Review

Is the combination of a mood stabilizer plus an antipsychoticmore effective than mono-therapies in long-term treatmentof bipolar disorder? A systematic review

Massimiliano Buoli n, Marta Serati, A. Carlo AltamuraDepartment of Psychiatry, University of Milan, Fondazione IRCCS Ca'Granda Ospedale Maggiore Policlinico, Via F. Sforza 35, 20122 Milan, Italy

a r t i c l e i n f o

Article history:Received 10 May 2013Received in revised form24 July 2013Accepted 20 August 2013Available online 31 August 2013

Keywords:Bipolar DisorderMood stabilizersAntipsychoticsCombined treatment

a b s t r a c t

Background: Bipolar Disorder (BD) long-term treatment is aimed to prevent relapses associated withworsening cognitive impairment and chronicity. Available mood stabilizers, including lithium, fail toprevent relapses in about 40% of bipolar patients. Purpose of the present paper is to review the availabledata about the efficacy and tolerability of mood stabilizer plus antipsychotic combined treatments.Method: A research in the main database sources has been conducted to obtain an overview about theefficacy and tolerability of the combination of a mood stabilizer plus an antipsychotic in the long-termtreatment of BD. Papers with different methodologies but having relapse prevention as main outcomehave been included.Results: Despite the heterogeneity of studies in terms of methodology, almost all papers reported a majorefficacy of combined treatments respect to mood stabilizer mono-therapies but lower tolerability. Theantipsychotic that presents more evidence of efficacy in combination with mood stabilizers is quetiapine.Discussion: Combined treatments can be a valid option to improve relapse prevention in BD. However,the higher risk for side effects has to be taken into account and specific combinations should be preferredaccording to patients' medical comorbidity.

& 2013 Elsevier B.V. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132. Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133. Mood stabilizer plus first generation antipsychotic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

3.1. Haloperidol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133.2. Flupenthixol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

4. Mood stabilizer plus second generation antipsychotic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144.1. Risperidone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144.2. Risperidone long-acting. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144.3. Olanzapine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144.4. Quetiapine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144.5. Aripiprazole . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154.6. Ziprasidone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

5. Tolerability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155.1. First-generation antipsychotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155.2. Risperidone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155.3. Risperidone long-acting. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155.4. Olanzapine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155.5. Quetiapine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165.6. Aripiprazole . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165.7. Ziprasidone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

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Journal of Affective Disorders

0165-0327/$ - see front matter & 2013 Elsevier B.V. All rights reserved.http://dx.doi.org/10.1016/j.jad.2013.08.024

n Corresponding author. Tel.: þ39 02 55035934; fax: þ39 02 55033190.E-mail address: massimiliano.buoli@hotmail.it (M. Buoli).

Journal of Affective Disorders 152-154 (2014) 12–18

6. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16Role of funding source . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16Conflict of interest. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16Acknowledgment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

1. Introduction

Bipolar Disorder (BD) is a disabling condition affecting about 1%of European population (Pini et al., 2005) and Bipolar SpectrumDisorders can show a prevalence till 8% in general population(Judd and Akiskal, 2003). Despite BD enormous social burden,the diagnosis of this condition is often delayed with obviousimplications for outcome (Altamura et al., 2010). Objectives ofBD treatment include not only the resolution of acute episodes,but also the prevention of relapses (maintenance treatment)(Fountoulakis et al., 2012). The importance of maintenance treat-ment has been remarked in last years in light of

- negative impact of number of episodes on cognition (Bellivier,2012),

- association between relapses and brain changes (Strakowskiet al., 2002), and

- poor quality of life in patients with numerous mood episodes(Scott and Colom, 2005).

Mood stabilizers, with most of the data about lithium, havetotally changed long-term prognosis of bipolar patients (Malhiet al., 2012). These molecules (with obvious differences amongthem) showed their superiority respect to placebo both in acuteepisodes and in relapse prevention (Licht, 2012). On the otherhand the coming of atypical antipsychotics helped the clinicians tohave a rapid resolution of manic symptoms with a limiteddepressive switch and to ameliorate psychotic symptoms thatare poorly controlled by traditional mood stabilizers (Bourin andThibaut, 2013).

