Abstract

In recent years, combinations of pharmacological treatments have become common for the treatment of bipolar disorder type I (BP I); however, this practice is usually not evidence-based and rarely considers monotherapy drug regimen (MDR) as an option in the treatment of acute phases of BP I. Therefore, we evaluated comparative data of commonly prescribed MDRs for both manic and depressive phases of BP I. Medline, PsycINFO, EMBASE, the Cochrane Library, the ClinicalStudyResults.org and other data sources were searched from 1949 to March 2009 for placebo and active controlled randomized clinical trials (RCTs). Risk ratios (RRs) for response, remission, and discontinuation rates due to adverse events (AEs), lack of efficacy, or discontinuation due to any cause, and the number needed to treat or harm (NNT or NNH) were calculated for each medication individually and for all evaluable trials combined. The authors included 31 RCTs in the analyses comparing a MDR with placebo or with active treatment for acute mania, and 9 RCTs comparing a MDR with placebo or with active treatment for bipolar depression. According to the collected evidence, most of the MDRs when compared to placebo showed significant response and remission rates in acute mania. In the case of bipolar depression only quetiapine and, to a lesser extent, olanzapine showed efficacy as MDR. Overall, MDRs were well tolerated with low discontinuation rates due to any cause or AE, although AE profiles differed among treatments. We concluded that most MDRs were efficacious and safe in the treatment of manic episodes, but very few MDRs have demonstrated being efficacious for bipolar depressive episodes.

Background

A recent systematic review of 913 papers, suggested that lithium, some anticonvulsants and second-generation antipsychotics (SGAs) are valuable in the treatment of acute mania (Fountoulakis & Vieta, 2008). Up until recently, first-generation antipsychotics (FGAs) were often the preferred choice for treatment of acute mania, especially in European countries (Tohen et al.2001; Vestergaard, 1992); however, some reports suggest that they may induce or worsen depressive symptoms in patients with bipolar disorder (Esparon et al. 1986; Zarate & Tohen, 2004). Furthermore, patients with bipolar disorder compared to patients with schizophrenia appear to be more susceptible to extrapyramidal symptoms (EPS) (Cavazzoni et al.2006; Mukherjee et al.1986). For bipolar depressed patients, there is uncertainty about the role of antidepressants as they have been associated with manic relapse (Lewis & Winokur, 1982), lack of efficacy (Post et al.2006; Sachs et al.2007), and cycle acceleration (Wehr & Goodwin, 1979).

Although combination drug regimens (CDRs) have become ubiquitous in the treatment of non-refractory BP I around the world (Baldessarini et al.2007; Blanco et al.2002; Goldberg et al.2009; Kupfer et al.2002; Levine et al.2000; Wolfsperger et al.2007), the goal of this review was to examine the efficacy and safety of monotherapy drug regimens (MDRs). Despite treatment guidelines recommending the use of monotherapy as a first-line strategy (Grunze et al.2009), polypharmacy often occurs without evidence-based support or sometimes without clear or adequate optimization. For instance, Perlis et al. (2006) found that differences in acute efficacy in the treatment of mania with SGAs are likely to be small, if any, between monotherapy and add-on therapy. However, the literature suggests that there are patients who do not respond to acute treatment with monotherapy, especially in bipolar depression (Blanco et al.2002; Goldberg et al.2009; Kupfer et al.2002). A recent meta-analysis, however, compared co-therapy (antipsychotic plus mood stabilizer) with monotherapy (mood stabilizer alone) in the treatment of bipolar mania, and found higher response rates with co-therapy although with decreased tolerability (Smith et al.2007). Cipriani et al. (2007) have suggested that the small sample sizes and the heterogeneity of the study designs lead to biased results favouring co-therapy.

Material and methods

Search strategy and study selection

We conducted a comprehensive literature search of all the articles published up to March 2009 incorporating results of searches of Medline (from 1950), PsycINFO (from 1949), EMBASE (from 1988), the Cochrane Library (2009 January Issue), LILACS (from 1982), the ClinicalStudyResults.org, and two Internet search engines: PsiTri (www.psitri.stakes.fi) and Google Scholar (scholar.google.com). A limited update literature search using Medline was performed from 15 March 2009 to 13 August 2009.

To capture articles relevant to the scope of our review, we cross-referenced terms like ‘bipolar disorder’, ‘manic depressive’, ‘mania’, ‘mixed’, or ‘bipolar depression’, with trial characteristics search phrases and generic names of medications (approved or non-approved by regulatory agencies for their use in bipolar disorder). The full electronic search strategy is available upon request.

We planned a priori the inclusion of studies meeting the following criteria: randomized controlled trials (RCTs) comparing response and/or remission rates of a MDR with placebo or active treatment in patients with BP I (manic/mixed or depressive episodes). We chose discrete measures (response or remission rates) because they are clinically meaningful outcome measures (Lam & Kennedy, 2005). Exclusion criteria included: use of rating scales not validated in patients with bipolar mania, no clear definition of response or remission criteria, or inclusion of patients who had previously failed to respond to lithium or other mood stabilizers. Sample size was also an eligibility criteria to avoid weighting small studies inappropriately as suggested by Petitti (2000) when using random-effects models. The minimum median sample was 16.5 subjects in each group as suggested by a published empirical model (Richy et al.2004). Additional information required included trial duration, and medication dosage ranges. In addition, trials had to be peer-reviewed and published.

All RCTs were identified and reviewed by two of the authors (J. T. and G. V.). Any disagreements were discussed in order to reach consensus. Names of authors, institutions, or journals were not kept blind.

Evidence-based data for MDRs

We analysed the evidence supporting a therapeutic advantage for each MDR individually and for all evaluable trials combined vs. placebo or other active medication if they were classified as responders (a reduction of at least 50% in the initial score with any appropriate symptom rating scale) or remitters (a predetermined minimum absolute score as recommended in the literature (Tohen et al.2009); i.e. Young Mania Rating Scale (YMRS) ⩽12 or Mania Rating Scale (MRS) ⩽8 for patients with a manic/mixed episode, or Montgomery–Åsberg Depression Rating Scale (MADRS) ⩽12 or Hamilton Depression Rating Scale (HAMD) ⩽8 for patients with a depressive episode). Rates of discontinuation due to any cause, lack of efficacy, or adverse events (AEs) were also extracted.

