Clinical decision making in the treatment of mixed states.

The World Journal of Biological Psychiatry, 2014; Early Online: 1–14

REVIEW ARTICLE

World J Biol Psychiatry Downloaded from informahealthcare.com by Karolinska Institutet University Library on 06/07/14 For personal use only.

Clinical decision making in the treatment of mixed states

HEINZ GRUNZE1 & JEAN MICHEL AZORIN2 1Newcastle

University, Institute of Neuroscience, Newcastle upon Tyne, UK, 2Hôpital Sainte Marguerite, Marseille, France

Abstract Objectives. We reviewed the treatment of bipolar mixed states using efficacy data of licensed and non-licensed physical or pharmacological treatments. Methods. We conducted a literature search to identify published studies reporting data on mixed states. Grading was done using an in-house level of evidence and we compared the efficacy with treatment recommendations of mixed states in current bipolar disorder guidelines. Results. A total of 133 studies reported data on mixed states, and seven guidelines differentiate the acute treatment of mixed states from pure states. The strongest evidence in treating co-occurring manic and depressive symptoms was for monotherapy with aripiprazole, asenapine, extended release carbamazepine, valproate, olanzapine, and ziprasidone. Aripiprazole was recommended in three guidelines, asenapine in one, and carbamazepine and ziprasidone in two. As adjunctive treatment, the strongest evidence of efficacy was for olanzapine plus lithium or valproate. For maintenance, there is evidence for the efficacy of monotherapy with valproate, olanzapine, and quetiapine. In the six guidelines valproate or olanzapine are first line monotherapy options; one recommends quetiapine. Recommended add-on treatments are lithium or valproate plus quetiapine. Conclusions. There is a lack of studies designed to address the efficacy of medications in mixed affective symptoms. Guidelines do not fully reflect the current evidences. Key words: mixed states, bipolar disorder, clinical management, pharmacotherapy, clinical guidelines

Introduction Bipolar mixed states, in which a hypo/manic or a depressive episode coexists with symptoms of the opposite polarity, are a highly prevalent presentation of the disorder that remain a challenge for clinicians to diagnose, and treatment can be complex and lengthy (Tavormina 2013). The recently launched fifth version of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5; American Psychiatric Association 2013) does not consider mixed episodes as a separate entity anymore, and a mood episode with concomitant manic or depressive symptoms of the opposite polarity is to be described with the specifier “with mixed features”. This is likely to even increase awareness and frequency of diagnosis of mixed mood states compared to the time when the rather restrictive DSM-IV criteria were applied. The clinical picture of mixed presentations is usually more

complex than that of pure states, with episodes of longer duration, more severe affective symptomatology, a higher recurrence of episodes, suicidality, and comorbid conditions such as substance abuse (Swann et al. 2013; Vieta and Valenti 2013). Traditionally, the response of mixed patients to pharmacological agents has been extrapolated from studies or trials that have enrolled both pure and mixed manic patients, assuming a comparable response for both subgroups of patients. Few of these reports, though, have examined whether there is differential efficacy in the subset of patients with mixed manic states. In general, mixed depression has received much less attention than mixed mania, and reliable data on its differential treatment response is even scarcer. The lack of available information redounds in current clinical guidelines that, with exceptions, suggest treating pure manic states similar to mixed presentations.

Correspondence: Heinz Grunze, Newcastle University, Institute of Neuroscience, Academic Psychiatry, Campus of Aging and Vitality, Wolfson Research Centre, Westgate Road, Newcastle upon Tyne NE4 5PL, UK. Tel: ⫹ 44 (0) 191 208 1372. Fax: ⫹ 44 (0) 191 208 1387. E-mail: [email protected] (Received 28 November 2013 ; accepted 17 March 2014 ) ISSN 1562-2975 print/ISSN 1814-1412 online © 2014 Informa Healthcare DOI: 10.3109/15622975.2014.908238

2

H. Grunze & J. M. Azorin

With the aim of having a comprehensive view of acute and maintenance treatment of mixed affective symptoms in bipolar disorder, we reviewed published data on the efficacy of approved and non-approved pharmacological or physical therapies for mixed states. Moreover, we compared the evidence with the recommendations given by current bipolar disorder guidelines to treat mixed states.


Methods Guidelines watch We reviewed guidelines on clinical recommendations for the treatment of bipolar disorder (BD) published after 2005. Documents were retrieved by searching electronic databases (PubMed) and websites of national or international bipolar disorder societies, or were made available by experts in the field. Literature search We reviewed the literature for available data on the efficacy of approved and non-approved medications in bipolar states with data on mixed episodes (mixed or dysphoric mania, and mixed depression). The search was conducted on 29 May 2013, and included electronic databases and citation tracking services, clinical trial registries and results databases. A detailed description of the search strategy and terms used can be found in Appendix 1 as Supplementary Appendix 1 to be found online at http://informahealthcare.com/ doi/abs/10.3109/15622975.2014.908238. To be eligible, studies had to enrol patients with mixed mania/depression, or with both mixed/pure episodes. We retrieved evidence from randomized controlled medication trials (RCTs), open-label studies, case series or reports, and retrospective and prospective studies. We also retrieved data on other physical therapies, such as electroconvulsive therapy (ECT) or deep brain stimulation (DBS). We excluded publications in languages other than English, French, German, Italian, Portuguese, or Spanish; containing duplicated data; with no data stratified by mixed and pure manic or pure depressive patients; reviews; and meta-analyses. Two reviewers evaluated the results of the searches on the basis of title and/or abstract, and assessed the citations for their suitability for inclusion based on the full publications. Grading the strength of the evidence For each medication, an in-house system for grading the level of evidence of efficacy was used: (a) “Good evidence” was defined as data from at least one

RCT with a minimum of 25 patients with mixed episodes and treatment superiority vs placebo (PLC), or superiority or non-inferiority vs an active comparator established as effective for mixed states (valproate or divalproate [VAL], olanzapine [OLZ], asenapine [ASE], aripiprazole [ARP], or carbamazepine [CBZ] or oxcarbazepine [OXC]); (b) “Limited evidence” was defined as data for those RCTs not fulfilling the criteria for “good evidence”, and for data from prospective, retrospective, open-label, and case-report studies; (c) “No or conflicting evidence” was used when both positive and negative results are reported; and (d) “Negative evidence” was used when, at the moment, studies point to more harm than benefit. For the sake of brevity, we have reported the results corresponding to top medications, defined as the ones for which we considered that there is a good level of evidence. Results are provided by medication class (anticonvulsants, antipsychotics), individual medications, and are divided into treatment of acute mixed episodes, and maintenance or long-term treatment after recovery of a mixed index episode. A complete descriptive summary, and details on all entered studies for each medication/ physical therapy, together with the corresponding individual evidence grading are included in Supplementary Appendix 1 to be found online at http://informahealthcare.com/doi/abs/10.3109/ 15622975.2014.908238.