However, despite the available treatment options, unmet needsstill remain. First, some patients experience full-blown relapsesdespite long-term mono-therapies with mood stabilizers. Forexample in a long-term study a mean relapse rate of 40% wasreported for bipolar patients treated with lithium (Geddes et al.,2004). A relapse rate of 67.15% was reported for valproate mono-therapy in a 4-year follow-up study (Altamura et al., 2008).Second, sub-threshold episodes are unsatisfactorily prevented bymood stabilizer mono-therapies and complicate BD outcome(Homish et al., 2013). Finally some clinical dimensions such aspsychotic and cognitive ones are poorly improved by long-term bymood stabilizer mono-therapies (Mora et al., 2012). Combinedtreatments with a mood stabilizer plus an atypical antipsychoticmight be a valid option to satisfy the described unmet needs. Inlight of these considerations purpose of the present paper is acritical review of the available data about combination of anti-psychotics plus mood stabilizers in long-term treatment of BD.

2. Methods

A careful search of articles on MEDLINE, PsycINFO, Isi Web ofKnowledge, Medscape was performed in order to obtain a com-prehensive review about the combination of an antipsychotic plusa mood stabilizer in the maintenance treatment of BD. Papers withrelapse prevention as main endpoint were selected, being euthy-mia maintenance the most frequent outcome measure among

long-term studies. In particular, the word “Bipolar Disorder” hasbeen associated with “maintenance treatment”, “relapse preven-tion”, “antipsychotic”, and “mood stabilizers”. No restriction cri-teria were established in relation to study design, but efficacystudies had to be longer than 12 weeks. All types of publications,including letter to the editors, were considered. Papers from 1980to 2013, mostly in English, have been included. For the preparationof this paper the indications of PRISMA statement have been takeninto account (Liberati et al., 2009; Moher et al., 2009).

According to the criteria described above, 1086 papers wereinitially identified. 520 out of 1086 related to the pharmacologicaltreatment and 186 out of 520 had prevention of relapse as mainoutcome. Nineteen studies were finally considered as they eval-uated the effectiveness of the combination of a mood stabilizerplus an antipsychotic.

Finally, evidence rating was attributed according to the numberof double-blind placebo-controlled trials and the presence of anadequate total sample size (4200)

Level A: at least three double-blind placebo-controlled trialswith a total sample size 4200.Level B: at least two double-blind placebo-controlled trialswith a total sample size 4200.Level C: at least one double-blind placebo-controlled trials witha total sample size 4200.Level D: at least two open-label studies with a total sample size4200 or one double blind-placebo controlled trial with asample size o200.Level E: case reports.Level F: no studies.

These rating criteria are a modified version of PORT criteria(Lehman and Steinwachs, 1998).

3. Mood stabilizer plus first generation antipsychotic

Few studies have investigated the efficacy of combined treat-ments with a mood stabilizer and a neuroleptic in light of thedepressogenic effects of first generation antipsychotics and pooreffects of neuroleptic mono-therapies in preventing relapses ofbipolars (Bourin et al., 2005).

3.1. Haloperidol

Haloperidol decanoate injections (100–400 mg monthly formore than 3 years) were given to 12 patients treated with lithium,showing beneficial effects on hypomanic relapse prevention (Loweand Batchelor, 1986) (Level E).

3.2. Flupenthixol

A 2-year double-blind placebo-controlled study comparedbipolars treated with lithium versus patients treated with acombination of lithium and flupenthixol injections every 4 weeks.No differences were found between groups in terms of days of

M. Buoli et al. / Journal of Affective Disorders 152-154 (2014) 12–18 13

hospitalization. Affective symptoms were significantly worse influpenthixol group (Esparon et al., 1986).

