160 S. Magiria et al.AbbreviationsBD Bipolar DisorderECT Electroconvulsive TherapyHDRS-21 Hamilton Depression Rating Scale-21Li LithiumMADRS Montgomery-Asberg Depression Rating ScaleOFC Olanzapine-ﬂuoxetine combinationRCT Randomised Controlled StudiesYMRS Young Mania Rating Scale9.1 IntroductionThere have been made many important developments in the understanding of bipo-lar disorder (BD) and its treatment, during the recent years. The ﬁrst to describemanic-depressive illness as an illness of the mind were Hippocrates (460–357 BC),Galen (131–201 AD) and Areteus from Kappadokia (second century AD) who isalso considered to be the one who saw the strong connection between mania andmelancholy and his description of manic episodes was very close to modern theo-ries, including, seasonality and psychotic features. Eventually, it was Emil Kraepelin(1856–1926) who separated manic-depressive illness from schizophrenia and estab-lished it as a nosological entity on the basis of longitudinal follow-up, heredity anda relatively favourable outcome. Lately, BD-I and II subtypes were deﬁned anddescribed, and some more subtypes such as BD-III and IV have been suggested tofurther improve the nosology [1–3].BD (previously described as manic-depressive psychosis) according to the for-mal contemporary classiﬁcation consists of a depressive episode and at least onemanic (BD-I), hypomanic (BD-II), or mixed episode. Symptoms as mood altera-tions are described for several other DSM disorders which have a bipolar character. The deﬁnition ‘rapid cycling’ refers to patients who are suffering from at leastfour mood episodes in a year. Females are more often rapid-cyclers and also highersocial class subjects. In bipolar patients is common to meet psychotic featuresincluding hallucinations or delusions of any type and those features can either becongruent or non-congruent and both could occur in the context of any type of epi-sode. Substance and alcohol abuse seem to be very common problems amongpatients with BD . Recent studies report that there is an important degree of psy-chosocial impairment even during the euthymic period and suggest that only aminority of them achieves a complete functional recovery [6–12].Although BD was considered, according to traditional understanding, as an epi-sodic illness with a return to premorbid level of functioning between the episodes anda favourable outcome compared to schizophrenia , today we know that this is notalways the case  and the Kraepelinian concept largely corresponds to BD-I.
1619 Evidence Based Combination Therapy for Bipolar DisorderEarlier studies suggested that the classic manic-depressive psychosis had alifetime prevalence of around 1% (0.4–1.6%). However, the prevalence seems todepend on the deﬁnition, with the wider spectrum of bipolarity (‘the bipolar spec-trum’) having an overall rate of 3–6.5% [15–19].All the above put further more weight on the fact that the treatment approach toBD till now was too simplistic and unsatisfactory. Nowadays, the suboptimal out-come of mood disorders is better documented, and is related more to younger age ofonset and to substance and alcohol abuse. Another important issue is that 75% ofpatients who commit suicide were found to suffer from some type of mood disorder.The World Health Organization has recently ranked bipolar disorder amongst theten most disabling medical conditions world-wide .The treatment of bipolar illness still is complex and full of caveats for the clini-cians [21–23], and it seems that at least some aspects of the disorder are ratherrefractory to treatment.9.2 Combination Treatment of Acute ManiaAcute mania is the best-studied phase with a signiﬁcant number of monotherapytreatment strategies existing and with solid evidence support.Concerning combination treatment, the data are few. An older study on the com-bination of haloperidol plus lithium failed to increase response rates compared tohaloperidol alone . On the contrary a more recent study combining valproate orlithium with 2–12 mg haloperidol or 1–6 mg risperidone suggested that the combi-nation was more efﬁcacious against acute mania than adding placebo (response rate50% vs. 53% vs. 35% respectively for the combined lithium-valproate sample) .Another study reports that the combination of lithium with haloperidol at low dose(5 mg/daily) but not at high dosage (25 mg/daily) increases the efﬁcacy againstacute mania. Lorazepam was found to be of no effect neither on the low nor on thehigh dosage . Adding haloperidol on lithium was reported to be similar toadding lorazepam , but this was not a placebo controlled study. Lithium pluscarbamazepine was equal to lithium plus haloperidol , and haloperidol pluscarbamazepine was superior to haloperidol plus lithium  especially in improv-ing agitation in manic patients. Olanzapine plus carbamazepine was not better thancarbamazepine alone  and lithium plus tamoxifen was superior to lithium alone. An add-on study of gabapentin was negative  while another one of pheny-toin was positive but the sample size was small .There are also a few add-on RCTs (Randomised Controlled Studies) on the treat-ment of acute mania in patients previously considered to be partial responders tolithium or valproate.In partial responders under lithium, carbamazepine or valproate at therapeuticlevels adding 1–6 mg risperidone proved to be superior to lithium, valproate orcarbamazeprine alone (response rate: 48% vs. 31% at week 1; 61% vs. 43% atweek 3) . An 8-week trial on 52 incomplete responders to lithium utilized adding
162 S. Magiria et al.carbamazepine or oxcarbazepine (600–1,200 mg daily) during maintenance treatment.Although this trial was designed on patients in the ‘maintenance’ phase the designand the results are more relevant to the acute manic phase. The study sample con-stituted of manic, mixed and depressed patients. Both groups improved with theaddition of either of the two drugs, but those receiving oxcarbazepine improvedsigniﬁcantly more, also their YMRS score  did. In partially responsive manicpatients already receiving valproate or lithium, adding olanzapine 5–20 mg dailyimproves the outcome after 6 weeks (response rate 67.7% vs 44.7% with placebo)with a robust effect on mixed-depressive symptoms  and on suicidality . Ina 3-weeks combination treatment study, patients under lithium (0.7–1.0 mEq/L) orvalproate (50–100 mg/mL) were randomized to receive quetiapine (up to 800 mgdaily) or placebo and the response rate was higher for the quetiapine group (54.3%vs. 32.6%) . Adding up to 800 mg of quetiapine daily on lithium or valproatein partial responders, improved the response rate at week 3 (55.7% vs. 41.6% withplacebo) . However a more recent 6-week RCT does not support adding que-tiapine to lithium or valproate in partial responders . Adding aripiprazole onlithium (0.6–1.0 mmol/liter) or valproate (50–125 mg/ml) in partial responders pro-duced higher response rate at week 6 (62.8% vs. 48.5% concerning both lithiumand valproate groups) . One study reported that adding valproate to neurolep-tics improves the outcome (70% vs. 46%) .Two unpublished studies of add on ziprasidone exist and are both negative con-cerning the primary