Results Review of the guidelines We reviewed 18 guidelines: three from North America, one from South America, eight from Europe, one from Asia, one from Australia, and four international. The complete references of all consulted guidelines are included in Supplementary Appendix 1 to be found online at http://informahealthcare.com/doi/abs/10.3109/15622975.2014. 908238. As a general rule, most of the guidelines include the treatment of mixed episodes in the chapter on mania; drugs are mentioned in cases where they were tested in mixed episodes. Most guidelines advice to stop antidepressant treatment when manic and depressive symptoms coexist, and mention the superiority of valproate (VAL) over lithium (Li) to treat mixed states. Detailed information on these guidelines’ recommendations is presented in Figures 1 and 2, and summarized in Supplementary Appendix 1. Out of the 18 guidelines, seven treat acute management of mixed states as a separate condition (Crismon et al. 2007; Grunze et al. 2009; Goodwin

Figure 1. Recommendations from guidelines for first-line therapy for the acute treatment of mixed states (when considering them as a separate clinical entity from a pure manic or depressive state). A summary of the recommendations are described in cases where advice is provided for the treatment of mixed mania and/or mixed depression (blank squares denotes no advice given). ACs, anticonvulsants; AAPs, atypical antipsychotics; ARP, aripiprazole; ASATHU, Asociación Argentina de Trastornos del Humor; ASE, asenapine; BAP, The British Association for Psychopharmacology; CANMAT, Canadian Network for Mood and Anxiety Disorders and the International Society for Bipolar Disorders; CBZ, carbamazepine; Dep, depression; DVP, divalproate; FX, fluoxetine; Li, Lithium; LTG, lamotrigine; MT, monotherapy; NHRMC, Australian National Health and Medical Research Council; NRC, non rapid cycler; OLZ, olanzapine; OXC, oxcarbazepine; QTP, quetiapine; RC, rapid cycler; RFE, the French Recommendations Formalisées d’Experts; RIS, risperidone; TIMA, Texas Implementation of Medical Algorithms for bipolar disorder; VAL, valproate; WFSBP, The World Federation of Societies of Biological Psychiatry; ZIP, ziprasidone; “⫹”, in combination with.


Treatment of mixed states 3


4


Figure 2. Recommendations from guidelines for first-line therapy for maintenance treatment of mixed states (when considering them as a separate clinical entity from a pure manic or depressive state). Blank squares denotes no advice given. ACs, anticonvulsants; AAPs, atypical antipsychotics; ARP, aripiprazole; ASATHU, Asociación Argentina de Trastornos del Humor; ASE, asenapine; BAP, The British Association for Psychopharmacology; CANMAT, Canadian Network for Mood and Anxiety Disorders and the International Society for Bipolar Disorders; CBZ, carbamazepine; Dep, depression; DVP, divalproate; FX, fluoxetine; Li, Lithium; LTG, lamotrigine; MT, monotherapy; NHRMC, Australian National Health and Medical Research Council; NRC, non rapid cycler; OLZ, olanzapine; OXC, oxcarbazepine; Pred., predominantly; QTP, quetiapine; RC, rapid cycler; RFE, the French Recommendations Formalisées d’Experts; RIS, risperidone; TIMA, Texas Implementation of Medical Algorithms for bipolar disorder; VAL, valproate; WFSBP, The World Federation of Societies of Biological Psychiatry; ZIP, ziprasidone; “⫹”, in combination with.

2009; Malhi et al. 2009; Llorca et al. 2010; Strejilevich et al. 2010; Yatham et al. 2013b). Regarding maintenance treatment, four out of the 18 differentiate treatment based on predominant manic or depressed polarity (Crismon et al. 2007; Goodwin 2009; Llorca et al. 2010; Strejilevich et al. 2010) and one gives advice for “mixed states” (Yatham et al. 2013b). Evidence from the review of the literature The search of the literature led to the identification of 1388 publications for further evaluation. After the exclusion of non-relevant articles for this review, we extracted data on the efficacy outcomes of medications or physical therapies for acute or maintenance treatment of mixed episodes from 133 studies. The vast majority of data were from uncontrolled studies (62.4%) but since they may have clinical value, we included detailed information in Supplementary Appendix 1. Briefly, we found limited data or conflicting evidence for the use of clonidine, donezepil, gabapentin, lamotrigine, risperidone, topiramate, verapamil, and physical therapies. Acute treatment The best evidence for the efficacy of monotherapy for the acute treatment of mixed states was found for

the anticonvulsants VAL and CBZ; and for the following atypical antipsychotics (AAPs): ARP, ASE, paliperidone (PLP), and ziprasidone (ZIP). Finally, there is also very strong evidence for the use of OLZ as monotherapy or as add-on to Lithium (Li) or VAL (Table I and Figures 1 and 3).

Anticonvulsants. Two different 3-week RCTs compared short-term efficacy of extended release CBZ vs PLC with inconsistent results: a first study (Weisler et al. 2004) included 192 DSM-IV manic or mixed patients, and improvement of depressive symptoms (Hamilton rating scale for depression [HAM-D] scores) was higher for CBZ than PLC (n ⫽ 48) (P ⫽ 0.01) in the subgroup of mixed patients (n ⫽ 60), with no difference for manic symptoms (Young Mania Rating Scale [YMRS] scores). Another study reported improvement for manic symptoms in both pure and mixed patients (N ⫽ 239; P ⬍ 0.0001), whereas the decrease in depressive symptoms was not significant for the subgroup of mixed patients (n ⫽ 50; P ⫽ 0.07) (Weisler et al. 2005). A post-hoc analysis, pooling data from these two trials (Weisler et al. 2006) found that the improvement in manic symptoms was significant in both the pure (n ⫽ 280) and mixed (n ⫽ 147) subgroup of patients (P ⬍ 0.01 and P ⬍ 0.05, respectively), while significant reductions in HAM-D scores were only seen in mixed patients (P ⬍ 0.05).

Treatment of mixed states 5 Table I. Summary of the studies showing “good evidence” of treatment efficacy in manic or depressive symptoms during acute treatment of mixed episodes.

Treatment Monotherapy ARP


ASE

ER-CBZ

VAL

OLZ

PLP ZIP

Add-on

OLZ

Evidences in the Current Study (number of studies), symptoms (references) ARP ⬎ PLC (n ⫽ 2; 1 pooled), manic & depressive (Sachs et al. 2006; Suppes et al. 2008)

ASE ⬎ PLC; ASE ⫽ OLZ (n ⫽ 3; post-hoc), manic & depressive (Szegedi et al. 2011; Azorin et al. 2013; McIntyre et al. 2013) ER-CBZ ⬎ PLC, (n ⫽ 3; 1 pooled), manic & depressive (Weisler et al. 2006; Weisler et al. 2004; Weisler et al. 2005) VAL ⬎ PLC & Li, (n ⫽ 2; 1 post-hoc), manic & depressive (Swann et al. 1997; Bowden et al. 2006)

Guidelines recommending the treatment as first-line option BAP 2009: in acute mixed states RFE 2010: in acute dysphoric mania and mixed depression if non-rapid cyclers TIMA 2007: in mixed mania WSFBP-M 2009: in mixed mania CANMAT 2013: in mixed mania

RFE 2010: in acute dysphoric mania (CBZ or OXC), and mixed depression if non-rapid cyclers TIMA 2007: in mixed mania as alternative to VAL, ARP, RIS, or ZIP ASATHU 2010: in acute mixed mania BAP 2009: superior to Li only in irritable dysphoric (rather than depressed) cases RFE 2010: in mixed mania, and mixed depression if non-rapid cycler NHRMC 2009: in acute mixed states TIMA 2007: in acute mixed mania WSFBP-M 2009: in mixed mania ASATHU 2010: in acute mixed mania/hypomania OLZ ⬎ PLC (n ⫽ 4; 2 post-hoc), manic & BAP 2009: in acute mixed states depressive (Tohen et al. 1999, 2000; Baker et al. 2003; CANMAT 2013: in acute mixed depression RFE 2010: in acute mixed mania, and in acute mixed Baldessarini et al. 2003) depression if non-rapid cycler NHRMC 2009: In mixed sates TIMA 2007: in mixed mania as alternative to VAL, ARP, RIS, or ZIP WSFBP-M 2009: in mixed mania PLP ⬎ PLC, (n ⫽ 2), manic (Vieta et al. 2010; NONE Berwaerts et al. 2012) TIMA 2007: in acute mixed mania ZIP ⬎ PLC, (n ⫽ 3; 1 pooled), manic & WSFBP-M 2009: in mixed mania depressive (Keck et al. 2003b; Stahl et al. 2010; Patkar et al. 2012) ASATHU 2010: in acute mixed mania/hypomania with Li OLZ ⫹ Li/VAL (or VAL) ⬎ Li/VAL (n ⫽ 3; 1 or VAL post-hoc), manic & depressive BAP 2009: in acute mixed states (Tohen et al. 2002b; Baker et al. 2004; CANMAT 2013: in acute mixed mania/hypomania Houston et al. 2009) adjunctive to VAL RFE 2010: in acute mixed mania in combination with VAL, and in acute mixed depression with VAL if rapid cycler NHRMC 2009: In acute mixed mania in combination with VAL