4. Mood stabilizer plus second generation antipsychotic

The efficacy of atypical antipsychotics in the long-term treat-ment of BD is corroborated by different studies. In a large samplesize study olanzapine (15 mg/day) revealed non-inferiority withrespect to lithium in preventing recurrences of any polarity duringthe 12-month follow-up period: recurrences occurred in 30.0% ofolanzapine-treated patients and in 38.8% of lithium-treatedpatients (Tohen et al., 2005). In addition, in patients stabilizedduring acute quetiapine treatment (300–800 mg/day), continua-tion of quetiapine was shown to significantly increase time torecurrence of any mood, manic, or depressive event comparedwith switching to placebo (HR¼0.29) (Weisler et al., 2011). Similarresults were found for aripiprazole (15–30 mg/day) in a 26 weekfollow-up study (relapses in 25% of active treatment group versus43% of placebo) (Keck et al., 2006) and for paliperidone (3–12 mg/day) in an olanzapine-controlled study (24-month recurrence rateplacebo 71.9%, paliperidone 58.2% and olanzapine 34.3%)(Berwaerts et al., 2012). Finally atypical antipsychotic depotmedications are promising molecules for long-term treatment ofpoor-compliant bipolar patients. A placebo-controlled trial (Quirozet al., 2010) and an olanzapine-controlled study (Vieta et al.,2012a) both showed less frequent relapses in patients treatedwith long-acting risperidone versus placebo. However, in thepaper by Vieta et al. (2012a, 2012b), the risperidone group showedno statistical superiority over placebo group.

Despite the promising results, the data about the efficacy ofatypical antipsychotic mono-therapies in long-term treatment ofBD are preliminary and controversial (Malhi et al., 2012). Of note,the studies have short follow-up periods (Tohen et al., 2004; Kecket al., 2006) or consider special population (e.g. patients treatedwith quetiapine during acute phase) (Weisler et al., 2011). Inaddition no studies have demonstrated the superiority of atypicalantipsychotic mono-therapies respect to lithium in preventingrelapses in long-term period with the exception of the quetiapinemono-therapy trial by Weisler et al. (2011).

In light of an unsatisfactory stabilization of mono-therapies(lithium and atypical antipsychotics) in about 40% of bipolarpatients, a number of authors assessed the efficacy of moodstabilizers (mainly lithium and valproate) combined with anatypical antipsychotic in long-term treatment of BD (Table 1).

4.1. Risperidone

In an open-label prospective trial with pediatric bipolarsrisperidone (till 3 mg/day) in combination with lithium/divalproexsodium showed its effectiveness on clinical stabilization afterremission of a manic episode (Pavuluri et al., 2004). In a 1-yearfollow-up study patients treated with a combination of risperi-done plus topiramate (50–400 mg/day) benefited a decrease ofrate of relapses respect to the year before the beginning oftreatment (Vieta et al., 2003). Finally two patients were success-fully stabilized by lithium and low-dose risperidone combination(Yoshimura et al., 2006) (Level E).

4.2. Risperidone long-acting

A 52-week double-blind placebo controlled study showed thatadjunctive risperidone long-acting (25–50 mg every 2 weeks) to amood stabilizer (lithium, valproate and lamotrigine) was moreeffective than placebo in preventing relapses in 124 bipolar Ipatients (risperidone relapse rate 23.1%; placebo relapse rate

45.8%) (Macfadden et al., 2009). These results were replicated bya more recent 16-week open label study with 162 bipolar patients(Macfadden et al., 2011) (Level D).

4.3. Olanzapine

A preliminary 43-week open-label study showed as adjunctiveolanzapine (mean dose 8.1 mg/day) to mood stabilizers (lithium,valproate, carbamazepine) was effective in achieving clinical stabiliza-tion of 23 treatment-resistant bipolar patients (Vieta et al., 2001). Asubsequent randomized placebo-controlled study showed as adjunc-tive olanzapine (5–20mg/day) to lithium/valproate reduced the risk ofsymptomatic relapses in the follow-up period (18 months) (relapserate for poly-therapy 37% versus 55% for mono-therapy) (Tohen et al.,2004). However, no differences were found between the two arms interms of syndromic relapses defined according to DSM-IV criteria(Level D).