Data synthesis

Studies were first qualitatively summarized. When more than one RCT was available for each MDR-comparator contrast, a meta-analytical calculation was used for each MDR. Efficacy and safety dichotomous data were statistically combined using a random-effects model. The relative risk (RR), which is defined as the ratio of the risk of an unfavourable outcome (non-response or non-remission) among treatment-allocated participants to the corresponding risk of an unfavourable outcome among those in the control group, was estimated along with their 95% confidence intervals (CIs) using the Review Manager 5.0.21 version software (The Cochrane Collaboration, UK). We also calculated RRs along with their 95% CIs for discontinuation due to any cause or discontinuation due to AEs for each MDR. Effect sizes such as number needed to treat (NNT) and number needed to harm (NNH) were also calculated. For this purpose we calculated risk differences (RDs), so NNT and NNH were estimated from the RD by the formula NNT or NNH=1/RD, with the 95% CI of NNT or NNH being the inverse of the upper and lower limits of the 95% CI of the RD. Only NNTs or NNHs <10 are considered clinically meaningful (Cook & Sackett, 1995; Kraemer & Kupfer, 2006).

Finally, we assessed the quality of the report on every RCT included in this review using a scale designed by Jadad et al. (1996). We performed χ2 and I2 statistics and the visual inspection of the forest plots derived from the χ2 values to test the proportion of total variation in study estimates that is due to heterogeneity. This analysis contrasts the RR of the individual trials with the pooled RR or the subgroups of trials. An I2 of at least 50% was taken as indicator of heterogeneity of outcome and considered inconclusive (Egger et al.1997, 2001; Higgins & Thompson, 2002; Higgins et al.2003).

Results

Included studies

We identified 101 non-duplicated RCTs, of which 40 fulfilled search criteria (Fig. 1). Some of the RCTs used a three-arm design thus could be used to make two comparisons each. In some cases, two or more articles/references provide data for the same RCT. The duration of most studies was 3 wk and most of them used the YMRS for the assessment of severity of manic symptoms. For bipolar depression, most studies were at least 7 wk in duration and utilized either the HAMD or the MADRS for the assessment of severity of depressive symptoms.

Fig. 1

Flow of information diagram through the different phases of the systematic review.

Fig. 1

Flow of information diagram through the different phases of the systematic review.

MDRs for acute mixed/mania episodes

Since the first evidence of lithium's efficacy in mania reported by Cade (1949) a considerable number of RCTs evaluating the efficacy of lithium salts, anticonvulsants, FGAs and SGAs used as MDRs in patients with acute mania have been published. Many studies that were reviewed did not meet our inclusion criteria due to their small sample size. Other studies were excluded because they had used rating scales neither specific nor validated for mania, had not included a clear definition of response or remission criteria, or had included patients that had previously not responded to lithium or other mood stabilizers [Ballenger & Post (1978, 1980), Berk et al. (1999), Bradwejn et al. (1990), Brown et al. (1989), Clark et al. (1997), Cookson et al. (1981), DelBello et al. (2005), Esparon et al. (1986), Findling et al. (2007), Freeman et al. (1992), Garfinkel et al. (1980), Garza-Treviño et al. (1992), Goncalves & Stoll (1985), Goodwin et al. (1969), Harrison & Keating (2005), Ichim et al. (2000), Janicak et al. (1998), Johnson et al. (1968), Kowatch et al. (2000), Kudo et al. (1987), Lerer et al. (1987), Lyseng-Williamson & Perry (2004), McElroy et al. (1991), Mishory et al. (2000), Moreno et al. (2007), Okuma et al. (1979, 1990), Ortega et al. (1993), Platman (1970), Pope et al. (1991), Post et al. (1987), Prien et al. (1972), Segal et al. (1998), Shopsin et al. (1975), Small et al. (1991), Spring et al. (1970), Storosum et al. (2007), Takahashi et al. (1975), Vasudev et al. (2000), Walton et al. (1996), and Zajecka et al. (2002) ]. Four RCTs with topiramate (n=433) vs. placebo (n=437) were presented in a combined analysis by Kushner et al. (2006) showing no significant efficacy difference between treatment groups. Two of those RCTs included lithium (n=227) as an active comparator. Unfortunately, separate data for our primary efficacy measures were not available.

In summary, 31 RCTs in acute mania fulfilled our study criteria (Table 1). Patients treated with MDR (n=3798) had a 1.61 (95% CI 1.49–1.75, I2=26%) higher chance of response, a 0.86 (95% CI 0.77–0.95, I2=40%) lower risk of discontinuation due to any cause, and a 0.55 (95% CI 0.47–0.63, I2=30%) lower risk of discontinuation due to lack of efficacy, but a 1.57 (95% CI 1.22–2.03, I2=18%) greater risk of discontinuation due to AEs than patients treated with placebo (n=2299). Additional comparisons showed that patients treated with mood stabilizers (n=1112) had a 1.57 (95% CI 1.36–1.81, I2=33%) higher chance of response, a 1.42 (95% CI 1.15–1.75) higher chance of remission (I2=40%), and a 0.55 (95% CI 0.41–0.74, I2=44%) lower risk of discontinuation due to lack of efficacy, but a 2.07 (95% CI 1.46–2.93, I2=0%) greater risk of discontinuation due to AEs than those patients treated with placebo (n=975). Furthermore, patients treated with SGAs (n=2107) had a 1.59 (95% CI 1.44–1.75, I2=22%) higher chance of response, a 0.55 (95% CI 0.46–0.65, I2=16%) lower risk of discontinuation due to lack of efficacy, and a 0.87 (95% CI 0.79–0.95, I2=0%) lower risk of discontinuation due to any cause, but a 1.36 (95% CI 1.03–1.79, I2=0%) higher risk of discontinuation due to AEs than patients treated with placebo (n=1691).

