled evidence thatlamotrigine may be an effective add-on to lith-ium in bipolar depressed patients insufficiently

responsive to lithium. An investigator initiated,double-blind, placebo-controlled study found asignificant improvement in depression relatedoutcomes, including MADRS score reductionand response/remission rates, in patients receiv-ing adjunctive lamotrigine (van der Loos et al.2009). This augmentation study protocol can beconsidered as enriched for lithium nonresponse,albeit as a not clinically inappropriate design aspatients were required to have continuing depres-sion in the face of lithium use. Furthermore, asmall proof-of-concept study in treatment resis-tant bipolar depression as part of the STEP-BDprogram randomized 66 patients to lamotrigine,inositol or risperidone added to ongoing lithiumor valproate treatment (Nierenberg et al. 2006).No statistically significant difference was foundbetween treatments, but lamotrigine showednumerically clearly higher recovery rates (20%)which might, together with the study of Frye et al.(2000) warrant further research of lamotrigine-addon for treatment refractory bipolar depression.

In addition, a large randomized, double-blind,but not placebo-controlled comparison of lamotrig-ine against combined olanzapine/fluoxetine treat-

ment (Brown et al. 2006) has been conducted.Olanzapine/fluoxetine combination was superior ina number of efficacy related outcomes, including theprimary outcome (CGI-S) whereas tolerability wasbetter with lamotrigine.

Unfortunately, at present there are no large con-trolled monotherapy trials published comparinglamotrigine with a standard antidepressant. Twosmall randomized studies compared the addition oflamotrigine or an antidepressant to ongoing moodstabilizer treatment. Whereas in one study compar-ing add-on citalopram and lamotrigine no differencein reducing depressive symptomatology was observed

(Schaffer et al. 2006), the other one adding tranyl-cypromine or lamotrigine in treatment resistantbipolar depression observed numerically betteroutcomes with tranylcypromine; however due to the

4 Within the description of CE A, there is a clause In the case of existing negative studies (studies showing non-superiority to placeboor inferiority to comparator treatment), these must be outweighed by at least two more positive studies or a metaanalysis of all availablestudies showing superiority to placebo andnon-inferiority to an established comparator treatment. However, this clause is difficult toapply for lamotrigine. Although the metaanalysis is supportive, the only sufficiently powered comparative study of lamotrigine againstanother established treatment (OFC) was negative (Brown et al. 2006). Frye et al. (2000) is also not supportive evidence as gabapentincannot be considered as an established comparator treatment.


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98 H. Grunze et al.

at all, which is at odds with clinical practice andexperience, as well as especially with the positiveevidence for adjunctive use together with lithium.This study, together with the metaanalysis of themonotherapy study, might outweigh the negativeevidence from the single monotherapy studies.Thus, more members of the task force felt that a

CE B and a RG of 3 may be more appropriatefor lamotrigine monotherapy and especially forcombination treatment with lithium.

Olanzapine

Efficacy. Olanzapine was the first atypical antipsy-chotic tested in a randomized, controlled 8-weektrial (Tohen et al. 2003). Both olanzapine and thefixed combination of olanzapine and fluoxetine(OFC) were superior to placebo treatment in theprimary outcome, reduction of the MADRS score,

from week 1 onwards. However, OFC was also supe-rior to olanzapine monotherapy from week 4onwards, and the therapeutic effect size for OFCwas twice what it was for olanzapine (0.68 and0.32). Olanzapine monotherapy separated from pla-cebo in the MADRS total score, but was not supe-rior on the core depressive items, such as reportedsadness, apparent sadness, and inability to feel,whereas OFC also significantly improved theseitems. In a comparator trial, OFC was also superiorto lamotrigine in several outcomes (Brown et al.2006). These results were the basis for approval ofa fixed olanzapine/fluoxetine combination prepara-

tion for bipolar depression by the FDA, whereasolanzapine monotherapy has no label for bipolardepression.