4.4. Quetiapine

A preliminary 18-month retrospective study demonstrated thatadjunctive quetiapine (mean dose 173mg/day) to mood stabilizer waseffective in stabilizing bipolar patients partially responsive to mono-therapies (Sokolski and Denson, 2003). A subsequent naturalistic studyconfirmed the ability of adjunctive quetiapine (mean dose 537mg/day) to mood stabilizers in reducing the risk of depressive relapses ofbipolar I patients (Hardoy et al., 2007). In a 4-year follow-upnaturalistic study with 232 bipolar patients augmentative quetiapineto lithium (223.5 mg/day)/valproate (215.2 mg/day) resulted in redu-cing significantly the rate of relapses respect to mood stabilizer orquetiapine mono-therapies (percentages of patients who maintainedeuthymia: 29.3% for quetiapine, 46.2% for lithium, 32.9% for sodiumvalproate, 41.9% lamotrigine, 80% for quetiapine plus lithium, and78.3% for quetiapine plus sodium valproate) (Altamura et al., 2008). Adouble-blind placebo-controlled trial showed that augmentative que-tiapine (400–800mg/day) to lithium/divalproate significantly reducedthe risk of relapses in bipolar I patients during 104-week follow-upperiod (Vieta et al., 2008a). These results were replicated in twofollowing double-blind placebo-controlled international trials (Suppeset al., 2009; Vieta et al., 2012b) (Level A).

Table 1Summary of the data about the efficacy of combined pharmacotherapy (atypicalsplus mood stabilizer) in the maintenance treatment of bipolar disorder.

Drug Number of studies

Risperidone 1 (Lithium/valproate) (Pavuluri et al., 2004a,b)þ1(topiramate) (Vieta et al., 2003a,b) Level E

Risperidonelong-acting

2 (Lithium, lamotrigine, divalproate, topiramate)(Macfadden et al., 2009b; Macfadden et al., 2011a) Level D

Olanzapine 1 (Lithium/valproate) (Tohen et al., 2004b)þ1 (resistantpatients) (lithium, valproate, carbamazepine) (Vieta et al.,2001a) Level D

Quetiapine 4 (Lithium, lamotrigine, divalproate) (Altamura et al.,2008a; Vieta et al., 2008a, 2012bb; Suppes et al., 2009b)þ2(resistant patients) (Sokolski and Denson, 2003a,b; Hardoyet al., 2007a,b) Level A

Aripiprazole 1 (Lithium and divalproate, resistant patients)(Marcuset al., 2011b)þ1 (lithium/divalproate) (Yatham et al., 2013b)A negative study with lamotrigine (Carlson et al., 2012b)Level B

Ziprasidone 1 (Lithium and divalproate) (Bowden et al., 2010b) Level D

Notes: all the studies showed the major efficacy of combined treatments with theexception of Carlson et al., 2012.

a Not double-blind placebo-controlled studies.b Studies with only bipolar I patients.

M. Buoli et al. / Journal of Affective Disorders 152-154 (2014) 12–1814

4.5. Aripiprazole

A double-blind 52-week placebo-controlled study with 337bipolar patients showed a significant reduction of the relapse ratein the combined-treatment group respect to the patients treatedwith lithium/valproate mono-therapies (Marcus et al., 2011). Theseresults have been confirmed by a very recent double-blind placebocontrolled trial which showed that combined aripiprazole withlithium/valproate was more efficacious in preventing manic(hazard ratio¼0.30) and mixed relapses (hazard ratio¼0.78)respect to lithium/divalproate alone (Yatham et al., 2013) (LevelB). In contrast a double-blind placebo-controlled study failed tofind a statistically significant efficacy of adjunctive aripiprazole(10–30 mg/day) to lamotrigine (100–200 mg/day) respect to pla-cebo in preventing manic/mixed episodes (Carlson et al., 2012).