outcome. The ﬁrst utilized 80–120 mg ziprasidone daily vsplacebo on top of lithium  while the second concerned a comparison of ziprasi-done (40–80 or 80–160 mg daily) vs. placebo on top of lithium or divalproex .Data as an adjunctive therapy are negative for topiramate . There is also onenegative study for paliperidone 3–12 mg daily as adjunctive therapy to lithium orvalproate .The results of a 12-week placebo controlled study on the safety and efﬁcacy ofasenapine when added to lithium or valproate was positive. Recent trials with licar-bazepine reported negative results.A recent placebo-controlled 4-week RCT supported the efﬁcacy and safety of thepurinergic agents allopurinol and dipyridamole adjunctive to lithium in acute bipo-lar mania . Also another placebo controlled RCT supported the usefulness ofcelecoxib as an adjunct in the treatment of mixed episodes with a rapid action .Folic acid was also found to be useful as an adjunct to valproate . A small pilotstudy suggested that adding valnoctamide 600–1,200 mg/day (which is an anticon-vulsant analog of valproate that does not undergo biotransformation to the corre-sponding free acid and in mice has been shown to be distinctly less teratogenic thanvalproate) on risperidone was more efﬁcacious against acute mania in comparisonto risperidone plus placebo . A pilot study on the usefulness of adjunctiveramelteon was positive .The grading of efﬁcacy data for the acute mania/mixed treatment phase (up to12 weeks) is shown in Table 9.1.In conclusion, combination and add-on studies suggest that in acutely manicpatients partial responders to lithium, valproate or carbamazepine, a good strategy
1639 Evidence Based Combination Therapy for Bipolar DisorderTable 9.1 Grading of efﬁcacy data for the acute mania/mixed treatment phase (up to 12 weeks)Agent/modality(alphabeticalorder)Combination with:Mood stabilizer Carbamazepine Lamotrigine Lithium ValproateAripiprazole − − − GoodaGoodAsenapine − − − Good GoodHaloperidol − Fairb− Good GoodLithium − Fair − − −Olanzapine − Negative data − Good GoodOxcarbazepine − − − + −Paliperidone − − − NegativedataNegative dataQuetiapine − − − Good GoodRisperidone,oral− Good − Good GoodTopiramate Negative data − − − −Valproate − − − − −Ziprasidone − − − Negative data −aGood research-based evidence, supported by at least one placebo controlled study of sufﬁcientmagnitude. If there are non-placebo trials controlled with a comparator and with different results,the placebo controlled is the only taken into considerationbFair research-based evidence, from at least one randomised, double-blind controlled trial which,however, fail to fulﬁl all the criteria above (e.g., very small sample size or no placebo control)would be to add haloperidol, risperidone, olanzapine, quetiapine or aripiprazole.Adding oxcarbazepine to lithium is also a choice. The clinician could also choose toadd alternative agents for whose usefulness data are available (purinergic agents,celecoxib, folic acid).9.3 Combination Treatment of Acute Bipolar DepressionAcute bipolar depression is not well studied, only a limited number of RCTs existand the common practice to carry the clinical data and wisdom from the treatmentof unipolar to bipolar depression is proven to be wrong. Quetiapine is the onlymonotherapy with proven efﬁcacy.As for combination treatment, the ﬁrst add on studies used imipramine as adjunc-tive therapy on lithium in bipolar depression and were negative [52–54]. More recentlyone study used imipramine or paroxetine vs placebo as add on to lithium and reportedthat antidepressants were beneﬁcial for patients with low but not for high levels oflithium . Desipramine was reported to be equal to bupropion when added on amood stabilizer . Another study reported that adding venlafaxine, sertraline orbupropion on a mood stabilizer increases the response rate [57–59]. Similar ﬁndingswere reported for citalopram  and paroxetine and amitriptyline .RCTs fulﬁlling the modern quality standards suggest that the Olanzapine-Fluoxetine combination (OFC) is efﬁcacious against bipolar I depression with
164 S. Magiria et al.remission rates 24.5% for placebo 32.8% for olanzapine and 48.8% for the OFC.However, the study sample was small concerning the OFC arm (N = 86) .Another study suggested that the OFC is somewhat superior to lamotriginealthough the response rates did not differ between groups. (OFC: 68.8% vs. lam-otrigine 59.7%). Thus one could interpret this study as somewhat negative for theOFC since lamotrigine is proven to be non-effective. Secondary indices showedthat the time to response was signiﬁcantly shorter for the OFC-treated patients(OFC 17 days vs. lamotrigine 23 days) and there were lesser ‘suicidal and self-injurious behavior’ among OFC treated patients (OFC, 0.5% vs. lamotrigine3.4%) .In a recent double-blind, placebo-controlled study, adding an antidepressant(including paroxetine) on a mood stabilizer in 179 bipolar depressed patientswas not signiﬁcant better than placebo after 26 weeks of treatment and therecovery rates (23.5% in the antidepressant group vs. 27.3% in the placebogroup) and switch rates were similar. Thus this study does not support the use-fulness of adjunctive antidepressant therapy , while on the contrary anotherearlier one supported the usefulness of paroxetine as add on therapy .Adding L-sulpiride was similar to adding amitriptyline on lithium but the studywas not controlled . A more recent trial reported that the combination ofrisperidone plus paroxetine was not more efﬁcacious than either agent alone. However these data should be read with caution because paroxetine playeda signiﬁcant role in the design since these trials predated the negative trial ofparoxetine vs. quetiapine . A more recent study reported that adding lam-otrigine to lithium was better than placebo in patients with bipolar depression atweek 8,  however it is doubtful that the effect persists beyond week 12 [70,71]. Another recent 8-week trial on 52 incomplete responders utilized addingcarbamazepine or oxcarbazepine (600–1,200 mg daily) during maintenancetreatment with lithium. Although this trial was on patients in ‘maintenance’phase the design and the results are more relevant to the acute depressive phasesince the study sample included depressed patients. Both groups improved withthe addition of either drug but those receiving oxcarbazepine improvedsigniﬁcantly more concerning their Montgomery-Asberg Depression RatingScale (MADRS) and Hamilton Depression Rating Scale (HDRS-21) scores. A small placebo-controlled adjunctive study of aripiprazole on lithium andcitalopram was negative .Recently one study with ziprasidone was negative . The small add on studyof leviracetam was negative . A placebo controlled study suggested that inpatients with treatment-resistant bipolar depression under lithium or valproate,robust and rapid antidepressant effects resulted from a single intravenous dose ofketamine hydrochloride (an N-methyl-D-aspartate antagonist) .The grading of efﬁcacy data for the acute depressive treatment phase (up to12 weeks) is shown in Table 9.2.Treatment algorithms with adding agents on a step-by-step basis are yet to beresearched adequately .