ARP, aripiprazole; ASATHU, Asociación Argentina de Trastornos del Humor; ASE, Asenapine; BAP, the British Association for Psychopharmacology; CANMAT, Canadian Network for Mood and Anxiety Disorders and the International Society for Bipolar Disorders collaborative update; ER-CBZ, extended release carbamazepine; Li, lithium; NHRMC, Australian National Health and Medical Research Council; OLZ, olanzapine; OXC, oxcarbazepine; PLC, placebo; PLP, paliperidone; RFE, the French Recommendations Formalisées d’Experts; RIS, risperidone; TIMA, Texas Implementation of Medical Algorithms for bipolar disorder; ZIP, ziprasidone; VAL, valproate; WFSBP-M, The World Federation of Societies of Biological Psychiatry; “⬎”, shows superiority in efficacy.

The superior efficacy of VAL over Li in manic patients presenting with depressive symptoms was first reported in a post-hoc analysis of a 3-week RCT enrolling 179 adult patients with Research Diagnostic Criteria (RDC) criteria for acute mania; of these, 103 manic patients scored at least for two

depressive symptoms on the Schedule for Affective Disorder and Schizophrenia Change [SADS-C] depression subscale, and were classified as subjects with “depressive mania” (Swann et al. 1997). Patients with “depressive mania” improved more in their manic symptoms when treated with VAL compared

Figure 3. Graphic representation of the level of evidence for the efficacy of the most representative medications in the acute and maintenance treatment of mixed episodes. Grey boxes on the diagonal represent monotherapy; the combination with other medications is only depicted in the right upper bottom triangle.


6 H. Grunze & J. M. Azorin

Treatment of mixed states 7


to Li (P ⬍ 0.005), while Li did not differentiate from PLC. Another 3-week RCT study, recruiting DSMIV-TR mixed or manic patients (n ⫽ 166 mixed), showed that extended release VAL was superior to PLC in improving manic scores (P ⫽ 0.013) and response rates (P ⫽ 0.012), independently of having a manic or a mixed episode (Bowden et al. 2006). Atypical antipsychotics: Aripiprazole. ARP was first studied in a 3-week RCT including DSM-IV manic and mixed patients: in the subgroup of mixed patients (n ⫽ 113), ARP produced significantly greater improvements from baseline compared with placebo in YMRS total score (P ⫽ 0.01), and significantly greater improvements from baseline in Montgomery–Åsberg Depression Scale (MADRS) total score compared with PLC at endpoint (P ⫽ 0.04) (Sachs et al. 2006). When these patients were pooled with the subgroup of mixed patients of a similarly designed short-term RCT (n ⫽ 190) (Keck et al. 2003a) ARP was found to be superior to PLC in improving manic symptoms in both manic and mixed subgroups regardless whether the level of baseline depressive symptoms was high (MADRS ⬎ 18), intermediate (MADRS 9–18), or low (MADRS ⱕ 8) (Suppes et al. 2008). Moreover, ARP was associated with higher percentages of responders and remitters than PLC regardless of patients presenting with a manic or mixed episode (P ⫽ 0.0006 for responder rates, and P ⫽ 0.01 for remitters’ rates in mixed patients). Asenapine. A short-term 3-week trial in 488 patients with DSM-IV diagnosis of manic/mixed episodes studied the efficacy of ASE as monotherapy vs PLC. An OLZ arm was included as internal reference (McIntyre et al. 2009a). Patients with a mixed episode at baseline (n ⫽ 115) had a trend to have more significant mean changes in manic symptoms vs PLC, although it was not superior to OLZ. A posthoc analysis in patients with clinically relevant symptoms of depression included in this and in a 9-week extension of this trial (McIntyre et al. 2009b), found that ASE was better in improving depressive symptoms (mean changes in MADRS total score) than PLC (P ⫽ 0.04) (Szegedi et al. 2011). Moreover, remission rates of depressive symptoms were significantly larger than with PLC (P ⫽ 0.019), and larger than with OLZ at day 7 (P ⫽ 0.007). Mean changes in depression severity (Clinical Global Impression for Bipolar Disorder-Depression scale [CGI-BP-D] score) were also significantly greater than with PLC on day 7 (P ⫽ 0.008), and approached significance on day 21 (P ⫽ 0.089), but did not separate from OLZ on either day. Another recent post-hoc analysis, which included the subset of mixed patients from the

two previous RCTs and from an additional 3-week RCT (McIntyre et al. 2010), found that, at 3 weeks, mixed patients (n ⫽ 295) experienced greater improvement in both manic and depressive symptoms (decrease in YMRS and MADRS scores, respectively) with ASE than with PLC (P ⬍ 0.01), while OLZ did not separate from PLC (Azorin et al. 2013). Moreover, these effects were maintained over the 9-week treatment extension, although not significantly different from OLZ. Finally, a recent posthoc analysis on the previous two 3-week trials studied the efficacy of ASE vs OLZ and PLC based on the presence of ⱖ 2 (n ⫽ 828) or ⱖ 3 (n ⫽ 537) depressive features as defined in the DSM-5 mixed specifier for manic episodes (McIntyre et al. 2013). The study found that in patients with ⱖ 3 depressive features, the remission of symptoms was superior for ASE than PLC across all severity levels (P ⱕ 0.05). Moreover, there was a higher improvement in manic symptoms in patients with ⱖ 3 depressive features in the ASE group than in the PLC group (P ⱕ 0.01) already at day 2, a difference that increased with increasing severity of depressive symptoms, and in the case of the most severe patients this improvement was greater than in the OLZ group (P ⱕ 0.01). Olanzapine. The efficacy of OLZ as monotherapy was demonstrated in two consecutive short-term RCTs comparing OLZ efficacy vs PLC in patients with DSM-IV criteria for manic and mixed episodes. In a 3-week study conducted in 139 patients (17.3% mixed) (Tohen et al. 1999), the OLZ group showed significantly greater mean improvement in manic symptoms (YMRS score) in both pure and mixed manic patients, but there were no treatment advantages regarding improvement of depressive symptoms (HAM-D score), and again there was no difference between pure and mixed manic patients. A 4-week RCT that recruited 115 patients (42.6% mixed) confirmed the advantage of OLZ vs PLC on manic symptoms and response rate in both manic and mixed patients (Tohen et al. 2000). Moreover, among those patients with moderate to severe depressive symptoms (HAM-D ⱖ 20 at baseline), there was a greater improvement in the OLZ group in the reduction of ratings in depressive symptoms. Two post-hoc studies reanalysed the pooled data of the above two RCTs: one found that OLZ was superior to PLC in improving both manic and depressive symptoms in mixed (n ⫽ 73) and non-mixed patients (n ⫽ 181) (Baldessarini et al. 2003). The other study focused in patients with moderate to severe depressive symptoms (or dysphoric, defined by a HAM-D score ⱖ 20 at