4.6. Ziprasidone

In a double-blind placebo-controlled study with 113 bipolarpatients adjunctive treatment with ziprasidone (80–160 mg/day)was associated with a lower number of relapse (19.7%) respect toplacebo (32.4%) during the follow-up period (Bowden et al., 2010).Of note, patients receiving a 120 mg/day dose of ziprasidone werethe best stabilized as reported by a subsequent post-hoc analysis(Bowden et al., 2013) (Level D).

5. Tolerability

Synergistic activity of combined treatments is expected toincrease the risk of side effects with obvious implications forlong-term compliance. Of note, both mood stabilizers and anti-psychotics can be the cause of dangerous conditions (e.g. pro-longed QTc and metabolic side effects for antipsychotics, Steven–Johnson syndrome for lamotrigine or renal failure for lithium)even as mono-therapies. In this paragraph data about the risk ofside effects of combined treatments versus mono-therapies aresummarized (Table 2).

5.1. First-generation antipsychotics

A number of studies with different methodologies indicate anincreased risk of extrapyramidal side effects (EPS) by the combi-nation of lithium (Lenox et al., 1992; Small et al., 1995)/valproate(Ouyang et al., 2012) plus haloperidol. Early onset of severedyskinesia (Mann et al., 1983) and irreversible tardive dyskinesia(Spring and Frankel, 1981; Goldman, 1996) has been reported,while a recent study found an increased risk of parkinsonism andakathisia in patients treated with lithium plus haloperidol combi-nation respect to lithium and zotepine combined treatment (Chanet al., 2010). In contrast, a retrospective study (Goldney andSpence, 1986) and a randomized one (Garfinkel et al., 1980) failedto find more side effects in lithium–haloperidol combinationrespect to haloperidol mono-therapy.

5.2. Risperidone

In the open-label study by Pavuluri et al. (2004) on a pediatricsample, the most reported side effects of lithium/valproate com-bination with risperidone were weight gain (37.8%) and sedation(21.6%). Sedation (12.3%) is also the most reported side effects incase of risperidone and topiramate combined treatment (Vietaet al., 2003). Continuation treatment of mania with risperidonecombined with lithium/valproate was associated with headache(22.7%) without differences between lithium and valproate sub-groups (Yatham et al., 2004). In two patients reversible

encephalopathy was observed with lithium–risperidone combina-tion (Böker et al., 2007; Boora et al., 2008). Finally severegalactorrhea was observed after adjunctive low-dose risperidoneto valproate (Peitl et al., 2010).

5.3. Risperidone long-acting

In the first paper by Macfadden et al. (2009) common adverseevents of adjunctive risperidone versus placebo were tremor(24.6% versus 10.2%), insomnia (20.0% versus 18.6%), musclerigidity (12.3% versus 5.1%), weight gain (6.2% versus 1.7%) andhypokinesia (7.7% versus 0.0%). Similar results were found in thesubsequent open-label paper by the same author: the mostcommon adverse events of adjunctive long-acting risperidoneresulted to be tremor (22.8%), muscle rigidity (15.4%), weightincrease (13.6%), and headache (11.1%) (Macfadden et al., 2011).

5.4. Olanzapine

In the first paper by Vieta et al. (2001) the most frequent sideeffects of adjunctive low-dose olanzapine to mood stabilizers weresomnolence (17%) and weight gain (13%). These results wereconfirmed in the paper by Tohen et al. (2004) in which

Table 2Summary of the side effects that have been more frequently associated withcombined treatments respect to mood stabilizer mono-therapies.