1659 Evidence Based Combination Therapy for Bipolar DisorderTable 9.2 Grading of efﬁcacy data for the acute depressive treatment phase (up to 12 weeks)Agent/modality(alphabeticalorder)Combination with:Mood stabilizer Carbamazepine Lamotrigine Lithium ValproateAripiprazole − − − Negative data −Bupropion − Negative data − Negative data Negative dataLamotrigine − − − Gooda−Lithium − − Good − −Oxcarbazepine − − − Fairb−Paroxetine Negative data Negative data − Negative data Negative dataZiprasidone Negative data − − − −aGood research-based evidence, supported by at least one placebo controlled study of sufﬁcientmagnitude. If there are non-placebo trials controlled with a comparator and with different results,the placebo controlled is the only taken into considerationbFair research-based evidence, from at least one randomised, double-blind controlled trial which,however, fail to fulﬁl all the criteria above (e.g., very small sample size or no placebo control)9.4 Combination Treatment During the Maintenance PhaseThree combination studies with lithium plus imipramine, carbamazepine or per-phenazine and carbamazepine or valproate plus perphenazine were negative. In theﬁrst one, 22 bipolar II patients in remission for at least 6 months and randomlyassigned them to lithium, imipramine, lithium plus imipramine, or placebo. Noeffect or interaction of imipramine was found in either group . In the secondstudy, the combination of lithium plus carbamazepine did not produce furtherimprovement for patients although rapid cycling patients do better under combina-tion than under monotherapy (28.0% responded to lithium; 19.0% responded tocarbamazepine and 56.3% to their combination) . In the third study, which wasa 6-months maintenance study with a placebo-controlled double blind design ofperphenazine plus lithium, carbamazepine, or valproate or a mood stabilizer plusplacebo in patients just remitted from an acute manic episode, the results suggestedthat patients receiving perphenazine had not a better course in comparison to thosereceiving placebo, but on the contrary they had a shorter time to depressive relapse,more drop-outs, and have increased rates of dysphoria and depressive symptoms.The olanzapine-ﬂuoxetine combination (OFC) data have already been reportedabove .On the contrary, a recent placebo-controlled combination trial of quetiapine plusmood stabilizer during maintenance treatment, suggests that quetiapine is superiorto placebo in the prevention of manic and depressive recurrences in either manic,depressive, or mixed index episode over a period of 2-years [79, 80]. This combina-tion study appears to be the ﬁrst to report prevention on both depression and maniaregardless of the type of index episode.
166 S. Magiria et al.One small study of add-on gabapentin to ongoing treatment was positive howeverthe sample size was too small (N=25) . The same holds true for phenytoin ,while a small pilot study on oxcarabazepine plus lithium was negative .One placebo controlled 18-month discontinuation study on olanzapine as add onlithium or valproate during the 6-weeks acute phase suggested that patients whichresponded to the combination during the acute phase did not do longitudinally betterunder the combination than under monotherapy with lithium or valproate . Anotherdiscontinuation 6 month RCT of the combination of mood stabilizer plus ziprasidone(80–160 mg/day) vs mood stabilizer alone was in favour of the combination (relapse rate19.7% vs 32.4%; longer median time to intervention for the combination: 43.0 days vs.26.5 days) [85, 86]. Refractory patients to lithium or valproate during the acute phase arereported to beneﬁt from continuation treatment with adjunctive aripiprazole .The recently published BALANCE could neither reliably conﬁrm nor refute abeneﬁt of combination therapy compared with lithium monotherapy  at leastpartially because of methodological ﬂaws .Add on studies suggest that at least some strategies could be useful in patientswith inadequate response to monotherapy.One randomized add-on study suggested clozapine is superior to treatment asusual in the prevention of mania in refractory patients . Adding olanzapine tolithium or valproate improves outcome  and may reduce suicidality .Another study reported that valproate was more efﬁcacious than lithium when addedon antidepressants for the prevention of bipolar depression , and a recent doubleblind study suggested that adding an antidepressant (bupropion, sertraline or venla-faxine) on a mood stabilizer improved both the acute phase outcome and after 1 yearfollow up without inducing mania . One study reports that adding lamotrigineto lithium was better than placebo in patients with bipolar depression  and itsextension with the addition of paroxetine gave some additional positive results .There is also one positive add on study on long acting injectable risperidone .A 40-week placebo controlled study of the safety and efﬁcacy of Asenapinewhen added to lithium or valproate and a 40 week extension study of asenapine vs.olanzapine (Ares 7501007) are expected to be announced.The efﬁcacy data for the maintenance treatment phase is shown in Table 9.3.Overall, there is no compelling data that combination treatment does better thanmonotherapy. However patients stabilized on combination treatment might do worseif shifted to monotherapy, and patients refractory to monotherapy could beneﬁt withadd on treatment with olanzapine, valproate, an antidepressant or lamotrigine, depend-ing on the index acute phase.9.5 Combination Treatment of Mixed EpisodesMost studies include mixed patients; however they include mixed episodes togetherwith manic/hypomanic episodes. Mixed depressive cases are not usually reportedin depressive RCTs. Thus there are not much data available speciﬁcally for
1679 Evidence Based Combination Therapy for Bipolar DisorderTable 9.3 Efﬁcacy data for the maintenance treatment phaseAgent/modality(alphabeticalorder)IndexepisodeEnrichedsampleCombination with:Treatmentas usualMoodstabilizer Lamotrigine Lithium ValproateAripiprazole m Yes − − − m mLamotrigine m/d Yes − − − d −Lithium m/d No − − d − −Olanzapine m Yes − m/d − m/d m/dPerphenazine m Yes − neg − − −Quetiapine m/d Yes − m/d − m/d m/dLong-actinginjectablerisperidonem Yes m − − − −Valproate m Yes − − − − −Ziprasidone m Yes − m − m mCognitive-behavioraltherapyd No d − − − −Psychoeducation m/d No m/d − − − −m mania/mixed, d depression, m/d both mania and depressionmixed patients. Some studies report separately the outcome for mixed patients;however there is a signiﬁcant question concerning methodology that is most studiesreport the response only of the manic component of the mixed episode.Adding risperidone or haloperidol on valproate or lithium signiﬁcantly improvesthe manic component but there was no report on the depressive one . Addingolanzapine on valproate or lithium improved both components .The efﬁcacy of olanzapine versus placebo as augmentation strategy to ongoingvalproate treatment was also assessed in mixed patients during a more recent6-week, placebo-controlled RCT. This study is the only existing RCT examiningtreatment effects on mixed bipolar patients. It included 202 mixed bipolar patientsrefractory to divalproex, who were administered adjunctive olanzapine or placebo.Adjunctive olanzapine was superior to placebo in improving both manic and depres-sive symptoms. The manic component responded from day 2 and the depressivefrom day 14 . A secondary analysis of this study suggested early response of acomponent (at day 2) predicted full remission of the speciﬁc component .The meta-analysis of the olanzapine-ﬂuoxetine RCT against acute bipolar depres-sion  separated patients suffering from non-mixed versus mixed depression and reported that the response rates in patients with non-mixed versus those withmixed depression were similar in the OFC arm (48.9% vs. 43.2%; odds ratio=1.24),but somewhat differed in the olanzapine arm (39.9% vs. 26.6%; odds ratio=1.84)and in the placebo arm (27.5% vs. 16.3%; OR=1.94). OFC response was indepen-dent of the number of manic/hypomanic symptoms, whereas a higher number ofbaseline concurrent manic/hypomanic symptoms predicted a lower response rate inthe olanzapine and placebo arms .