Safety, tolerability and practicability. The adverseevents of greatest concern with olanzapine are relatedto metabolic issues and weight gain. This topic hasalready been dealt with in the recent WFSBP maniaguideline (Grunze et al. 2009) and will receive moreattention in the upcoming maintenance guideline ofthis series. For an update on this topic, we refer thereader meanwhile to a recent comprehensive review

(Kantrowitz and Citrome 2008).As far as other tolerability issues are concerned,

olanzapine was generally well tolerated as an acutetreatment. In all controlled trials until 2003, exceptfor one in acute mania, the drop out rates due toadverse events have not been significantly higherthan in patients taking placebo (McCormack andWiseman 2004). Somnolence and dizziness wereassociated significantly more frequently with olan-zapine treatment than with placebo. In the bipolardepression study of Tohen et al. (2003), the

Number-needed-to-harm (NNH) was 24 for discon-tinuation due to sedation (Gao et al. 2008a). EPS,however, were not significantly more frequent whencompared to placebo independent from dosage. Anti-cholinergic side effects like dry mouth or constipa-tion occurred in the controlled studies. Olanzapineseems to have a very safe cardiac profile, in none of

the olanzapine trials significant QTc prolongationshave been observed. However, with intramuscularinjections of olanzapine, there is an increased risk ofrespiratory arrest when patients are on concomitantbenzodiazepines.

Side effects seen more frequently with OFCthan olanzapine monotherapy were diarrhoea andnausea, otherwise the side effect profile was compa-rable (Tohen et al. 2003). Side effects significantlymore frequent with OFC than with lamotriginein the head-to head comparison included som-nolence, dizziness, sedation, dry mouth, tremor,increased appetite and weight gain, both in shortterm (Brown et al. 2006) and continuation treatment(Brown et al. 2008).

Concerning TEAS, OFC did not differ fromolanzapine or placebo in the placebo-controlledstudy, or from lamotrigine in the comparator study.Rates of treatment-emergent mania were 6.7%(23/345) for the placebo group, 5.7% (19/335) forthe olanzapine group, and 6.4% (5/78) for the olan-zapinefluoxetine group. In the comparator study,rates for TEAs were 4.0% for OFC and 5.2% forlamotrigine.

Recommendation.Both olanzapine and OFC showedefficacy in one double-blind, placebo-controlledtrial, corresponding to a CE B and RG 3. How-ever, if a choice has to be made between these two,OFC appears clearly to be the more effective alterna-tive with a more specific action on depressive coreitems as depicted by single item analysis of theMADRS and a much faster onset of antidepressantaction.

Quetiapine

Efficacy.The record of quetiapine in acute bipolardepression is substantial: five out of five double-blind,placebo-controlled studies in adults showed efficacyfor quetiapine 300 or 600 mg/day, four of them usingthe immediate release formulation (Calabrese et al.2005; Thase et al. 2006), one the extended releaseformulation (Suppes 2008). In addition, two of thesestudies had a comparator arm for assay sensitivity,in one study paroxetine (McElroy et al. 2008), in theother lithium (Young et al. 2008). Effect sizesobserved in these studies were moderate to large.


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Quetiapine was effective both in Bipolar I and IIdepression (Suppes et al. 2008) with or withoutrapid cycling (Vieta et al. 2007). Although patientswith psychotic symptoms were not excluded, thereis no information on the proportion of patients withthese symptoms, and whether their outcome differedfrom the patients without psychotic symptoms.

A feature of quetiapines pharmacology whichmight explain its better antidepressant response thanthat of other atypicals is the noradrenaline reuptakeinhibiting properties of its major metabolite nor-quetiapine (Jensen et al. 2008). There may, however,be a general problem with more sedative medicationsin placebo-controlled bipolar depression trials whichapplies not only to quetiapine. They have advantagesover non-sedative medications as they might attenu-ate antidepressant discontinuation syndromes,thereby increasing the effect size in patients previ-ously on anrtidepressant treatment. In addition, itwill be more difficult to maintain the blind in studiesgiven their sedative properties.

Safety, tolerability and practicability. The drop-outrates due to side effects were not different from pla-cebo in the quetiapine trials. As expected, somno-lence, sedation and dizziness, especially shortly aftertreatment initiation, were the most frequent sideeffects. Excesive sedation was also the primary rea-son for early study discontinuation with a NNH of7 (Gao et al. 2008a). Other side effects were mostlyof anticholinergic nature, such as dry mouth and

constipation.Extrapyramidal side effects were assessed usingthe Barnes

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