Drug Side effects

Risperidone Weight gain, sedation (lithium/valproate) (Pavuluri et al.,2004)Sedation (topiramate) (Vieta et al., 2003)Headache (lithium/valproate) (Yatham et al., 2004)Reversible encephalopathy (lithium, case reports) (Bökeret al., 2007; Boora et al., 2008)Galactorrhea (valproate, one case) (Peitl et al., 2010)

Risperidonelong-acting

Tremor, insomnia, muscle rigidity, weigh gain, hypokinesia(lithium, lamotrigine, divalproate, topiramate) (Macfaddenet al., 2009)Tremor, muscle rigidity, weight increase, headache(lithium, lamotrigine, divalproate, topiramate) (Macfaddenet al., 2011)

Olanzapine Somnolence, weight gain (lithium, valproate,carbamazepine) (Vieta et al., 2001)Somnolence, weight gain (lithium/valproate) (Tohen et al.,2004)Higher fasting blood glucose (valproate) (Houston et al.2009)High trigliceride levels and weight gain(carbamazepine) (Tohen et al., 2008)Neuroleptic malignant syndrome (lithium, one case) (Berryet al., 2003)

Quetiapine Transient sedation and dizziness (lithium/valproate)(Sokolski and Denson, 2003)Weight gain, sedation, EPS (Hardoy et al., 2007)Sedation (lithium/valproate) (Vieta et al., 2008a, 2012b)Sedation, weight increase, hypothyroidism (lithium/valproate) (Suppes et al., 2009)Somnolence, dry mouth, constipation, weight gain(lithium/valproate) (Yatham et al., 2007)Neutropenia (valproate, one case)

Aripiprazole Headache, weight increase, tremor (lithium/valproate)(Marcus et al., 2011)EPS, insomnia (lithium, valproate), tremor (lithium) (Vietaet al., 2010)Akathisia (lithium, valproate) (Vieta et al., 2008b)Neuroleptic malignant syndrome (lithium, one case) (Aliet al., 2006)Intention tremor (lamotrigine, one case) (Ali et al., 2012)Steven–Johnson syndrome (two cases) (Shen et al., 2007)

Ziprasidone Tremor (lithium and divalproate)

M. Buoli et al. / Journal of Affective Disorders 152-154 (2014) 12–18 15

somnolence (19.6% versus 8.3%) and weight gain (19.6% versus6.3%) resulted to be more frequently in the olanzapine grouprespect to the placebo group. A 6-week study found significantlyhigher fasting blood glucose in patients treated with adjunctiveolanzapine to valproate in comparison with valproate mono-therapy (Houston et al. 2009) In another 6-week study thecombination of carbamazepine plus olanzapine resulted to bemore frequently associated with high triglyceride levels andweight gain (24.6% versus 3.4%) (Tohen et al., 2008). Finally onepatient developed neuroleptic malignant syndrome after receivinglithium–olanzapine combination treatment (Berry et al., 2003).

5.5. Quetiapine

In the retrospective study by Sokolski and Denson (2003)transient sedation and dizziness were observed in patients treatedwith quetiapine plus lithium/valproate. In the subsequent study byHardoy et al. (2007) quetiapine/mood stabilizer combination wasfrequently associated with weight gain (34.4% out of patients),sedation (24.6% out of patients) and EPS. Sedation was confirmedto be one of the most frequent concerns in the two papers by Vietaet al. (2008a, 2012b). In the study by Suppes et al. (2009) onlythree adverse events were found to have significantly greateroccurrences in the quetiapine group compared with the placebogroup during the randomized treatment phase: sedation, weightincrease, and hypothyroidism. In a short-term study with manicpatients quetiapine and mood stabilizer (lithium/valproate) com-bination was found to be more frequently associated with somno-lence (28.3% versus 8.7%), dry mouth (19.8% versus 1.9%),constipation (10.4% versus 5.8%), weight gain (10.4% versus 3.9%)respect to mood stabilizer mono-therapy (Yatham et al., 2007). Inone case neutropenia associated with valproate and quetiapinecombination was observed (Estabrook and Pheister, 2012).