168 S. Magiria et al.Concerning the maintenance phase, combination of quetiapine with lithiumor valproate protected from any mood episode in patients with an index mixedepisode .9.6 Combination Treatment of Rapid CyclingThere are no studies investigating the efﬁcacy of treatment modalities in rapidcycling patients. All the data we have comes from post-hoc and meta-analytic stud-ies and are poor concerning the overall response of the disorder.Combination of lithium plus carbamazepine is better for rapid cycling patientsdo better under combination than under monotherapy (28.0% responded to lithium;19.0% responded to carbamazepine and 56.3% to their combination) but not fornon-rapid cyclers . A 6-months study comparing lithium monotherapy vs. lith-ium plus valproate in rapid cycling patients with comorbid substance abuse reportedthat both options are equal, however the dropout rate was extremely high .A 12-week study of adjunct lamotrigine vs. placebo on lithium or valproate inrapid cycling depressive bipolar patients was positive . Also negative was a6-month add-on study with lamotrigine vs. or placebo monotherapy on 182 patientswith rapid-cycling bipolar disorder (DSM-IV criteria) although it showed somebeneﬁts for lamotrigine .From 1,742 bipolar I and II patients in the STEP-BD at entry, 32% met theDSM-IV criteria for rapid cycling in the pre-study year. Of the 1,742 patients, 551(32%) did not complete 1 year of treatment. Rapid cyclers were more likely to havefurther recurrences, although not necessarily more than four episodes per year. Atthe end of 12 months, only 5% of the patients could be classiﬁed as rapid cyclers.Antidepressant use during follow-up was associated with more frequent mood epi-sodes .9.7 Treatment of Comorbid ConditionsComorbidity is a signiﬁcant issue in bipolar patients and often needs speciﬁc thera-peutic intervention. Often it requires to combine the standard anti-bipolar therapywith another treatment modality.Lithium can be used for the treatment of concomitants substance abuse [100,101], quetiapine for alcohol abuse  and anxiety symptoms , while risperi-done can reduce drug craving  and anxiety . Benzodiazepines can be usedas adjunctive medication for sedation or for the treatment of anxiety, although abuse,tolerance and dependence constitute important problems. Pregabaline might be auseful agent for the treatment of anxiety disorders that commonly accompany bipo-lar illness and could substitute bendodiazepines. A signiﬁcant advantage is that it isnot metabolized in the liver. Topiramate is unique because of its ability to cause
1699 Evidence Based Combination Therapy for Bipolar Disorderweight loss at dosages of 50–200 mg daily. It is reported that more than 70% ofpatients taking topiramate for a mean duration of 5 months lost a mean of 5–6 kilo-grams. Thus topiramate could be useful to treat weight gain which is a commonproblem in bipolar patients . Naltrexone could be useful in outpatients withbipolar disorder and alcohol dependence .9.8 Combination Treatment with Other Agentsand Therapeutic ModalitiesA variety of agents and treatment modalities are useful in the treatment of bipolarillness. Benzodiazepines can be used as adjunctive medication for sedation or forthe treatment of anxiety, although abuse, tolerance and dependence constituteimportant problems. Dopaminergic agents and especially pramipexole could beuseful in the treatment of bipolar depression either as monotherapy or as add ontherapy . In refractory depressive patients, inositol  and N-acetyl cysteinefor maintenance [110, 111] could also be used as augmenting agents. Recently aplacebo-controlled study of adjunctive modaﬁnil has been shown to improve theoutcome of bipolar depression without switching to mania or hypomania ,however subclinical switches could be present . The proof of concept study foradjunct armodaﬁnil (the longer lasting isomer of modaﬁnil) on lithium, valproate orolanzapine was positive . Celecoxib was proved efﬁcient an adjunct in thetreatmentofdepressiveormixedwithrapidonsetoftheeffect.Electroconvulsivetherapy (ECT) could be a valuable option in mania [115, 116] and in treatmentresistant bipolar depression [116, 117]. Transcranial Magnetic Stimulation espe-cially when combined with brain navigation could be efﬁcient and well toleratedagainst refractory bipolar depression . Sleep deprivation and other noninvasivecircadian-related interventions could be useful add-on treatment in order to acceler-ate and sustain antidepressant response . Some data are in support of the use-fulness of omega-3 fatty acids as adjunctive therapy in bipolar depression but notmania [120–125].Naltrexone could be useful in outpatients with bipolar disorder and alcoholdependence .A list of agents studied for augmentation strategies is shown in Table 126.96.36.199 Conclusions and Future DirectionsHistorically, the modern approach in the treatment of bipolar illness starts with lithiumwhen Frederik Lange in the late 19th century , and latter John Cade in 1949[127–129] used it for the treatment of affective patients. However, Mogens Schouestablished the effectiveness of Li for the treatment of Bipolar Disorder [130, 131]
170 S. Magiria et al.Table 9.4 List of agents studied for augmentation strategiesAgent/modality Indication for augmentationCelecoxib Mania/mixedDopaminergic agents (pramipexole) Bipolar depressionElectroconvulsive therapy Bipolar depression or mania/mixedFolic acid Mania/mixedInositol Bipolar depressionModaﬁnil/armodaﬁnil Bipolar depressionN-acetyl cysteine Bipolar depressionPurinergic agents Mania/mixedSleep deprivation Bipolar depressionTranscranial magnetic stimulation Bipolar depression or mania/mixedtogether with Poul Christian Baastrup [132–134] by performing among other thingsa placebo-control discontinuation study of prophylaxis .Our knowledge concerning the treatment of BD has changed radically during thelast couple of decades. Earlier studies report a global and high effectiveness forolder agents on all facets of bipolar disorder and a high prevalence of switching withantidepressants, which were not conﬁrmed by newer studies. However the subopti-mal outcome is well established and the need to go beyond the ﬁrst line monother-apy treatment is pressing.Concerning the treatment of acute mania some studies suggest that combinationtherapies give equivocal results and do not support combination treatment as ﬁrstline treatment for all patients [24–30]. On the contrary, many combination andadd-on studies report that in acutely manic patients the combination of Li or val-proate with aripiprazole, olanzapine, risperidone, and maybe quetiapine or asenap-ine is recommended. Adding oxcarbazepine to lithium is also a choice. Anecdotaldata suggest the use of ECT or higher dosages of neuroleptics, but the data areinsufﬁcient.Unfortunately, there are few data to support a valid strategy about combinationtherapy in bipolar depressive cases. Quetiapine and the OFC are the only treatmentoptions with proven efﬁcacy against this condition. Some data on the combinationof lithium plus lamotrigine also exist.About the maintenance phase, favorable data exist concerning the OFC, quetiap-ine olanzapine or ziprasidone plus a mood stabilizer, speciﬁc antidepressants plus amood stabilizer and lithium plus lamotrigine.The paucity of data leaves the clinician with the heavy burden to decide on thebasis of clinical experience and wisdom. In this frame, existing treatment guidelinescannot be considered to rely on hard data after their ﬁrst step recommendations.Future research is essential and necessary to test possible treatment approaches forrefractory patients of all kinds. Add-on studies or combination studies might givesome kind of information; however the interpretation is complex and so far failed toprovide reliable ground for decision-making.