Table 1

Features and results of randomized trials of monotherapy drug regimen in patients with a bipolar disorder type I

ALT, Alanine aminotransferase; AM, acute mania; ARI, aripiprazole; CCMD-3, Chinese Classification and Diagnosis Criteria of Mental Disorder, 3rd version; Chol, cholesterol; EPS, extrapyramidal symptoms; ER-CBZ, extended-release carbamazepine capsules; GI, gastrointestinal; Glu, glucose; HAL, haloperidol; HAMD, Hamilton Depression Rating Scale; H, hospitalization; LAM, lamotrigine; LAM50, lamotrigine 50 mg/day; LAM200, lamotrigine 200 mg/d; Li, lithium; MADRS, Montgomery–Åsberg Depression Rating Scale; MDE, major depressive episode; MRS, Mania Rating Scale; n.a., non-available; O, outpatients; OLZ, olanzapine; OXC, oxcarbazepine; PLA, placebo; QUE, quetiapine; QUE300, quetiapine 300 mg/d; QUE600, quetiapine 600 mg/d; RCT, randomized clinical trial; RIS, risperidone; SADS, Schedule for Affective Disorders and Schizophrenia; TGl, triglycerides; TOP, topiramate 400 mg/d; TSH, thyroid stimulant hormone; VAL, valproate/divalproex; VER, verapamil; YMRS, Young Mania Rating Scale; ZIP, ziprasidone.

a

RCT quality using Jadad et al. (1996) criteria (0=high chance of bias to 5=very low chance of bias) based on three questions: (1) was the study described as randomized? (2) Was the study described as double-blind? (3) Was there a description of withdrawals and dropouts?

b

No prolactin values reported.

c

Includes data from three participants of a site withdrawn because of concerns about quality data.

d

Mean prolongation of QTc (11 ms and 10.1 ms per trial): ZIP>PLA (no percentages informed).

e

Calculation based on the MacFadden et al. (2005) data.

Included studies were heterogeneous with respect to inclusion of patients with/without a rapid-cycling course, manic/mixed states, presence/absence of psychotic symptoms, severity of mania, rates of study completion, and proportion of mood stabilizer-naive subjects. Almost all the included RCTs were sponsored by the pharmaceutical industry, therefore, there were not enough non-industry-sponsored studies to explore differences related to funding source. Of note, for tamoxifen, an experimental medication for the treatment of acute mania, we found two small RCTs (Yildiz et al.2008; Zarate et al.2007) including 40 patients treated with tamoxifen (dose range 40–80 mg/d) with a 7.46 (95% CI 1.90–29.32) higher chance of response and similar risk of discontinuation due to AEs than patients treated with placebo (n=34). Some analyses suggested marginal differences in favour of the MDR or the comparator. In these cases we decided to use the term ‘possibly’ to note that the difference was not conclusive.

We considered each MDR separately:

Lithium

We found (Fig. 2; Tables 1 and 2) six RCTs (Bowden et al.1994, 2005; Keck et al.2009; Li et al.2008; Niufan et al.2008; Singh, 2008). Patients treated with lithium (n=294) had a 1.65 (95% CI 1.23–2.21, I2=40%) higher chance of response, but possibly a greater risk of discontinuation due to AEs than patients treated with placebo (n=336). Inclusion of a combined analysis with two RCTs comparing lithium vs. placebo (Kushner et al.2006) did not significantly change the RR of response (1.61, 95% CI 1.36–1.91, I2=12%). In comparison with other MDRs (n=503), patients treated with lithium (n=467) had a 0.90 (95% CI 0.81–1.00, I2=0%) lower chance of response.

Fig. 2

Random risk ratios and 95% confidence intervals (CIs) for response rates with a monotherapy drug regimen (MDR) vs. placebo in the treatment of acute manic episodes. Response is defined as a reduction ⩾50% in the baseline total score in the primary efficacy measure after 3–6 wk of treatment. ER-CBZ, Extended-release carbamazepine capsules; M-H, Mantel–Haenszel.

Fig. 2

Random risk ratios and 95% confidence intervals (CIs) for response rates with a monotherapy drug regimen (MDR) vs. placebo in the treatment of acute manic episodes. Response is defined as a reduction ⩾50% in the baseline total score in the primary efficacy measure after 3–6 wk of treatment. ER-CBZ, Extended-release carbamazepine capsules; M-H, Mantel–Haenszel.

Table 2

Secondary efficacy and safety measures of randomized trials using monotherapeutic drug regimen in patients with a bipolar disorder type I

ARI, Aripiprazole; CBZ, carbamazepine; CI, confidence interval; ER-CBZ, extended-release carbamazepine capsules; Li, lithium; LAM, lamotrigine; MDR, monotherapy drug regime; MS, mood stabilizers; n.a., non-available; NNH, number needed to harm; NNT, number needed to treat; OLZ, olanzapine; OXC, oxcarbazepine; PLA, placebo; QUE, quetiapine; RIS, risperidone; SGA, second-generation antipsychotics; VAL, valproate/divalproex; VER, verapamil; ZIP, ziprasidone.

a

Based on one RCT.

b

Based on combined data from two RCTs.

Carbamazepine

Two RCTs with the extended release formulation of carbamazepine (ER-CBZ) (Weisler et al.2004, 2005) were included. Patients treated with ER-CBZ (n=221) had a 2.02 (95% CI 1.56–2.62, I2=0%) higher chance of response and possibly a lower risk of discontinuation due to lack of efficacy, but a greater risk of discontinuation due to AEs than patients treated with placebo (n=218). The NNH analysis suggested that four patients treated with carbamazepine instead of placebo are needed to observe an additional AE.