8


baseline; n ⫽ 68), and compared them against the non-dysphoric patients (n ⫽ 178). While manic symptoms improved in both groups, depressive symptoms improved only in the dysphoric group (P ⫽ 0.04) (Baker et al. 2003), suggesting that OLZ is effective for treating coexisting manic and depressive symptoms, especially when depressive symptoms are moderate to severe. There is good evidence from two RCTs and 1 post-hoc analysis of OLZ as an add-on treatment. A 6-week RCT enrolled both DSM-IV manic and mixed patients (179 and 165, respectively), and compared the efficacy of OLZ plus Li/VAL vs PLC plus LI/VAL (Tohen et al. 2002). Among mixed patients, OLZ was superior when adjunctive to VAL (P ⬍ 0.0001), but not to Li regarding manic symptoms, while there was no difference between Li or VAL in pure manic patients. Mixed patients with moderate to severe depressive symptoms (HAM-D score ⱖ 20) showed better response and improvement in depressive symptoms in the OLZ combination group. A secondary post-hoc analysis of this original study (Baker et al. 2004) in 85 patients with mania or mixed disorder with substantial comorbid depression at baseline, defined as a HAM-D score ⱖ 20 (dysphoric mania), found that dysphoric patients showed higher improvement of depressive symptoms than non-dysphoric patients (P ⬍ 0.001), while improvement in manic symptoms was independent of dysphoric/non-dysphoric categorization. Although the findings on improvement of manic symptoms appear valid, the reported higher improvement of depressive symptoms in dysphoric patients should be seen with caution, as baseline values were not comparable. Finally, a 6-week RCT enrolled DSM-IV-TR mixed patients partially nonresponsive to ⱖ 14 days of VAL monotherapy (Houston et al. 2009), and showed that adjunctive OLZ resulted in higher improvements in manic symptoms, depressive symptoms, or mania severity vs only VAL (P ⬍ 0.001, P ⫽ 0.022, and P ⫽ 0.05, respectively), and a shorter time to partial response and response with adjunctive OLZ.

different dosages of ER-PLP (3, 6, and 12 mg) vs PLC in 469 patients with DSM-IV criteria for a manic or mixed episode (n ⫽ 163 mixed) (Berwaerts et al. 2012); the highest dose was found to be superior to PLC in reducing manic symptoms in both the manic and mixed subgroup of patients (P ⫽ 0.025), but not different from PLC in reducing depressive symptoms. Ziprasidone. A 3-week RCT including both DSM-IV manic and mixed patients with bipolar I disorder (BPI) (n ⫽ 127 manic, and n ⫽ 70 mixed) (Keck et al. 2003b) showed that ZIP was superior to PLC in improving manic symptoms (decrease in Mania Rating Scale [MRS] scores) and mania severity (Clinical Global Impression–Severity scale [CGI-S]), being associated with a higher rate of responders that were comparable in both manic and mixed subsets of patients. These observations were further confirmed in a pooled analysis of this original shortterm study and a posterior replication trial (Potkin et al. 2005) that studied the subgroup of 179 patients with subsyndromal depressive symptomatology (Cincinnati Criteria or experiencing ⱖ 2 prominent depressive symptoms) (Stahl et al. 2010). Improvement in manic symptomatology was greater in the ZIP group, and depressive symptoms were significantly lower at all visits (P ⬍ 0.05), with higher response and remission rates than PLC. Finally, a recent RCT enrolled 73 patients with bipolar II disorder (BDII) or major depressive disorder (MDD) who met DSM-IV criteria for major depressive episode (MDE) together with two or three DSM-IV manic criteria (Patkar et al. 2012). Both mixed BDII and MDD patients on ZIP had higher response and remission rates (P ⫽ 0.04 and P ⫽ 0.0045, respectively); manic symptoms (MRS scores) did not change over time, but there was a reduction in depressive symptoms (MADRS scores; P ⫽ 0.001) vs PLC, with BDII patients having more benefit than MDD patients. Maintenance treatment

Paliperidone. Evidence for the use of PLP monotherapy comes from two different 3-week RCTs: one compared the efficacy of extended-release preparation PLP (ER-PLP) with quetiapine (QTP) and PLC in 439 adult DSM-IV bipolar I disorder patients (n ⫽ 268 manic, and n ⫽ 171 mixed) (Vieta et al. 2010), and found that at 3 weeks ER-PLP was superior to PLC in manic symptom reductions, and non-inferior to QTP at 9-week follow-up, an effect not due to the baseline diagnosis of mixed or manic episode (P ⫽ 0.3). Another trial compared three

The best evidence for the long-term treatment after recovery from a mixed index episode supports monotherapy with VAL, OLZ, or QTP, or the combination of QTP with Li or VAL to prevent both manic and depressive recurrences, the combination of ARP with LTG to increase the time to relapse of a depressive episode, or with Li/VAL to reduce manic symptoms (Table II and Figures 2 and 3). Anticonvulsants. A single long-term RCT recruited 372 adult BPI patients who had recovered from an

Treatment of mixed states 9 Table II. Summary of the studies showing “good evidence” of treatment efficacy in manic or depressive symptoms during maintenance treatment of mixed episodes. Evidences in the Current Study (number of studies), symptoms (references)


Monotherapy

Add-on

VAL

VAL ⬎ Li (n ⫽ 1), manic & depressive (Bowden et al. 2005)

OLZ

OLZ ⬎ PLC (n ⫽ 2; 1 post-hoc), manic & depressive (Tohen et al. 2006, 2009)

QTP

QTP ⬎ PLC; QTP ⬎ Li, (n ⫽ 1), manic & depressive (Weisler et al. 2011) ARP ⫹ LTG ⬎ LTG ⫹ PLC, (n ⫽ 1), depressive (Carlson et al. 2012) ARP ⫹ Li/VAL ⬎ Li/VAL (n ⫽ 1; post-hoc), manic (Yatham et al. 2013a) QTP ⫹ Li/VAL ⬎ Li/VAL, (n ⫽ 3; 1 post-hoc), manic & depressive (Vieta et al. 2008, 2012; Suppes et al. 2009)

ARP

QTP

Guidelines recommending the treatment as first-line option ASATHU 2010: if Li not possible BAP 2009: in predominantly manic RFE 2010: in predominantly manic TIMA 2007: in a most recent hypomanic/manic/mixed episode. BAP 2009: in predominantly manic CANMAT 2013: in predominantly manic or depressed RFE 2010: in predominantly manic if non-rapid cycler, and in predominantly depressed. TIMA 2007: in a most recent hypomanic/manic/mixed episode as alternative to Li, VAL, or LTG BAP 2009: in predominantly manic or depressed NONE NONE