1719 Evidence Based Combination Therapy for Bipolar DisorderReferences1. Ng B, Camacho A, Lara DR et al (2007) A case series on the hypothesized connectionbetween dementia and bipolar spectrum disorders: bipolar type VI? J Affect Disord107:307–3152. Akiskal HS (1996) The prevalent clinical spectrum of bipolar disorders: beyond DSM-IV. JClin Psychopharmacol 16(2 Suppl 1):4S–14S3. Akiskal HS, Pinto O (1999) The evolving bipolar spectrum prototypes I, II, III, and IV.Psychiatr Clin North Am 22(3):517–534, vii4. Akiskal HS, Benazzi F (2004) Validating Kraepelin’s two types of depressive mixed states:“depression with ﬂight of ideas” and “excited depression”. World J Biol Psychiatry5(2):107–1135. Winokur G, Turvey C, Akiskal H et al (1998) Alcoholism and drug abuse in three groups—bipolar I, unipolars and their acquaintances. J Affect Disord 50(2–3):81–896. Goldberg JF, Harrow M, Grossman LS (1995) Course and outcome in bipolar affective disor-der: a longitudinal follow-up study. Am J Psychiatry 152(3):379–3847. Goldberg JF, Harrow M, Grossman LS (1995) Recurrent affective syndromes in bipolar andunipolar mood disorders at follow-up. Br J Psychiatry 166(3):382–3858. Keck PE Jr, McElroy SL, Strakowski SM et al (1998) 12-month outcome of patients with bipolardisorder following hospitalization for a manic or mixed episode. Am J Psychiatry155(5):646–6529. Strakowski SM, Keck PE Jr, McElroy SL et al (1998) Twelve-month outcome after a ﬁrsthospitalization for affective psychosis. Arch Gen Psychiatry 55(1):49–5510. Martinez-Aran A, Vieta E, Torrent C et al (2007) Functional outcome in bipolar disorder: therole of clinical and cognitive factors. Bipolar Disord 9(1–2):103–11311. Mur M, Portella MJ, Martinez-Aran A et al (2007) Persistent neuropsychological deﬁcit ineuthymic bipolar patients: executive function as a core deﬁcit. J Clin Psychiatry68(7):1078–108612. Daban C, Martinez-Aran A, Torrent C et al (2006) Speciﬁcity of cognitive deﬁcits in bipolardisorder versus schizophrenia a systematic review. Psychother Psychosom 75(2):72–8413. Kraepelin E (1921) Manic-depressive insanity and paranoia. Robertson GM, Barclay RM(translator, ed), Livingstone, Edinburgh14. Tohen M, Waternaux CM, Tsuang MT (1990) Outcome in mania. A 4-year prospective fol-low-up of 75 patients utilizing survival analysis. Arch Gen Psychiatry 47(12):1106–111115. Angst J (1998) The emerging epidemiology of hypomania and bipolar II disorder. J AffectDisord 50:143–15116. Judd LL, Akiskal HS (2003) The prevalence and disability of bipolar spectrum disorders inthe US population: re-analysis of the ECA database taking into account subthreshold cases.J Affect Disord 73(1–2):123–13117. Acorn S (1993) Mental and physical health of homeless persons who use emergency sheltersin Vancouver. Hosp Community Psychiatry 44(9):854–85718. Angst J, Azorin JM, Bowden CL et al (2011) Prevalence and characteristics of undiagnosedbipolar disorders in patients with a major depressive episode: the BRIDGE study. Arch GenPsychiatry 68(8):791–79819. Angst J, Gamma A, Bowden CL et al (2011) Diagnostic criteria for bipolarity based on aninternational sample of 5,635 patients with DSM-IV major depressive episodes. Eur ArchPsychiatry Clin Neurosci20. World Health Organization (2003) The world health report 2003—shaping the future. WHO,Geneva21. Fountoulakis KN, Grunze H, Panagiotidis P et al (2008) Treatment of bipolar depression: anupdate. J Affect Disord 109(1–2):21–3422. Fountoulakis KN, Vieta E, Sanchez-Moreno J et al (2005) Treatment guidelines for bipolardisorder: a critical review. J Affect Disord 86(1):1–10
172 S. Magiria et al.23. Fountoulakis KN, Vieta E, Siamouli M et al (2007) Treatment of bipolar disorder: a complextreatment for a multi-faceted disorder. Ann Gen Psychiatry 6:2724. Garﬁnkel PE, Stancer HC, Persad E (1980) A comparison of haloperidol, lithium carbonateand their combination in the treatment of mania. J Affect Disord 2(4):279–28825. Sachs GS, Grossman F, Ghaemi SN et al (2002) Combination of a mood stabilizer withrisperidone or haloperidol for treatment of acute mania: a double-blind, placebo-controlledcomparison of efﬁcacy and safety. Am J Psychiatry 159(7):1146–115426. Chou JC, Czobor P, Charles O et al (1999) Acute mania: haloperidol dose and augmentationwith lithium or lorazepam. J Clin Psychopharmacol 19(6):500–50527. Lenox RH, Newhouse PA, Creelman WL et al (1992) Adjunctive treatment of manicagitation with lorazepam versus haloperidol: a double-blind study. J Clin Psychiatry53(2):47–5228. Small JG, Klapper MH, Marhenke JD et al (1995) Lithium combined with carbamazepine orhaloperidol in the treatment of mania. Psychopharmacol Bull 31(2):265–27229. Klein E, Bental E, Lerer B et al (1984) Carbamazepine and haloperidol v placebo andhaloperidol in excited psychoses a controlled study. Arch Gen Psychiatry 41(2):165–17030. Tohen M, Bowden CL, Smulevich AB et al (2008) Olanzapine plus carbamazepine v.carbamazepine alone in treating manic episodes. Br J Psychiatry 192(2):135–14331. Amrollahi Z, Rezaei F, Salehi B, et al (2010) Double-blind, randomized, placebo-controlled6-week study on the efﬁcacy and safety of the tamoxifen adjunctive to lithium in acute bipolarmania. J Affect Disord (in press)32. Pande AC, Crockatt JG, Janney CA et al (2000) Gabapentin in bipolar disorder: a placebo-controlled trial of adjunctive therapy gabapentin bipolar disorder study group. Bipolar Disord2(3 Pt 2):249–25533. Mishory A, Yaroslavsky Y, Bersudsky Y et al (2000) Phenytoin as an antimanic anticonvul-sant: a controlled study. Am J Psychiatry 157(3):463–46534. Yatham LN, Grossman F, Augustyns I et al (2003) Mood stabilisers plus risperidone orplacebo in the treatment of acute mania. International, double-blind, randomised controlledtrial. Br J Psychiatry 182:141–14735. Juruena MF, Ottoni GL, Machado-Vieira R et al (2009) Bipolar I and II disorder residualsymptoms: oxcarbazepine and carbamazepine as add-on treatment to lithium in a double-blind, randomized trial. Prog Neuropsychopharmacol Biol Psychiatry 33(1):94–9936. Tohen M, Chengappa KN, Suppes T et al (2002) Efﬁcacy of olanzapine in combination withvalproate or lithium in the treatment of mania in patients partially nonresponsive to valproateor lithium monotherapy. Arch Gen Psychiatry 59(1):62–6937. Houston JP, Ahl J, Meyers AL et al (2006) Reduced suicidal ideation in bipolar I disordermixed-episode patients in a placebo-controlled trial of olanzapine combined with lithium ordivalproex. J Clin Psychiatry 67(8):1246–125238. Sachs G, Chengappa KN, Suppes T et al (2004) Quetiapine with lithium or divalproex for thetreatment of bipolar mania: a