Oxcarbazepine

One 7-wk RCT with the use of oxcarbazepine in children and adolescents was included (Wagner et al.2006). Although it was reported that oxcarbazepine did not significantly improve YMRS scores at endpoint compared with placebo, we found that patients treated with oxcarbazepine (n=59) had a 1.56 (95% CI 1.13–2.16) higher chance of response, although a greater risk of discontinuation due to AEs than patients treated with placebo (n=57). Nine patients are needed to observe an additional AE if patients are treated with oxcarbazepine instead of placebo.

Valproate/divalproex

Seven RCTs were included (Bowden et al.1994, 2006; DelBello et al.2006; McElroy et al.1996; Tohen et al.2002, 2008; Wagner et al.2009). Patients treated with valproate (n=555) had a 1.39 (95% CI 1.16–1.65, I2=0%) higher chance of response, a 1.27 (95% CI 1.05–1.54) higher chance of remission (I2=72%) and a lower risk of discontinuation due to lack of efficacy, but had a greater risk of discontinuation due to AEs than patients treated with placebo (n=457). Nine patients are needed to observe an additional AE if patients are treated with valproate instead of placebo. In comparison with other MDRs (n=416), patients treated with valproate (n=439) had a similar chance of response, but a lower risk of discontinuation due to AEs. The exclusion of RCTs in children and adolescents (DelBello et al.2006; Wagner et al.2009) does not change the RR for either response vs. placebo or remission vs. other MDRs.

Haloperidol

Seven RCTs with haloperidol were included (McElroy et al.1996; McIntyre et al.2005; Smulevich et al.2005; Tohen et al.2003a; Vieta et al.2005, 2008; Young et al.2009). Patients treated with haloperidol (n=579) had a 1.31 (95% CI 1.04–1.65, I2=0%) higher chance of remission and a 1.63 (95% CI 1.25–2.12) higher chance of response (I2=64%) than patients treated with placebo (n=481). Although patients treated with haloperidol showed no increased risk of discontinuation for any cause or AE, a study showed that only two patients treated with haloperidol instead of placebo are needed to observe an additional AE. In comparison with other MDRs (n=985), patients treated with haloperidol (n=1030) showed a similar chance of response (I2=62%) or remission (I2=51%). The NNT analyses indicated that five patients treated with haloperidol instead of another MDR are needed to observe an additional AE.

Aripiprazole

Five RCTs were included (Keck et al.2003a, 2009; Sachs et al.2006; Vieta et al.2005; Young et al.2009). Patients treated with aripiprazole (n=582) had a 1.50 (95% CI 1.22–1.84, I2=44%) higher chance of response and a 1.28 (95% CI 1.05–1.57, I2=0%) higher chance of remission than patients treated with placebo (n=573). Eight patients treated with aripiprazole instead of placebo are needed to observe an additional AE. In comparison with other MDRs (n=497), patients treated with aripiprazole (n=497) had a similar chance of response and remission.

Olanzapine

Eight RCTs were included (Niufan et al.2008; Perlis et al.2006; Tohen et al.1999, 2000, 2002, 2003a, 2007, 2008). Patients treated with olanzapine (n=446) had a 1.62 (95% CI 1.27–2.08, I2=27%) higher chance of response, a 1.68 (95% CI 1.06–2.64) higher chance of remission (I2=62%), and had a lower risk of discontinuation due to any cause or lack of efficacy than patients treated with placebo (n=284). Six patients treated with olanzapine instead of placebo are needed to observe an additional AE. In comparison with other MDRs (n=778), patients treated with olanzapine (n=808) had a 1.17 (95% CI 1.06–1.30, I2=0%) higher chance of remission, and a similar chance of response.

Quetiapine

Four RCTs were included (Bowden et al.2005; DelBello et al.2006; Li et al.2008; McIntyre et al.2005). Patients treated with quetiapine (n=208) had a similar chance of response (1.52, 95% CI 0.97–2.37, I2=68%) and remission (1.59, 95% CI 0.86–2.94, I2=73%), but a lower risk of discontinuation due to lack of efficacy than patients treated with placebo (n=197) during the first 3 wk of treatment. However, the NNT was six (95% CI 3–9) and seven (95% CI 3–11) for response and remission vs. placebo, respectively. When data for the 12-wk studies were included, patients treated with quetiapine had a higher chance of response and remission vs. placebo. Differences between 3 and 12 wk may be due to the dose titration design in RCTs with quetiapine where the therapeutic dose is reached several days after the first study visit. In comparison with other MDRs (n=299), patients treated with quetiapine (n=310) had a similar chance of response (I2=69%) and remission (I2=69%).

Risperidone

Data from three RCTs available in four publications were included (Gopal et al.2005; Hirschfeld et al.2004; Khanna et al.2005; Smulevich et al.2005). Patients treated with risperidone (n=425) had a 1.77 (95% CI 1.44–2.17, I2=33%) higher chance of response, a 2.43 (95% CI 1.47–400) higher chance of remission (I2=63%), and a lower risk of discontinuation due to lack of efficacy in comparison with patients treated with placebo (n=418). In comparison with other MDRs (n=309), patients treated with risperidone (n=318) had a similar chance of response and remission, and a similar risk of discontinuation due to AEs, but a higher risk of discontinuation due to any cause.

Ziprasidone

Three RCTs were included (Keck et al.2003b; Potkin et al.2005; Vieta et al.2008). Patients treated with ziprasidone (n=446) had a 1.58 (95% CI 1.25–2.00, I2=0%) higher chance of response and a lower risk of discontinuation due to lack of efficacy or any cause, but a greater risk of discontinuation due to AE than those patients treated with placebo (n=219). Six patients treated with ziprasidone instead of placebo are needed to observe an additional AE. Data from one RCT indicates that patients treated with haloperidol (n=171) had a 1.48 (95% CI 1.17–1.87) higher chance of response and a 1.43 (95% CI 1.01–2.03) higher chance of remission than patients treated with ziprasidone (n=178), but a 2.53 (95% CI 1.08–5.94) higher risk of discontinuation due to AEs.