NONE

ARP, aripiprazole; BAP, the British Association for Psychopharmacology; ASATHU, Asociación Argentina de Trastornos del Humor; CANMAT, Canadian Network for Mood and Anxiety Disorders and the International Society for Bipolar Disorders collaborative update; Li, lithium; LTG, lamotrigine; OLZ, olanzapine; PLC, placebo; QTP, quetiapine; RFE, the French Recommendations Formalisées d’Experts; TIMA, Texas Implementation of Medical Algorithms for bipolar disorder; VAL, valproate; “⬎”, shows superiority in efficacy

index manic episode within 3 months of onset, and compared the efficacy of maintenance treatment with VAL, Li or PLC (Bowden et al. 2005). Patients were classified as having euphoric (n ⫽ 123) or dysphoric mania during the index episode at the time of the highest scored MRS. The criteria for dysphoric mania were: the presence of the depressive item from the Schedule for Affective Disorders and Schizophrenia (SADS) Depressive Syndrome Scale (DSS), and at least one additional DSS item. There were no treatment and group differences regarding the prevention of a manic or depressive episode, but maintenance treatment with VAL was superior to Li in delaying time to any mood episode, and was associated with fewer premature discontinuations in both euphoric and dysphoric patients. Atypical antipsychotics: Aripiprazole. The combination of ARP and lamotrigine (LTG) has been studied in BD patients with symptomatic remission after open-label acute treatment with ARP⫹ LTG for an index manic or mixed episode (DSM-IV criteria; n ⫽ 173 mixed) (Carlson et al. 2012). Results from subgroup analyses showed that time to relapse to a depressive episode was significantly longer with the ARP combination compared with the PLC⫹ LTG

combination in the subgroup of patients presenting with a mixed episode at baseline (P ⫽ 0.04) but not in the subgroup of patients with a manic episode (P ⫽ 0.5). A post-hoc analysis compared the use of ARP⫹ Li or VAL and PLC⫹ Li or VAL in 337 adult patients with BPI (manic or mixed; mixed, n ⫽ 107) as defined by the DSM-IV-TR with inadequate response to Li or VAL monotherapy (Yatham et al. 2013a). ARP was not superior to Li or VAL monotherapy in the time to relapse to any mood episode in the subgroup of mixed patients after 52 weeks of treatment. Both manic and mixed subgroups showed a greater reduction of manic symptoms (mean change in total YMRS total score) vs only Li or VAL (P ⬍ 0.01 in pure manics; P ⫽ 0.02 in mixed), but the combination did not differentiate from monotherapy in decreasing depressive symptoms (mean change in MADRS total score). Olanzapine. A RCT studied the efficacy of OLZ vs PLC as monotherapy for maintenance treatment in 361 patients with a DSM-IV diagnosis of manic or mixed episodes (n ⫽ 121 mixed) (Tohen et al. 2006). In both patients with a manic or mixed index episode, the time to symptomatic relapse into any mood episode was significantly longer for patients

10 H. Grunze & J. M. Azorin


who received OLZ than for patients who received PLC (P ⬍ 0.001). A post-hoc analysis of this trial that focused on the subgroup of mixed patients (DSM-IV definition) found that OLZ-treated patients had significantly lower rates of symptomatic relapse of any kind or a recurrence of a manic (P ⬍ 0.001 and P ⫽ 0.001, respectively) but not mixed, hypomanic, or depressive episodes, and that the median times to relapse of any kind was 3 times longer in the OLZ group vs the PLC group (P ⬍ 0.001) (Tohen et al. 2009). Quetiapine. A RCT compared the efficacy of monotherapy with extended release QTP (QTP-XR) vs switching to placebo or Li in 1,172 adults with DSM-IV BPI (current or recent manic, depressive, or mixed episode; n ⫽ 216 mixed) stabilised on openlabel QTP for 24 weeks (Weisler et al. 2011). In the subgroup of mixed patients, the hazard ratios of time to recurrence of any (manic, mixed, or depressive) mood event, and of only manic or depressive events, were lower in the QTP-XR treatment group compared to Li and PLC. Two identically designed RCTs that studied maintenance treatment in mixed, manic, or depressive bipolar patients (DSM-IV criteria) compared the efficacy of the add-on treatment of QTP⫹ Li or VAL vs PL⫹ Li or VAL (Vieta et al. 2008; Suppes et al. 2009). Both studies (one recruiting 160 mixed patients, the other 285) found that, for the subgroup of mixed patients, the QTP combination increased the time to recurrence of a mood event (any, manic, or depressed). A post-hoc analysis of these two previous RCTs pooling the subgroup of patients fulfilling DSM-IV-TR criteria for a mixed episode (n ⫽ 445) confirmed these results (Vieta et al. 2012), and further described that both manic and depressive symptoms and illness severity improved with QTP combination vs Li/VAL alone (P ⫽ 0.004, P ⫽ 0.011, and P ⫽ 0.005, respectively). Moreover, there was a significant risk reduction (71%) in the time to recurrence of a mood event in the add-on treated group (P ⬍ 0.001).

Discussion We found that the vast majority of RCTs initially recruited both pure manic and mixed patients as defined in the DSM classification system, and that additional analyses were performed to identify effects in a subgroup of mixed patients.This approach has several shortcomings: first, the resulting sample sizes are usually small, and thus negative trials could have been underpowered to detect existing differences between groups or positive trials had a

large error probability of being false positive; second, mixed patients enrolled in RCTs are probably less severely ill than those seen in clinical practice (Swann 2011); and thirdly, the categorical definition of DSM prevents determining whether the therapy efficacy varies as a function of the number of concomitant manic or depressive symptoms, since it requires the co-occurrence of a full manic and a full depressive episode. We presented the results distinguishing between manic and depressive outcomes when available, which may be more in line with the clinical need to know to what extent the chosen medication is able to resolve both manic and depressive symptoms in mixed states or, conversely, to independently treat one or the other. Moreover, this is in line with the new “with mixed features” categorization of mood episodes in DSM-5, as the distinction in efficacy based on the polarity of concomitant symptoms may be closer to the real clinical setting. Our results are in agreement with two recently published reviews on the treatment of mixed bipolar disorders based on data exclusively obtained from RCTs (Fountoulakis et al. 2012; McIntyre and Yoon 2012), and with the first options recommended in one or more of the treatment guidelines considering mixed presentations as a separate clinical status from pure states. There are, however, discrepancies with current recommendations and the present findings that deserve further discussion. First, Li as monotherapy is considered in the vast majority of guidelines as the first option for maintenance treatment in mixed patients with predominantly manic symptoms. Evidence for long-term treatment with Li, though, is conflicting and comes from two uncontrolled studies and a single RCT; one retrospective study found that the presence of three symptoms of the opposite polarity was a predictor of poor outcome (Backlund et al. 2009); a 12-year observational study, reported that the risk of psychiatric hospital admissions was increased in patients treated with monotherapy/adjunctive VAL vs monotherapy/adjunctive Li (Kessing et al. 2011). Finally, a recent 104-week RCT found that only subjects with the recommended Li plasma levels higher than 0.6 mEq/l had a significant lower recurrence rate of any mood episode than PLC (Nolen and Weisler 2013). As for other anticonvulsants, LTG is recommended as the first option for maintenance treatment of predominantly depressive polarity in four of the specific guidelines, three of them as monotherapy. In our review we could not identify studies reporting its efficacy in monotherapy, and the evidence for the efficacy of adjunctive LTG in mixed populations comes from retrospective or observational studies with conflicting results (Ginsberg 2006; Born et al.