randomized, double-blind, placebo-controlled study. BipolarDisord 6(3):213–22339. Yatham LN, Paulsson B, Mullen J et al (2004) Quetiapine versus placebo in combinationwith lithium or divalproex for the treatment of bipolar mania. J Clin Psychopharmacol24(6):599–60640. Yatham LN, Vieta E, Young AH et al (2007) A double blind, randomized, placebo-controlledtrial of quetiapine as an add-on therapy to lithium or divalproex for the treatment of bipolarmania. Int Clin Psychopharmacol 22(4):212–22041. Vieta E, T’Joen C, McQuade RD et al (2008) Efﬁcacy of adjunctive aripiprazole to eithervalproate or lithium in bipolar mania patients partially nonresponsive to valproate/lithiummonotherapy: a placebo-controlled study. Am J Psychiatry 165(10):1316–132542. Muller-Oerlinghausen B, Retzow A, Henn FA et al (2000) Valproate as an adjunct toneuroleptic medication for the treatment of acute episodes of mania: a prospective,randomized, double-blind, placebo-controlled, multicenter study European ValproateMania Study Group. J Clin Psychopharmacol 20(2):195–203
1739 Evidence Based Combination Therapy for Bipolar Disorder43. Weisler R, Dunn J, English P (2003) Adjunctive Ziprasidone for acute bipolar mania:randomized, placebo-controlled trial. 4th international forum on mood and anxiety disorders,November 19–21, Monte Carlo, Monaco 200344. unpublished A three-week, double-blind, multicenter, placebo-controlled study evaluatingthe efﬁcacy and safety of add-on oral ziprasidone in subjects with acute mania treated withlithium or divalproex 2011 [September 5th, 2011]. Available from: http://www.clinical-studyresults.org/documents/company-study_9884_0.pdf45. Roy Chengappa KN, Schwarzman LK, Hulihan JF et al (2006) Adjunctive topiramate therapyin patients receiving a mood stabilizer for bipolar I disorder: a randomized, placebo-controlledtrial. J Clin Psychiatry 67(11):1698–170646. Berwaerts J, Lane R, Nuamah IF, et al (2010) Paliperidone extended-release as adjunctivetherapy to lithium or valproate in the treatment of acute mania: a randomized, placebo-controlled study. J Affect Disord (in press)47. Machado-Vieira R, Soares JC, Lara DR et al (2008) A double-blind, randomized, placebo-controlled 4-week study on the efﬁcacy and safety of the purinergic agents allopurinol anddipyridamole adjunctive to lithium in acute bipolar mania. J Clin Psychiatry 69(8):1237–124548. Nery FG, Monkul ES, Hatch JP et al (2008) Celecoxib as an adjunct in the treatment ofdepressive or mixed episodes of bipolar disorder: a double-blind, randomized, placebo-con-trolled study. Hum Psychopharmacol 23(2):87–9449. Behzadi AH, Omrani Z, Chalian M et al (2009) Folic acid efﬁcacy as an alternative drugadded to sodium valproate in the treatment of acute phase of mania in bipolar disorder: adouble-blind randomized controlled trial. Acta Psychiatr Scand 120(6):441–44550. Bersudsky Y, Applebaum J, Gaiduk Y et al (2010) Valnoctamide as a valproate substitutewith low teratogenic potential in mania: a double-blind, controlled, add-on clinical trial.Bipolar Disord 12(4):376–38251. McElroy SL, Winstanley EL, Martens B et al (2010) A randomized, placebo-controlled studyof adjunctive ramelteon in ambulatory bipolar I disorder with manic symptoms and sleepdisturbance. Int Clin Psychopharmacol 26(1):48–5352. Prien RF, Kupfer DJ, Mansky PA et al (1984) Drug therapy in the prevention of recurrencesin unipolar and bipolar affective disorders. Report of the NIMH Collaborative Study Groupcomparing lithium carbonate, imipramine, and a lithium carbonate-imipramine combination.Arch Gen Psychiatry 41(11):1096–110453. Prien RF, Klett CJ, Caffey EM Jr (1973) Lithium carbonate and imipramine in preventionof affective episodes. A comparison in recurrent affective illness. Arch Gen Psychiatry29(3):420–42554. Kane JM, Quitkin FM, Rifkin A et al (1982) Lithium carbonate and imipramine in theprophylaxis of unipolar and bipolar II illness: a prospective, placebo-controlled comparison.Arch Gen Psychiatry 39(9):1065–106955. Nemeroff CB, Evans DL, Gyulai L et al (2001) Double-blind, placebo-controlled compari-son of imipramine and paroxetine in the treatment of bipolar depression. Am J Psychiatry158(6):906–91256. Sachs GS, Lafer B, Stoll AL et al (1994) A double-blind trial of bupropion versus desipra-mine for bipolar depression. J Clin Psychiatry 55(9):391–39357. Post RM, Altshuler LL, Frye MA et al (2001) Rate of switch in bipolar patients prospectivelytreated with second-generation antidepressants as augmentation to mood stabilizers. BipolarDisord 3(5):259–26558. Post RM, Altshuler LL, Leverich GS et al (2006) Mood switch in bipolar depression: com-parison of adjunctive venlafaxine, bupropion and sertraline. Br J Psychiatry 189:124–13159. Altshuler LL, Post RM, Hellemann G et al (2009) Impact of antidepressant continuation afteracute positive or partial treatment response for bipolar depression: a blinded, randomizedstudy. J Clin Psychiatry 70(4):450–45760. Schaffer A, Zuker P, Levitt A (2006) Randomized, double-blind pilot trial comparing lam-otrigine versus citalopram for the treatment of bipolar depression. J Affect Disord96(1–2):95–99
174 S. Magiria et al.61. Pilhatsch M, Wolf R, Winter C et al (2010) Comparison of paroxetine and amitriptyline asadjunct to lithium maintenance therapy in bipolar depression: a reanalysis of a randomized,double-blind study. J Affect Disord 126(3):453–45762. Tohen M, Vieta E, Calabrese J et al (2003) Efﬁcacy of olanzapine and olanzapine-ﬂuoxetine combination in the treatment of bipolar I depression. Arch Gen Psychiatry60(11):1079–108863. Brown EB, McElroy SL, Keck PE Jr et al (2006) A 7-week, randomized, double-blind trialof olanzapine/ﬂuoxetine combination versus lamotrigine in the treatment of bipolar I depres-sion. J Clin Psychiatry 67(7):1025–103364. Sachs GS, Nierenberg AA, Calabrese JR et al (2007) Effectiveness of adjunctive antidepres-sant treatment for bipolar depression. N Engl J Med 356(17):1711–172265. Young LT, Joffe RT, Robb JC et al (2000) Double-blind comparison of addition of a secondmood stabilizer versus an antidepressant to an initial mood stabilizer for treatment of patientswith bipolar depression. Am J Psychiatry 157(1):124–12666. Bocchetta A, Bernardi F, Burrai C et al (1993) A double-blind study of L-sulpiride versusamitriptyline in lithium-maintained bipolar depressives. Acta Psychiatr Scand 88(6):434–43967. Shelton RC, Stahl SM (2004) Risperidone and paroxetine given singly and in combinationfor bipolar depression. J Clin Psychiatry 65(12):1715–171968. McElroy SL, Weisler RH, Chang W et al (2010) A double-blind, placebo-controlled study ofquetiapine and paroxetine as monotherapy in