MDRs for acute depressive episodes

Many mood stabilizers (Ballenger & Post, 1980; Baron et al.1975; Davis et al.2005; Donnelly et al.1978; Fieve et al.1968; Geddes et al.2009 (Trial SCAA2010); Ghaemi et al.2007; Goodwin et al.1969, 1972; Mendels, 1976; Noyes et al.1974; Post et al.1986; Stokes et al.1971), antidepressants (Baumhackl et al.1989; Cohn et al.1989; Grossman et al.1999; Himmelhoch et al.1991; Silverstone et al.2001; Thase et al.1992), antipsychotics (DelBello et al.2009) or other medications (Smeraldi et al.1999) have been evaluated as monotherapies in bipolar depression. Not one of those RCTs fulfilled our study criteria therefore they were all excluded from the present analyses.

Nine RCTs fulfilling the study criteria on bipolar depression were included (Table 2). The overall RR for meta-analysis for response in bipolar depressed patients treated with MDR (n=1419) compared with placebo (n=1214) was 1.26 (95% CI 1.11–1.44, I2=54%) (Fig. 3). Further, patients treated with MDR had a 0.51 (95% CI 0.36–0.73, I2=46%) lower risk of discontinuation due to lack of efficacy, but a 1.77 (95% CI 1.38–2.26, I2=0%) greater risk of discontinuation due to AEs than those patients treated with placebo. We did not observe a significant difference vs. placebo for the RR for remission, nor for discontinuation due to any cause. Again, analyses including those trials with small sample sizes (n=3) did not significantly change the final results but increased their heterogeneity. The included studies were all sponsored by the pharmaceutical industry. They were heterogeneous with respect to inclusion of subjects with history of a rapid-cycling course or manic/mixed states, proportion of people with/without psychotic symptoms, severity of depression, rates of study completion, and proportion of mood stabilizer-naive or antidepressant-naive subjects.

Fig. 3

Random risk ratios and 95% confidence intervals (CIs) for response rates with a monotherapy drug regimen (MDR) vs. placebo in the treatment of depressive episodes Response is defined as a reduction ⩾50% in the baseline total score in the primary efficacy measure after 7–10 wk of treatment. M-H, Mantel–Haenszel.

Fig. 3

Random risk ratios and 95% confidence intervals (CIs) for response rates with a monotherapy drug regimen (MDR) vs. placebo in the treatment of depressive episodes Response is defined as a reduction ⩾50% in the baseline total score in the primary efficacy measure after 7–10 wk of treatment. M-H, Mantel–Haenszel.

Considering each MDR separately, we did not find any trials fulfilling our inclusion criteria to confirm or reject any potential role for valproate as monotherapy in acute bipolar depression, although a small RCT suggests better remission rates for valproate vs. placebo (Davis et al.2005). For other MDRs we found (Fig. 3; Tables 1 and 2) the following:

Lamotrigine

Data from three RCTs available in five publications/data sources were considered for analysis (Calabrese et al.1999, 2008; Geddes et al.2009; Trials SCA40910, SCA30924). We found that patients treated with lamotrigine (⩾200 mg/d) (n=327) had a similar chance of response (I2=0%) and remission (one study), and a similar risk of discontinuation due to lack of efficacy or AEs than those patients treated with placebo (n=317). Similar results were observed when we included the BP I and BP II patients, and all the doses evaluated for lamotrigine.

Aripiprazole

Data from two RCTs available in three publications/data sources were included (Thase et al.2008; Trials CN138-096, CN138-146). Patients treated with aripiprazole (n=373) had a similar chance of response (I2=0%) and remission (I2=0%), but greater risk of discontinuation due to lack of efficacy or any cause than those patients treated with placebo (n=376).

Olanzapine

Data from two RCTs available in three publications/data sources were included (Tohen et al.2003b; Trial 3077a). Patients treated with olanzapine (n=350) had a 1.34 (95% CI 1.02–1.76, I2=51%) higher chance of response, and a 1.24 (95% CI 1.05–1.46, I2=0%) higher chance of remission, and a lower risk of discontinuation due to lack of efficacy, but a greater risk of discontinuation due to AEs than those patients treated with placebo (n=356).

Quetiapine

Data from two RCTs available in four publications/data sources were included (Calabrese et al.2005; MacFadden et al.2005; Thase et al.2006; Weisler et al.2008). Patients treated with quetiapine (n=435) had a 1.58 (95% CI 1.10–2.26, I2=74%) higher chance of response, a 1.73 (95% CI 1.40–2.14) (combined data) higher chance of remission, and a lower risk of discontinuation due lack of efficacy, but a greater risk of discontinuation due to AEs than those patients treated with placebo (n=222). Similar results were observed when we evaluated together the BP I and BP II patients in terms of response, remission or discontinuations due to lack of efficacy or AE.

Discussion

We found in most studies that MDRS are efficacious in the treatment of acute manic episodes. In these studies the entire range of confidence intervals exceeds the cut-off point below which the effect size is defined as no different to placebo (Fig. 2). We also found that it is necessary to treat six (95% CI 5–7) or seven (95% CI 5–8) patients to observe a significant difference in response or remission rates, respectively, with MDR over placebo in the treatment of acute manic episodes (Table 2). Finally, a combined analysis with several RCTS suggests that topiramate is not efficacious in the treatment of acute mania (Kushner et al.2006). In patients with acute manic episodes, study discontinuation due to AEs was significantly more likely to be observed with a MDR than with placebo, but study discontinuation due to lack of efficacy or discontinuation to any cause were significantly lower with SGAS than with placebo. Regarding the comparisons between an active compound against another MDR (usually lithium, valproate or haloperidol), we did not find significant differences in terms of response, remission, or discontinuation due to AEs, lack of efficacy, or discontinuation due to any cause.