Treatment of mixed states 11 2009; Kessing et al. 2012). However, a recent posthoc analysis showed the superiority of adjunctive use of LTG and ARP vs LTG alone in the time to relapse to a depressive episode in mixed patients (Carlson et al. 2012) suggesting that the efficacy of LTG alone might be suboptimal in mixed patients. There are also some discrepancies between the reported efficacy and the guidelines’ recommendations for the use of AAPs. For instance, RIS is recommended as the first-line agent for monotherapy or adjunctive therapy to VAL in three guidelines for the acute treatment of mixed mania, and in one for maintenance treatment as add-on to Li or VAL in patients with both predominantly manic and depressive polarity. However, the only RIS monotherapy trial did not show improvement of manic symptoms vs PLC (Khanna et al. 2005), and only uncontrolled studies or RCTs with a small sample of mixed subjects preliminarily suggest that adjunctive RIS to Li or VAL is efficacious in improving both manic and depressive symptoms in short and long-term treatment (Benabarre et al. 2001; Vieta et al. 2001; Yatham et al. 2003; Woo et al. 2010). Other discrepancies include the frequent omission of the use of ASE, PLP, and ZIP monotherapy in acute treatment, probably because of their relative recent market approval and lack of available data when guidelines were written. For instance, there is recent evidence for the effectiveness of ASE to treat both manic and depressive symptoms (Szegedi et al. 2011; Azorin et al. 2013; McIntyre et al. 2013), and ASE has very recently been included in a guideline for the treatment of mixed mania (Yatham et al. 2013b). PLP is not recommended in any guideline, but has been recently shown to improve manic symptoms in mixed patients (Vieta et al. 2010; Berwaerts et al. 2012), and only two guidelines recommend ZIP monotherapy in mixed mania (Crismon et al. 2007; Grunze et al. 2009), while there are positive data on depressive symptomatology from the only positive RCT that has included mixed depressive patients, together with a post-hoc analysis performed in dysphoric manic patients showing that it improves both manic and depressive symptoms (Stahl et al. 2010; Patkar et al. 2012). As for maintenance treatment, QTP monotherapy is only recommended in one guideline (Goodwin 2009), and none mentions its efficacy in combination with Li or VAL. As in other cases, recent data point to the efficacy of monotherapy and add-on options as effective in the reduction of both manic and depressive symptoms, and also preventing the recurrence of any type of mood episode (Vieta et al. 2008; Suppes et al. 2009; Weisler et al. 2011; Vieta et al. 2012). Similarly, the combination of ARP with Li or VAL has been recently reported to

improve manic symptoms in mixed manic patients inadequately responding to Li or VAL (Yatham et al. 2013a), and not yet recommended in any guideline. Almost all guidelines recommend not initiating or tapering off antidepressants when a mixed state is diagnosed, although in clinical practice they remain widely prescribed together with antimanic agents (Azorin et al. 2009). Current evidence from prospective or retrospective studies shows that mixed patients are at higher risk of worsening of manic symptoms or, when in a depressive mixed state, for a maniform switch (Bottlender et al. 2004; Strejilevich et al. 2011; Valenti et al. 2011). Moreover, two independent studies have found that treatment emergent mania in bipolar depression is associated with the presence of minimal concurrent manic symptoms (Goldberg et al. 2009; Frye et al. 2009). On the other hand, a post-hoc analysis of an RCT focusing on patients with mixed depression (defined as the co-occurrence of a MDE and ⱖ 2 manic/hypomanic symptoms concurrent with depression), found that the efficacy of the combination of OLZ and fluoxetine in the reduction of depressive symptoms was similar to OLZ alone (Benazzi et al. 2009). The response was independent of the number of manic/hypomanic symptoms, and the rates of switching to hypo/mania were similar between treatments. Some limitations must be acknowledged: firstly, although our search strategy was comprehensive and included several search terms, there is still the chance that we have missed relevant papers or studies. Secondly, the review did not include books, or clinical trials that have looked at the effects of other treatment modalities such as psychosocial interventions. In conclusion, the evidence for available medications to treat the acute phase of mixed episodes is mainly based on limited data coming from RCTs originally including patients with mixed manic episodes, with strikingly little evidence available to help delineate a potential differential response between mixed manic and depressive episodes, and practically no evidence on how efficacy varies based on the quantitative presence of co-occurring symptoms of the opposite polarity. Thus, the currently available evidence appears not adequately tailored to meet clinicians’ needs. Therefore, there is a clear need to conduct well-powered trials specifically designed to enrol manic or depressive patients with different numbers and severity of mixed features to replicate these findings. Finally, current guidelines on the treatment of bipolar disorder do not always consider the differential response to treatment of mixed states, and do not always reflect the latest existing evidence.

12 H. Grunze & J. M. Azorin Acknowledgements We thank Dr Mònica Gratacòs from CHC-Europe, who provided valuable editorial support funded by H. Lundbeck A/S. Funding body agreement


Funding for this manuscript was provided by H. Lundbeck A/S. Statement of Interest Dr. Heinz Grunze received grants/research support, consulting fees and honoraria within the last 3 years from Astra Zeneca, BMS, Desitin, Eli Lilly, Gedeon-Richter, Hoffmann-LaRoche, Janssen-Cilag, Lundbeck, Merck, Otsuka, SanofiAventis, Servier, Sepracor, and UBC. Dr. Jean-Michel Azorin has undertaken consultancy work for Lilly, Aventis, Janssen, Lundbeck, Astra Zeneca, and BMS. He has received honoraria and hospitality from Lilly, Janssen, Lundbeck, BMS, Pfizer, and Novartis in relation to conference presentations.

References American Psychiatric Association. 2013. Diagnostic and statistical manual of mental health disorders: DSM-5. 5th ed. Washington, DC: American Psychiatric Publishing. Azorin JM, Aubrun E, Bertsch J, Reed C, Gerard S, Lukasiewicz M. 2009. Mixed states vs pure mania in the French sample of the EMBLEM study: results at baseline and 24 months – European mania in bipolar longitudinal evaluation of medication. BMC Psychiatry 9:33. Azorin JM, Sapin C, Weiller E. 2013. Effect of asenapine on manic and depressive symptoms in bipolar I patients with mixed episodes: results from post hoc analyses. J Affect Disord 145:62–69. Backlund L, Ehnvall A, Hetta J, Isacsson G, Agren H. 2009. Identifying predictors for good lithium response – a retrospective analysis of 100 patients with bipolar disorder using a life-charting method. Eur Psychiatry 24:171–177. Baker RW, Brown E, Akiskal HS, Calabrese JR, Ketter TA, Schuh LM, et al. 2004. Efficacy of olanzapine combined with valproate or lithium in the treatment of dysphoric mania. Br J Psychiatry 185:472–478. Baker RW, Tohen M, Fawcett J, Risser RC, Schuh LM, Brown E, et al. 2003. Acute dysphoric mania: treatment response to olanzapine versus placebo. J Clin Psychopharmacol 23: 132–137. Baldessarini RJ, Hennen J, Wilson M, Calabrese J, Chengappa R, Keck PE Jr, et al. 2003. Olanzapine versus placebo in acute mania: treatment responses in subgroups. J Clin Psychopharmacol 23:370–376. Benabarre A, Vieta E, Colom F, Martinez A, Reinares M, Corbella B. 2001. Treatment of mixed mania with risperidone and mood stabilizers. Can J Psychiatry 46:866–867. Benazzi F, Berk M, Frye MA, Wang W, Barraco A, Tohen M. 2009. Olanzapine/fluoxetine combination for the treatment of