5.6. Aripiprazole

In the study by Marcus et al. (2011) patients treated withcombined pharmacotherapy experienced more frequently head-ache (13.2% versus 10.8%), weight increase (9.0% versus 6.6%),tremor (6.0% versus 2.4%). In contrast in the very recent study byYatham et al. (2013) no significant differences between adjunctivearipiprazole versus placebo groups were found in terms of toler-ability. In a 46-week open-label study patients treated with acombination of aripiprazole with lithium/valproate reported morefrequently EPS and insomnia in comparison with mono-therapies(Vieta et al., 2010). Tremor was more frequently associated withlithium plus aripiprazole (17.0%) respect to valproate plus aripi-prazole (12.1%) (Vieta et al., 2010). Early akathisia was morefrequently observed in patients treated with adjunctive aripipra-zole in comparison with the patients treated with lithium/valpro-ate mono-therapy (Vieta et al., 2008b). A case of neurolepticmalignant syndrome was reported during a combined treatmentwith aripiprazole and lithium (Ali et al., 2006). In contrast, nosignificant differences were observed in terms of tolerability inpatients treated with aripiprazole and lamotrigine combinationrespect to patients treated with lamotrigine mono-therapy(Carlson et al., 2012). Disabling intention tremor was reported inone patient treated with lamotrigine (300 mg/day) and aripipra-zole (5 mg/day) combination (Ali et al., 2012). In two cases ofconcomitant use of lamotrigine and aripiprazole Steven–Johnsonsyndrome was documented (Shen et al., 2007).

5.7. Ziprasidone

In the study by Bowden et al. (2010) only tremor occurred morefrequently in the adjunctive ziprasidone group in comparison with

placebo (6.3% versus 3.6%). In authors' knowledge no furthertolerability data have been reported with regard to a moodstabilizer and ziprasidone combination.

6. Discussion

With some exceptions the available data show combinedtreatments with an atypical antipsychotic plus a mood stabilizerare more effective with respect to mono-therapies in achievingclinical stabilization of bipolar patient.

With regard to first-generation antipsychotics, no evidenceexists to justify the use of these molecules in long-term treatmentalso in light of a potential increased risk of motor side effects by acombination of lithium/valproate plus haloperidol.

In relation to atypical antipsychotics, the panorama is veryheterogeneous. With regard to efficacy, the use of adjunctivequetiapine is supported by more evidence. However, if thepercentage of relapsed patients is considered as outcome measure,ziprasidone and risperidone long-acting show the lowest ratestogether with quetiapine.

In terms of tolerability all combined treatments are associatedwith an increased risk of side effects. Case reports indicate thepossibility of developing lethal conditions for all molecules (ence-phalopathy, Steven–Johnson syndrome, neutropenia, neurolepticmalignant syndrome) with the exception of ziprasidone. Olanza-pine, risperidone and quetiapine are associated with a higher riskof weight gain while aripiprazole/ziprasidone with EPS (lessfrequently for the second agent). If weight gain is associated withan increased mortality, tremor and akathisia reduce quality of lifeof patients.

In light of these considerations it is probably too early to have adefinitive opinion about the best atypical antipsychotic to combinewith mood stabilizers to achieve clinical stabilization in bipolarpatients. In addition, increased side effects should induce theclinicians to be cautious before prescribing long-term pharmaco-logical combinations. Combined treatments should be reserved topatients not achieving clinical stabilization with mono-therapiesand without significant medical comorbidities. In this sense futurestudies will be useful to define risk/benefit ratios and to betterdefine patients that can be really advantaged by combinedtreatments.

In addition, another consideration that must be made is thatmost of the presented data concern the clinical stabilization ofbipolar 1 patients so that definitive conclusions for bipolar IIpatients must be even more cautious.

Limits of the present review have to be shortly described. First,the evidence rating can be viewed as arbitrary but it can be usefulto give an immediate idea of the size of evidence about a specificmolecule and to balance results deriving from studies withdifferent methodologies. Second no specific restriction criteria inthe selection of studies has been applied with the objective toprovide the most comprehensive possible revision.

Role of funding sourceThe authors did not receive any funding source for the preparation of the

present paper.

Conflict of interestProf. Altamura has served as a consultant and on Advisory Boards for Roche,

Merck, Astra Zeneca, Bristol Myers Squibb, Janssen-Cilag and Lundbeck.Dr Buoli is a consultant to Roche.

AcknowledgmentNo acknowledgment.

M. Buoli et al. / Journal of Affective Disorders 152-154 (2014) 12–1816

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