Regarding acute bipolar depressive episodes, we found that only olanzapine and quetiapine showed response and/or remission rates superior to those reported with placebo (substantial heterogeneity was observed with both analyses), although the effect size for quetiapine in response was almost double that for olanzapine (Fig. 3). Early RCTs have shown significant therapeutic effects with lithium for bipolar depression (Thase & Sachs, 2000), but small samples and other methodological shortcomings limits the evidence for its use as a MDR for BP I depressed patients.

Although some patients with a bipolar depressive episode may certainly benefit from a MDR, the evidence is still limited and many BP I patients with a depressive episode appear to require the addition of another mood stabilizer (Kramlinger & Post, 1989) or an antidepressant (Tamayo et al.2009; Tohen et al. 2003b; Young et al.2000). Interestingly, some RCTs comparing a CDR with a MDR with no previous lack of response did not report statistical differences favouring the CDR in BP I-depressed patients (Amsterdam & Shults, 2005; Brown et al.2006; Nolen & Bloemkolk, 2000). On the other hand, although the literature supports the efficacy of lamotrigine in preventing bipolar depressive relapses (Goodwin et al.2004), it does not provide evidence to support the efficacy of this medication in the acute depressive phase of BP I patients. Recently, a review concluded that lamotrigine monotherapy did not demonstrate efficacy in the acute treatment of bipolar depression in four out of five RCTs (Calabrese et al.2008). However, a meta-analysis with the same RCT, reported a statistically significant small effect size of depressive symptom benefit only in patients with a HAMD score >24 (Geddes et al.2009).

The relevance of different therapeutic interventions for BP I and their efficacy must be evaluated based on the best available evidence. Unfortunately, the treatment of patients with BP I is usually complex, and many treatment interventions implemented by clinicians at times may not be evidence-based. A survey in an acute general psychiatric ward indicated that <65% of treatment decisions were based on evidence from RCTs (Goldner et al.2001). Studies in which pharmacological treatment is allocated by any method other than randomization tend to show larger (and frequently false-positive) treatment effects than do RCTs. Randomization prevents biased assignment of treatment and confounders that are unknown or unmeasured (Chalmers et al.1983). However, caution is needed in drawing clear-cut generalizations to clinical practice based on our analyses due to the heterogeneity in trial designs, the methodological quality of included trials, and the nature, timing, and dose of mood stabilizers or SGAs. Additionally, the fact that almost all the RCTs in the field of bipolar disorder are aimed at registration approval, there may be a gap between the evidence base of patients who participate in clinical trials and clinical populations (Vieta & Carné, 2005).

We examined the results from available studies to determine the possibility of publication bias or selective reporting bias. We additionally, compared the data published with that reported on the trial registry or at ‘ClinicalStudyResults.org’, and we excluded trials with small sample sizes that would tend to show larger estimates of the effects of the intervention. However, the quality of the studies varied and we were not blinded to their quality when determining their inclusion. Several analyses showed a heterogeneity statistic I2>50% that ‘may represent substantial heterogeneity’ (Deeks et al.2008) and the funnel plot for each of them showed evidence of considerable asymmetry. As noted by Higgins et al. (2003), regarding heterogeneity, ‘inconsistency of studies’ results in a meta-analysis with reduced confidence of recommendations about treatment'. Additionally, although we examined the ‘ClinicalStudyResults.org’ webpage and several conference proceedings using a combination of hand and electronic searching, we cannot exclude the possibility that there are unpublished negative studies that we were unable to access.

In conclusion, although there are patients who are unresponsive to acute treatment with monotherapy, these results suggest that MDRs should be considered as a first therapeutic option for the treatment of non-refractory manic episodes. This approach may result in the reduction of direct costs of medications, the number and magnitude of AEs and may improve treatment adherence and patient compliance (Grunze et al.2009). For depressive episodes, the new data with SGAs (quetiapine and olanzapine) suggest that these MDR, especially quetiapine, are efficacious and well tolerated.

Acknowledgements

The views held by Dr Zarate do not necessarily reflect those of the Federal Government.

Statement of Interest

Dr Tamayo was an employee of Eli Lilly Laboratories during the first analyses for this paper and has received honoraria from Eli Lilly, Janssen, Pfizer, and Wyeth. Dr Zarate is supported by the intramural research program at the NIMH and has not received any industry funding in the past year. Dr Vieta is supported by the Spanish Ministry of Science and Innovation (CIBERSAM), is a consultant to and received honoraria from AstraZeneca, Bristol–Myers, Eli Lilly, Janssen-Cilag, Lundbeck, Sanofi, has received grant or research support from Eli Lilly, GlaxoSmithKline, Janssen-Cilag, and Novartis, and has been on the advisory board of AstraZeneca, Bristol–Myers, Eli Lilly, Janssen-Cilag, Organon, and Pfizer. Dr Vázquez is a consultant to and received honoraria from AstraZeneca, GlaxoSmithKline, Roche and Eli Lilly. Dr Tohen was an employee of Eli Lilly Laboratories during the planning and analyses of this paper and has received honoraria from AstraZeneca, Bristol–Myers Squibb, GlaxoSmithKline, Eli Lilly and Wyeth. His spouse in an employee and stockholder of Eli Lilly.