mixed depression in bipolar I disorder: a post hoc analysis. J Clin Psychiatry 70:1424–1431. Berwaerts J, Xu H, Nuamah I, Lim P, Hough D. 2012. Evaluation of the efficacy and safety of paliperidone extended-release in the treatment of acute mania: a randomized, doubleblind, dose-response study. J Affect Disord 136:e51–e60. Born C, Bernhard B, Dittmann S, Seemüller F, Grunze H. 2009. Lamotrigine in bipolar disorder: results of a mirrorimage evaluation using the NIMH Lifechart-Methodology. J Affect Disord 115:241–245. Bottlender R, Sato T, Kleindienst N, Strauss A, Moller HJ. 2004. Mixed depressive features predict maniform switch during treatment of depression in bipolar I disorder. J Affect Disord 78:149–152. Bowden CL, Collins MA, McElroy SL, Calabrese JR, Swann AC, Weisler RH, et al. 2005. Relationship of mania symptomatology to maintenance treatment response with divalproex, lithium, or placebo. Neuropsychopharmacology 30:1932–1939. Bowden CL, Swann AC, Calabrese JR, Rubenfaer LM, Wozniak PJ, Collins MA, et al. 2006. A randomized, placebocontrolled, multicenter study of divalproex sodium extended release in the treatment of acute mania. J Clin Psychiatry 67:1501–1510. Carlson BX, Ketter TA, Sun W, Timko K, McQuade RD, Sanchez R, et al. 2012. Aripiprazole in combination with lamotrigine for the long-term treatment of patients with bipolar I disorder (manic or mixed): a randomized, multicenter, double-blind study (CN138-392). Bipolar Disord 14:41–53. Crismon L, Argo T, Bendele S, Suppes T. 2007. Texas Medication Algorithm Project Procedural Manual – Bipolar Disorder Algorithms. Texas Department of State Health Services. Available from: http://www.pbhcare.org/pubdocs/upload/ documents/TIMABDman2007.pdf (accessed 18 February 2014). Fountoulakis KN, Kontis D, Gonda X, Siamouli M, Yatham LN. 2012. Treatment of mixed bipolar states. Int J Neuropsychopharmacol 15:1015–1026. Frye MA, Helleman G, McElroy SL, Altshuler LL, Black DO, Keck PE Jr, et al. 2009. Correlates of treatment-emergent mania associated with antidepressant treatment in bipolar depression. Am J Psychiatry 166:164–172. Ginsberg LD. 2006. Efficacy and safety of lamotrigine for adults with bipolar disorder in a private practice setting. CNS Spectr 11:376–382. Goldberg JF, Perlis RH, Bowden CL, Thase ME, Miklowitz DJ, Marangell LB, et al. 2009. Manic symptoms during depressive episodes in 1,380 patients with bipolar disorder: findings from the STEP-BD. Am J Psychiatry 166:173–181. Goodwin GM. 2009. Evidence-based guidelines for treating bipolar disorder: revised second edition – recommendations from the British Association for Psychopharmacology. J Psychopharmacol 23:346–388. Grunze H, Vieta E, Goodwin GM, Bowden C, Licht RW, Moller HJ, et al. 2009. The World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for the Biological Treatment of Bipolar Disorders: Update 2009 on the Treatment of Acute Mania. World J Biol Psychiatry 10:85–116. Houston JP, Tohen M, Degenhardt EK, Jamal HH, Liu LL, Ketter TA. 2009. Olanzapine-divalproex combination versus divalproex monotherapy in the treatment of bipolar mixed episodes: a double-blind, placebo-controlled study. J Clin Psychiatry 70:1540–1547. Keck PE, Marcus R, Tourkodimitris S, Ali M, Liebeskind A, Saha A, et al. 2003a. A placebo-controlled, double-blind study of the efficacy and safety of aripiprazole in patients with acute bipolar mania. Am J Psychiatry 160:1651–1658.


Treatment of mixed states 13 Keck PE, Versiani M, Potkin S, West SA, Giller E, Ice K. 2003b. Ziprasidone in the treatment of acute bipolar mania: a three-week, placebo-controlled, double-blind, randomized trial. Am J Psychiatry 160:741–748. Kessing LV, Hellmund G, Andersen PK. 2012. An observational nationwide register based cohort study on lamotrigine versus lithium in bipolar disorder. J Psychopharmacol 26:644–652. Kessing LV, Hellmund G, Geddes JR, Goodwin GM, Andersen PK. 2011. Valproate v. lithium in the treatment of bipolar disorder in clinical practice: observational nationwide register-based cohort study. Br J Psychiatry 199:57–63. Khanna S, Vieta E, Lyons B, Grossman F, Eerdekens M, Kramer M. 2005. Risperidone in the treatment of acute mania: double-blind, placebo-controlled study. Br J Psychiatry 187: 229–234. Llorca PM, Courtet P, Martin P, Abbar M, Gay C, Meynard JA, et al. 2010. Recommandations formalisées d’experts (RFE). Dépistage et prise en charge du trouble bipolaire. Encéphale 36(Suppl)4:79–102. Malhi GS, Adams D, Lampe L, Paton M, O’Connor N, Newton LA, et al. 2009. Clinical practice recommendations for bipolar disorder. Acta Psychiatr Scand 119(Suppl)439: 27–46. McIntyre RS, Cohen M, Zhao J, Alphs L, Macek TA, Panagides J. 2009a. A 3-week, randomized, placebo-controlled trial of asenapine in the treatment of acute mania in bipolar mania and mixed states. Bipolar Disord 11:673–686. McIntyre RS, Cohen M, Zhao J, Alphs L, Macek TA, Panagides J. 2009b. Asenapine versus olanzapine in acute mania: a doubleblind extension study. Bipolar Disord 11:815–826. McIntyre RS, Cohen M, Zhao J, Alphs L, Macek TA, Panagides J. 2010. Asenapine in the treatment of acute mania in bipolar I disorder: A randomized, double-blind, placebocontrolled trial. J Affect Disord 122:27–38. McIntyre RS, Tohen M, Berk M, Zhao J, Weiller E. 2013. DSM-5 mixed specifier for manic episodes: evaluating the effect of depressive features on severity and treatment outcome using asenapine clinical trial data. J Affect Disord 150:378–383. McIntyre RS, Yoon J. 2012. Efficacy of antimanic treatments in mixed states. Bipolar Disord 14(Suppl)2:22–36. Nolen WA, Weisler RH. 2013. The association of the effect of lithium in the maintenance treatment of bipolar disorder with lithium plasma levels: a post hoc analysis of a doubleblind study comparing switching to lithium or placebo in patients who responded to quetiapine (Trial 144). Bipolar Disord 15:100–109. Patkar A, Gilmer W, Pae CU, Vohringer PA, Ziffra M, Pirok E, et al. 2012. A 6 week randomized double-blind placebocontrolled trial of ziprasidone for the acute depressive mixed state. PLoS One 7:e34757. Potkin SG, Keck PE Jr, Segal S, Ice K, English P. 2005. Ziprasidone in acute bipolar mania: a 21-day randomized, double-blind, placebo-controlled replication trial. J Clin Psychopharmacol 25:301–310. Sachs G, Sanchez R, Marcus R, Stock E, McQuade R, Carson W, et al. 2006. Aripiprazole in the treatment of acute manic or mixed episodes in patients with bipolar I disorder: a 3-week placebo-controlled study. J Psychopharmacol 20:536–546. Stahl S, Lombardo I, Loebel A, Mandel FS. 2010. Efficacy of ziprasidone in dysphoric mania: pooled analysis of two double-blind studies. J Affect Disord 122:39–45. Strejilevich S, Vazquez G, Garcia BG, Zaratiegui R, Vilaprino JJ, Herbst L, et al. 2010. II Consenso argentino sobre el tratamiento de los trastornos bipolares 2010. Vertex 21(Suppl II Consenso):3–55. Strejilevich SA, Martino DJ, Marengo E, Igoa A, Fassi G, Whitham EA, et al. 2011. Long-term worsening of bipolar