adults with bipolar depression (EMBOLDENII). J Clin Psychiatry 71(2):163–17469. van der Loos ML, Mulder PG, Hartong EG et al (2009) Efﬁcacy and safety of lamotrigine asadd-on treatment to lithium in bipolar depression: a multicenter, double-blind, placebo-controlled trial. J Clin Psychiatry 70(2):223–23170. van der Loos ML, Mulder P, Hartong EG et al (2011) Long-term outcome of bipolar depressedpatients receiving lamotrigine as add-on to lithium with the possibility of the addition ofparoxetine in nonresponders: a randomized, placebo-controlled trial with a novel design.Bipolar Disord 13(1):111–11771. van der Loos ML, Mulder P, Hartong EG et al (2010) Efﬁcacy and safety of two treatmentalgorithms in bipolar depression consisting of a combination of lithium, lamotrigine orplacebo and paroxetine. Acta Psychiatr Scand 122(3):246–25472. Quante A, Zeugmann S, Luborzewski A et al (2010) Aripiprazole as adjunct to a moodstabilizer and citalopram in bipolar depression: a randomized placebo-controlled pilot study.Hum Psychopharmacol 25(2):126–13273. Sachs GS, Ice KS, Chappell PB et al (2011) Efﬁcacy and safety of adjunctive oral ziprasidonefor acute treatment of depression in patients with bipolar I disorder: a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry 72:141374. Saricicek A, Maloney K, Muralidharan A et al (2010) Lvetiracetam in the management ofbipolar depression: a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry72:744–75075. Diazgranados N, Ibrahim L, Brutsche NE et al (2010) A randomized add-on trial of anN-methyl-D-aspartate antagonist in treatment-resistant bipolar depression. Arch Gen Psychiatry67(8):793–80276. Denicoff KD, Smith-Jackson EE, Disney ER et al (1997) Comparative prophylactic efﬁcacyof lithium, carbamazepine, and the combination in bipolar disorder. J Clin Psychiatry58(11):470–47877. Zarate CA Jr, Tohen M (2004) Double-blind comparison of the continued use of antipsy-chotic treatment versus its discontinuation in remitted manic patients. Am J Psychiatry161(1):169–17178. Brown E, Dunner DL, McElroy SL et al (2009) Olanzapine/ﬂuoxetine combination vs. lamotriginein the 6-month treatment of bipolar I depression. Int J Neuropsychopharmacol 12(6):773–78279. Vieta E, Suppes T, Eggens I et al (2008) Efﬁcacy and safety of quetiapine in combinationwith lithium or divalproex for maintenance of patients with bipolar I disorder (internationaltrial 126). J Affect Disord 109(3):251–263
1759 Evidence Based Combination Therapy for Bipolar Disorder80. Suppes T, Vieta E, Liu S et al (2009) Maintenance treatment for patients with bipolar I disorder:results from a north american study of quetiapine in combination with lithium or divalproex(trial 127). Am J Psychiatry 166(4):476–48881. Vieta E, Manuel Goikolea J, Martinez-Aran A et al (2006) A double-blind, randomized,placebo-controlled, prophylaxis study of adjunctive gabapentin for bipolar disorder. J ClinPsychiatry 67(3):473–47782. Mishory A, Winokur M, Bersudsky Y (2003) Prophylactic effect of phenytoin in bipolardisorder: a controlled study. Bipolar Disord 5(6):464–46783. Vieta E, Cruz N, Garcia-Campayo J et al (2008) A double-blind, randomized, placebo-controlledprophylaxis trial of oxcarbazepine as adjunctive treatment to lithium in the long-term treatmentof bipolar I and II disorder. Int J Neuropsychopharmacol 11(4):445–45284. Tohen M, Chengappa KN, Suppes T et al (2004) Relapse prevention in bipolar I disorder:18-month comparison of olanzapine plus mood stabiliser v. mood stabiliser alone. Br JPsychiatry 184:337–34585. Bowden CL, Vieta E, Ice KS et al (2010) Ziprasidone plus a mood stabilizer in subjects withbipolar I disorder: a 6-month, randomized, placebo-controlled, double-blind trial. J ClinPsychiatry 71(2):130–13786. Citrome L (2010) Ziprasidone HCl capsules for the adjunctive maintenance treatment ofbipolar disorder in adults. Expert Rev Neurother 10(7):1031–103787. Marcus R, Khan A, Rollin L et al (2011) Efﬁcacy of aripiprazole adjunctive to lithium orvalproate in the long-term treatment of patients with bipolar I disorder with an inadequateresponse to lithium or valproate monotherapy: a multicenter, double-blind, randomized study.Bipolar Disord 13(2):133–14488. Geddes JR, Goodwin GM, Rendell J et al (2010) Lithium plus valproate combination therapyversus monotherapy for relapse prevention in bipolar I disorder (BALANCE): a randomisedopen-label trial. Lancet 375(9712):385–39589. Fountoulakis KN (2010) The BALANCE trial. Lancet 375(9723):1343–1344, author reply134490. Suppes T, Webb A, Paul B et al (1999) Clinical outcome in a randomized 1-year trial ofclozapine versus treatment as usual for patients with treatment-resistant illness and a historyof mania. Am J Psychiatry 156(8):1164–116991. Gyulai L, Bowden CL, McElroy SL et al (2003) Maintenance efﬁcacy of divalproex in theprevention of bipolar depression. Neuropsychopharmacology 28(7):1374–138292. Macfadden W, Alphs L, Haskins JT et al (2009) A randomized, double-blind, placebo-controlled study of maintenance treatment with adjunctive risperidone long-acting ther-apy in patients with bipolar I disorder who relapse frequently. Bipolar Disord11(8):827–83993. Houston JP, Tohen M, Degenhardt EK et al (2009) Olanzapine-divalproex combinationversus divalproex monotherapy in the treatment of bipolar mixed episodes: a double-blind,placebo-controlled study. J Clin Psychiatry 70(11):1540–154794. Houston JP, Ketter TA, Case M et al (2011) Early symptom change and prediction of subse-quent remission with olanzapine augmentation in divalproex-resistant bipolar mixed episodes.J Psychiatr Res 45(2):169–17395. Benazzi F, Berk M, Frye MA et al (2009) Olanzapine/ﬂuoxetine combination for the treatmentof mixed depression in bipolar I disorder: a post hoc analysis. J Clin Psychiatry70(10):1424–143196. Kemp DE, Gao K, Ganocy SJ et al (2009) A 6-month, double-blind, maintenance trial oflithium monotherapy versus the combination of lithium and divalproex for rapid-cyclingbipolar disorder and co-occurring substance abuse or dependence. J Clin Psychiatry70(1):113–12197. Wang Z, Gao K, Kemp DE et al (2010) Lamotrigine adjunctive therapy to lithium and dival-proex in depressed patients with rapid cycling bipolar disorder and a recent substance usedisorder: a 12-week, double-blind, placebo-controlled pilot study. Psychopharmacol Bull43(4):5–21