References

Amsterdam
JD
Shults
J
(
2005
).
Comparison of fluoxetine, olanzapine, and combined fluoxetine plus olanzapine initial therapy of bipolar type I and type II major depression–lack of manic induction
.
Journal of Affective Disorders
 
87
,
121
130
.
[PubMed]
Baldessarini
RJ
Leahy
L
Arcona
S
Gause
D
et al
(
2007
).
Patterns of psychotropic drug prescription for U.S. patients with diagnoses of bipolar disorders
.
Psychiatry Services
 
58
,
85
91
.
Ballenger
JC
Post
RM
(
1978
).
Therapeutic effects of carbamazepine in affective illness: a preliminary report
.
Communications in Psychopharmacology
 
2
,
159
175
.
[PubMed]
Ballenger
JC
Post
RM
(
1980
).
Carbamazepine in manic-depressive illness: a new treatment
.
American Journal of Psychiatry
 
137
,
782
790
.
[PubMed]
Baron
M
Gershon
ES
Rudy
V
Jonas
WZ
et al
(
1975
).
Lithium carbonate response in depression. Prediction by unipolar/bipolar illness, average-evoked response, catechol-O-methyl transferase, and family history
.
Archives of General Psychiatry
 
32
,
1107
1111
.
[PubMed]
Baumhackl
U
Biziere
K
Fischbach
R
Geretsegger
C
et al
(
1989
).
Efficacy and tolerability of moclobemide compared with imipramine in depressive disorder (DSM-III): an Austrian double-blind, multicentre study
.
British Journal of Psychiatry
 
6
(
Suppl.
),
78
83
.
Berk
M
Ichim
L
Brook
S
(
1999
).
Olanzapine compared to lithium in mania: a double-blind randomized controlled trial
.
International Clinical Psychopharmacology
 
14
,
339
343
.
[PubMed]
Blanco
C
Laje
G
Olfson
M
Marcus
SC
et al
(
2002
).
Trends in the treatment of bipolar disorder by outpatient psychiatrists
.
American Journal of Psychiatry
 
159
,
1005
1010
.
[PubMed]
Bowden
CL
Brugger
AM
Swann
AC
Calabrese
JR
et al
(
1994
).
Efficacy of divalproex vs. lithium and placebo in the treatment of mania
.
Journal of the American Medical Association
 
271
,
918
924
.
[PubMed]
Bowden
CL
Grunze
H
Mullen
J
Brecher
M
et al
(
2005
).
A randomized, double-blind, placebo-controlled efficacy and safety study of quetiapine or lithium as monotherapy for mania in bipolar disorder
.
Journal of Clinical Psychiatry
 
66
,
111
121
.
[PubMed]
Bowden
CL
Swann
AC
Calabrese
JR
Rubenfaer
LM
et al
(
2006
).
A randomized, placebo-controlled, multicenter study of divalproex sodium extended release in the treatment of acute mania
.
Journal of Clinical Psychiatry
 
67
,
1501
1510
.
[PubMed]
Bradwejn
J
Shriqui
C
Koszycki
D
Meterissian
G
(
1990
).
Double-blind comparison of the effects of clonazepam and lorazepam in acute mania
.
Journal of Clinical Psychopharmacology
 
10
,
403
408
.
[PubMed]
Brown
D
Silverstone
T
Cookson
J
(
1989
).
Carbamazepine compared to haloperidol in acute mania
.
International Clinical Psychopharmacology
 
4
,
229
238
.
[PubMed]
Brown
EB
McElroy
SL
Keck
PE
Jr.
Deldar
A
et al
(
2006
).
A 7-week, randomized, double-blind trial of olanzapine/fluoxetine combination versus lamotrigine in the treatment of bipolar I depression
.
Journal of Clinical Psychiatry
 
67
,
1025
1033
.
[PubMed]
Cade
JF
(
1949
).
Lithium salts in the treatment of psychiatric excitement
.
Medical Journal of Australia
 
2
,
349
.
[PubMed]
Calabrese
JR
Bowden
CL
Sachs
GS
Ascher
JA
et al
(
1999
).
A double-blind placebo-controlled study of lamotrigine monotherapy in outpatients with bipolar I depression. Lamictal 602 Study Group
.
Journal of Clinical Psychiatry
 
60
,
79
88
.
[PubMed]
Calabrese
JR
Huffman
RF
White
RL
Edwards
S
et al
(
2008
).
Lamotrigine in the acute treatment of bipolar depression: results of five double-blind, placebo-controlled clinical trials
.
Bipolar Disorders
 
10
,
323
333
.
[PubMed]
Calabrese
JR
Keck
PE
MacFadden
W
Minkwitz
M
et al
(
2005
).
A randomized, double-blind, placebo-controlled trial of quetiapine in the treatment of bipolar I or II depression
.
American Journal of Psychiatry
 
162
,
1351
1360
.
[PubMed]
Cavazzoni
PA
Berg
PH
Kryzhanovskaya
LA
Briggs
SD
et al
(
2006
).
Comparison of treatment-emergent extrapyramidal symptoms in patients with bipolar mania or schizophrenia during olanzapine clinical trials
.
Journal of Clinical Psychiatry
 
67
,
107
113
.
[PubMed]
Chalmers
TC
Celano
P
Sacks
HS
Smith
H
Jr.
(
1983
).
Bias in treatment assignment in controlled clinical trials
.
New England Journal of Medicine
 
309
,
1358
1361
.
[PubMed]
Cipriani
A
Signoretti
A
Barbui
C
(
2007
).
Review: antipsychotic plus mood stabiliser co-therapy is more effective than mood stabiliser mono-therapy at reducing acute bipolar mania
.
Evidence-Based Mental Health
 
10
,
83
.
[PubMed]
Clark
HM
Berk
M
Brook
S
(
1997
).
A randomized controlled single blind study of the efficacy of clonazepam and lithium in the treatment of acute mania
.
Human Psychopharmacology
 
12
,
325
328
.
Cohn
JB
Collins
G
Ashbrook
E
Wernicke
JF
(
1989
).
A comparison of fluoxetine, imipramine and placebo in patients with bipolar depressive disorder
International Clinical Psychopharmacology
 
4
,
313
322
.
[PubMed]
Cook
RJ
Sackett
DL
(
1995
).
The number needed to treat: a clinically useful measure of treatment effect
.
British Medical Journal
 
310
,
452
454
.
[PubMed]
Cookson
J
Silverstone
T
Wells
B
(
1981
).
Double-blind comparative clinical trial of pimozide and chlorpromazine in mania. A test of the dopamine hypothesis
.
Acta Psychiatrica Scandinavica
 
64
,
381
397
.
[PubMed]
Davis
LL
Bartolucci
A
Petty
F
(
2005
).
Divalproex in the treatment of bipolar depression: a placebo-controlled study
.
Journal of Affective Disorders
 