disorder related with frequency of antidepressant exposure. Ann Clin Psychiatry 23:186–192. Suppes T, Eudicone J, McQuade R, Pikalov A III, Carlson B. 2008. Efficacy and safety of aripiprazole in subpopulations with acute manic or mixed episodes of bipolar I disorder. J Affect Disord 107:145–154. Suppes T, Vieta E, Liu S, Brecher M, Paulsson B. 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 166:476–488. Swann AC. 2011. Diagnosis and treatment of mixed states. In: Akiskal HS, Tohen M, eds. Bipolar psychopharmacology: caring for the patient. West Sussex: Wiley-Blackwell. p. 391–410. Swann AC, Bowden CL, Morris D, Calabrese JR, Petty F, Small J, et al. 1997. Depression during mania. Treatment response to lithium or divalproex. Arch Gen Psychiatry 54: 37–42. Swann AC, Lafer B, Perugi G, Frye MA, Bauer M, Bahk WM, et al. 2013. Bipolar mixed states: an international society for bipolar disorders task force report of symptom structure, course of illness, and diagnosis. Am J Psychiatry 170:31–42. Szegedi A, Zhao J, van WA, Nations KR, Mackle M, Panagides J. 2011. Effects of asenapine on depressive symptoms in patients with bipolar I disorder experiencing acute manic or mixed episodes: a post hoc analysis of two 3-week clinical trials. BMC Psychiatry 11:101. Tavormina G. 2013. A long term clinical diagnostic-therapeutic evaluation of 30 case reports of bipolar spectrum mixed states. Psychiatr Danub 25(Suppl)2:S190–193. Tohen M, Calabrese JR, Sachs GS, Banov MD, Detke HC, Risser R, et al. 2006. Randomized, placebo-controlled trial of olanzapine as maintenance therapy in patients with bipolar I disorder responding to acute treatment with olanzapine. Am J Psychiatry 163:247–256. Tohen M, Chengappa KN, Suppes T, Zarate CA, Calabrese JR, Bowden CL, et al. 2002. Efficacy of olanzapine in combination with valproate or lithium in the treatment of mania in patients partially nonresponsive to valproate or lithium monotherapy. Arch Gen Psychiatry 59:62–69. Tohen M, Jacobs TG, Grundy SL, McElroy SL, Banov MC, Janicak PG, et al. 2000. Efficacy of olanzapine in acute bipolar mania: a double-blind, placebo-controlled study. The Olanzapine HGGW Study Group. Arch Gen Psychiatry 57: 841–849. Tohen M, Sanger TM, McElroy SL, Tollefson GD, Chengappa KN, Daniel DG, et al. 1999. Olanzapine versus placebo in the treatment of acute mania. Olanzapine HGEH Study Group. Am J Psychiatry 156:702–709. Tohen M, Sutton VK, Calabrese JR, Sachs GS, Bowden CL. 2009. Maintenance of response following stabilization of mixed index episodes with olanzapine monotherapy in a randomized, double-blind, placebo-controlled study of bipolar 1 disorder. J Affect Disord 116:43–50. Valenti M, Pacchiarotti I, Rosa AR, Bonnin CM, Popovic D, Nivoli AM, et al. 2011. Bipolar mixed episodes and antidepressants: a cohort study of bipolar I disorder patients. Bipolar Disord 13:145–154. Vieta E, Herraiz M, Fernandez A, Gasto C, Benabarre A, Colom F, et al. 2001. Efficacy and safety of risperidone in the treatment of schizoaffective disorder: initial results from a large, multicenter surveillance study. Group for the Study of Risperidone in Affective Disorders (GSRAD). J Clin Psychiatry 62:623–630. Vieta E, Nuamah IF, Lim P, Yuen EC, Palumbo JM, Hough DW, et al. 2010. A randomized, placebo- and active-controlled study of paliperidone extended release for the treatment of


14 H. Grunze & J. M. Azorin acute manic and mixed episodes of bipolar I disorder. Bipolar Disord 12:230–243. Vieta E, Suppes T, Eggens I, Persson I, Paulsson B, Brecher M. 2008. Efficacy and safety of quetiapine in combination with lithium or divalproex for maintenance of patients with bipolar I disorder (international trial 126). J Affect Disord 109: 251–263. Vieta E, Suppes T, Ekholm B, Udd M, Gustafsson U. 2012. Long-term efficacy of quetiapine in combination with lithium or divalproex on mixed symptoms in bipolar I disorder. J Affect Disord 142:36–44. Vieta E, Valenti M. 2013. Mixed states in DSM-5: implications for clinical care, education, and research. J Affect Disord 148:28–36. Weisler RH, Hirschfeld R, Cutler AJ, Gazda T, Ketter TA, Keck PE, et al. A, Kalali A. 2006. Extended-release carbamazepine capsules as monotherapy in bipolar disorder: pooled results from two randomised, double-blind, placebocontrolled trials. CNS Drugs 20:219–231. Weisler RH, Kalali AH, Ketter TA. 2004. A multicenter, randomized, double-blind, placebo-controlled trial of extendedrelease carbamazepine capsules as monotherapy for bipolar disorder patients with manic or mixed episodes. J Clin Psychiatry 65:478–484. Weisler RH, Keck PE Jr, Swann AC, Cutler AJ, Ketter TA, Kalali AH. 2005. Extended-release carbamazepine capsules as monotherapy for acute mania in bipolar disorder: a

Supplementary material available online Supplementary Appendix 1.

multicenter, randomized, double-blind, placebo-controlled trial. J Clin Psychiatry 66:323–330. Weisler RH, Nolen WA, Neijber A, Hellqvist A, Paulsson B. 2011. Continuation of quetiapine versus switching to placebo or lithium for maintenance treatment of bipolar I disorder (Trial 144: a randomized controlled study). J Clin Psychiatry 72:1452–1464. Woo YS, Bahk WM, Jon DI, Chung SK, Lee SY, Ahn YM, et al. 2010. Risperidone in the treatment of mixed state bipolar patients: results from a 24-week, multicenter, open-label study in Korea. Psychiatry Clin Neurosci 64:28–37. Yatham LN, Binder C, Riccardelli R, Leblanc J, Connolly M, Kusumakar V. 2003. Risperidone in acute and continuation treatment of mania. Int Clin Psychopharmacol 18:227–235. Yatham LN, Fountoulakis KN, Rahman Z, Ammerman D, Fyans P, Marler SV, et al. 2013a. Efficacy of aripiprazole versus placebo as adjuncts to lithium or valproate in relapse prevention of manic or mixed episodes in bipolar I patients stratified by index manic or mixed episode. J Affect Disord 147:365–372. Yatham LN, Kennedy SH, Parikh SV, Schaffer A, Beaulieu S, Alda M, et al. 2013b. Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) collaborative update of CANMAT guidelines for the management of patients with bipolar disorder: update 2013. Bipolar Disord 15:1–44.

Clinical decision-making in the evaluation and treatment of insomnia.

[Clinical decision making algorithms].

Clinical Decision Making.

[Treatment of depressive mixed states].

Decision making. Stability of clinical decisions.

[Disagreements in the clinical relationship and the decision-making process].

Decision-making algorithm in treatment of the atrophic mandible fractures.

Clinical judgment and therapeutic decision making.

Psychiatric tertiary referral and clinical decision making.

Clinical decision making on extensive molar restorations.

Caregiver Perceptions of Clinical Decision-Making for the Treatment of Children.

Pulmonary Pathology Integral to Clinical Decision Making.

Risk assessment and clinical decision-making.

Clinical decision making in dementia: mapping the minefields.

Base rates and the decision making model in clinical neuropsychology.

Decision Making for Postpartum Depression Treatment.

Restorative treatment thresholds and agreement in treatment decision-making.

The ethics of forgoing life-sustaining treatment: theoretical considerations and clinical decision making.

The dangers of incorporating reimbursement data into clinical decision making.

Surgical decision making. The reliability of clinical judgment.

Clinical Reasoning: The Analysis of Medical Decision Making.

What are the decision-making preferences of patients in vascular surgery? A mixed-methods study.

The diffusion of evidence-based decision making among local health department practitioners in the United States.

The evolution of computational hemodynamics as a clinical tool in decision making, patient specific treatment and clinical management. Part II.