176 S. Magiria et al.98. Calabrese JR, Suppes T, Bowden CL et al (2000) A double-blind, placebo-controlled, pro-phylaxis study of lamotrigine in rapid-cycling bipolar disorder. Lamictal 614 study group. JClin Psychiatry 61(11):841–85099. Schneck CD, Miklowitz DJ, Miyahara S et al (2008) The prospective course of rapid-cyclingbipolar disorder: ﬁndings from the STEP-BD. Am J Psychiatry 165:370–377100. Geller B, Cooper TB, Sun K et al (1998) Double-blind and placebo-controlled study of lith-ium for adolescent bipolar disorders with secondary substance dependency. J Am Acad ChildAdolesc Psychiatry 37(2):171–178101. Geller B, Cooper TB, Watts HE et al (1992) Early ﬁndings from a pharmacokineticallydesigned double-blind and placebo-controlled study of lithium for adolescents comorbid withbipolar and substance dependency disorders. Prog Neuropsychopharmacol Biol Psychiatry16(3):281–299102. Brown ES, Garza M, Carmody TJ (2008) A randomized, double-blind, placebo-controlledadd-on trial of quetiapine in outpatients with bipolar disorder and alcohol use disorders.J Clin Psychiatry 69(5):701–705103. Lydiard RB, Culpepper L, Schioler H et al (2009) Quetiapine monotherapy as treatment foranxiety symptoms in patients with bipolar depression: a pooled analysis of results from 2double-blind, randomized, placebo-controlled studies. Prim Care Companion J ClinPsychiatry 11(5):215–225104. Nejtek VA, Avila M, Chen LA et al (2008) Do atypical antipsychotics effectively treatco-occurring bipolar disorder and stimulant dependence? A randomized, double-blindtrial. J Clin Psychiatry 69(8):1257–1266105. Sheehan DV, McElroy SL, Harnett-Sheehan K et al (2009) Randomized, placebo-controlledtrial of risperidone for acute treatment of bipolar anxiety. J Affect Disord 115(3):376–385106. Arnone D (2005) Review of the use of Topiramate for treatment of psychiatric disorders. AnnGen Psychiatry 4(1):5107. Sherwood Brown E, Carmody TJ, Schmitz JM et al (2009) A randomized, double-blind,placebo-controlled pilot study of naltrexone in outpatients with bipolar disorder and alcoholdependence. Alcohol Clin Exp Res 33(11):1863–1869108. Zarate CA Jr, Payne JL, Singh J et al (2004) Pramipexole for bipolar II depression: a placebo-controlled proof of concept study. Biol Psychiatry 56(1):54–60109. Eden Evins A, Demopulos C, Yovel I et al (2006) Inositol augmentation of lithium orvalproate for bipolar depression. Bipolar Disord 8(2):168–174110. Berk M, Copolov DL, Dean O et al (2008) N-acetyl cysteine for depressive symptoms inbipolar disorder—a double-blind randomized placebo-controlled trial. Biol Psychiatry64(6):468–475111. Magalhaes PV, Dean OM, Bush AI et al (2011) N-acetyl cysteine add-on treatment for bipolarII disorder: a subgroup analysis of a randomized placebo-controlled trial. J Affect Disord129(1–3):317–320112. Frye MA, Grunze H, Suppes T et al (2007) A placebo-controlled evaluation of adjunctivemodaﬁnil in the treatment of bipolar depression. Am J Psychiatry 164(8):1242–1249113. Fountoulakis KN, Siamouli M, Panagiotidis P et al (2008) Ultra short manic-like episodesafter antidepressant augmentation with modaﬁnil. Prog Neuropsychopharmacol BiolPsychiatry 32(3):891–892114. Calabrese JR, Ketter TA, Youakim JM et al (2010) Adjunctive armodaﬁnil for major depres-sive episodes associated with bipolar I disorder: a randomized, multicenter, double-blind,placebo-controlled, proof-of-concept study. J Clin Psychiatry 71(10):1363–1370115. Hiremani RM, Thirthalli J, Tharayil BS et al (2008) Double-blind randomized controlledstudy comparing short-term efﬁcacy of bifrontal and bitemporal electroconvulsive therapy inacute mania. Bipolar Disord 10(6):701–707116. Loo C, Katalinic N, Mitchell PB et al (2010) Physical treatments for bipolar disorder: areview of electroconvulsive therapy, stereotactic surgery and other brain stimulation tech-niques. J Affect Disord 132:1–13
1779 Evidence Based Combination Therapy for Bipolar Disorder117. Kessler U, Vaaler AE, Schoyen H et al (2010) The study protocol of the Norwegian random-ized controlled trial of electroconvulsive therapy in treatment resistant depression in bipolardisorder. BMC Psychiatry 10(1):16118. Dell’Osso B, Mundo E, D’Urso N et al (2009) Augmentative repetitive navigated transcranialmagnetic stimulation (rTMS) in drug-resistant bipolar depression. Bipolar Disord 11(1):76–81119. Wu JC, Kelsoe JR, Schachat C et al (2009) Rapid and sustained antidepressant response withsleep deprivation and chronotherapy in bipolar disorder. Biol Psychiatry 66(3):298–301120. Sarris J, Mischoulon D, Schweitzer I (2011) Omega-3 for bipolar disorder: meta-analyses ofuse in mania and bipolar depression. J Clin Psychiatry 73:81–86121. Frangou S, Lewis M, McCrone P (2006) Efﬁcacy of ethyl-eicosapentaenoic acid in bipolardepression: randomised double-blind placebo-controlled study. Br J Psychiatry 188:46–50122. Frangou S, Lewis M, Wollard J et al (2007) Preliminary in vivo evidence of increasedN-acetyl-aspartate following eicosapentanoic acid treatment in patients with bipolar disorder.J Psychopharmacol 21(4):435–439123. Keck PE Jr, Mintz J, McElroy SL et al (2006) Double-blind, randomized, placebo-controlledtrials of ethyl-eicosapentanoate in the treatment of bipolar depression and rapid cycling bipo-lar disorder. Biol Psychiatry 60(9):1020–1022124. Chiu CC, Huang SY, Chen CC et al (2005) Omega-3 fatty acids are more beneﬁcial in thedepressive phase than in the manic phase in patients with bipolar I disorder. J Clin Psychiatry66(12):1613–1614125. Stoll AL, Severus WE, Freeman MP et al (1999) Omega 3 fatty acids in bipolar disorder: apreliminary double-blind, placebo-controlled trial. Arch Gen Psychiatry 56(5):407–412126. Lange F (1894) De vigtigste sindssygdomme (The most important pychiatric disorders).Gyldendal, Copenhagen127. Cade J (1949) Lithium salts in the treatment of psychotic excitement. Med J Aust36:349–352128. Cade J (1970) The story of lithium. In: Ayd F, Blackwell B (eds) Discoveries in biologicalpsychiatry. Lippincott, Philadelphia129. Bech P (2006) The full story of lithium. A tribute to Mogens Schou (1918–2005). PsychotherPsychosom 75(5):265–269130. Schou M, Juel-Nielsen N, Stromgren E et al (1954) The treatment of manic psychosis by theadministration of lithium salts. J Neurol Neurosurg Psychiatry 17:250–260131. Schou M (1997) Forty years of lithium treatment. Arch Gen Psychiatry 54:9132. Baastrup P (1964) The use of lithium in manic-depressive psychosis. Compr Psychiatry5:396–408133. Baastrup PC, Schou M (1967) Lithium as a prophylactic agents its effect against recurrentdepressions and manic-depressive psychosis. Arch Gen Psychiatry 16(2):162–172134. Schou M, Baastrup PC (1967) Lithium treatment of manic-depressive disorder dosage andcontrol. JAMA 201(9):696–698135. Baastrup PC, Poulsen JC, Schou M et al (1970) Prophylactic lithium: double blind discon-tinuation in manic-depressive and recurrent-depressive disorders. Lancet 2(7668):326–330