85
,
259
266
.
[PubMed]
Deeks
JJ
Higgins
JP
Altman
D
(
2008
).
Analysing data and undertaking meta-analysis
. In:
Higgins
JP
Green
S
(Eds),
Cochrane Handbook for Systematic Reviews of Interventions
  (pp.
243
298
).
Chichester
:
John Wiley & Sons
.
DelBello
MP
Chang
K
Welge
JA
Adler
CM
et al
(
2009
).
A double-blind, placebo-controlled pilot study of quetiapine for depressed adolescents with bipolar disorder
.
Bipolar Disorders
 
11
,
483
493
.
[PubMed]
DelBello
MP
Findling
RL
Kushner
S
Wang
D
et al
(
2005
).
A pilot controlled trial of topiramate for mania in children and adolescents with bipolar disorder
.
Journal of the American Academy of Child and Adolescent Psychiatry
 
44
,
539
547
.
[PubMed]
DelBello
MP
Kowatch
RA
Adler
CM
Stanford
KE
et al
(
2006
).
A double-blind randomized pilot study comparing quetiapine and divalproex for adolescent mania
.
Journal of the American Academy of Child and Adolescent Psychiatry
 
45
,
305
313
.
[PubMed]
Donnelly
EF
Goodwin
FK
Waldman
IN
Murphy
DL
(
1978
).
Prediction of antidepressant responses to lithium
.
American Journal of Psychiatry
 
135
,
552
556
.
[PubMed]
Egger
M
Dickersin
K
Smith
GD
(
2001
).
Problems and limitations in conducting systematic reviews
. In:
Egger
M
Smith
GD
Altman
GD
(Eds.),
Systematic Reviews in Health Care
  (pp.
43
68
).
London
:
BMJ Books
.
Egger
M
Smith
GD
Phillips
AN
(
1997
).
Meta-analysis: principles and procedures
.
British Medical Journal
 
315
,
1533
1537
.
[PubMed]
Fieve
RR
Platman
SR
Plutchik
RR
(
1968
).
The use of lithium in affective disorders, I: acute endogenous depression
.
American Journal of Psychiatry
 
25
,
487
491
.
Findling
RL
Frazier
TW
Youngstrom
EA
McNamara
NK
et al
(
2007
).
Double-blind, placebo-controlled trial of divalproex monotherapy in the treatment of symptomatic youth at high risk for developing bipolar disorder
.
Journal of Clinical Psychiatry
 
68
,
781
788
.
[PubMed]
Fountoulakis
KN
Vieta
E
(
2008
).
Treatment of bipolar disorder: a systematic review of available data and clinical perspectives
.
International Journal of Neuropsychopharmacology
 
11
,
999
1029
.
[PubMed]
[PubMed]
Freeman
TW
Clothier
JL
Pazzaglia
P
Lesem
MD
et al
(
1992
).
A double-blind comparison of valproate and lithium in the treatment of acute mania
.
American Journal of Psychiatry
 
149
,
108
111
.
[PubMed]
Garfinkel
PE
Stancer
HC
Persad
E
(
1980
).
A comparison of haloperidol, lithium carbonate and their combination in the treatment of mania
.
Journal of Affective Disorders
 
2
,
279
288
.
[PubMed]
Garza-Treviño
ES
Overall
JE
Hollister
LE
(
1992
).
Verapamil versus lithium in acute mania
.
American Journal of Psychiatry
 
149
,
121
122
.
[PubMed]
Geddes
JR
Calabrese
JR
Goodwin
GM
(
2009
).
Lamotrigine for treatment of bipolar depression: independent meta-analysis and metaregression of individual patient data from five randomised trials
.
British Journal of Psychiatry
 
194
,
4
9
.
[PubMed]
Ghaemi
SN
Gilmer
WS
Goldberg
JF
Zablotsky
B
et al
(
2007
).
Divalproex in the treatment of acute bipolar depression: a preliminary double-blind, randomized, placebo-controlled pilot study
.
Journal of Clinical Psychiatry
 
68
,
1840
1844
.
[PubMed]
Goldberg
JF
Brooks
JO
3rd
Kurita
K
Hoblyn
JC
et al
(
2009
).
Depressive illness burden associated with complex polypharmacy in patients with bipolar disorder: findings from the STEP-BD
.
Journal of Clinical Psychiatry
 
70
,
155
162
.
[PubMed]
Goldner
EM
Abass
A
Leverette
JS
Haslam
DR
(
2001
)
Evidence-Based Psychiatric Practice: Implications for Education and Continuing Professional Development
 .
Ottawa, ON
:
Canadian Psychiatric Association Current Position Papers and Guidelines
.
Goncalves
N
Stoll
KD
(
1985
).
Carbamazepine in manic syndromes. A controlled double-blind study
.
Nervenarzt
 
56
,
43
47
.
[PubMed]
Goodwin
FK
Murphy
DL
Bunney
WE
Jr.
(
1969
).
Lithium-carbonate in depression and mania: a longitudinal double blind study
.
Archives of General Psychiatry
 
21
,
486
496
.
[PubMed]
Goodwin
FK
Murphy
DL
Dunner
DL
Bunney
WE
Jr.
(
1972
).
Lithium response in unipolar versus bipolar depression
.
American Journal of Psychiatry
 
129
,
44
47
.
[PubMed]
Goodwin
GM
Bowden
CL
Calabrese
JR
Grunze
H
et al
(
2004
).
A pooled analysis of 2 placebo-controlled 18-month trials of lamotrigine and lithium maintenance in bipolar I disorder
.
Journal of Clinical Psychiatry
 
65
,
432
441
.
[PubMed]
Gopal
S
Steffens
DC
Kramer
ML
Olsen
MK
(
2005
).
Symptomatic remission in patients with bipolar mania: results from a double-blind, placebo-controlled trial of risperidone monotherapy
.
Journal of Clinical Psychiatry
 
66
,
1016
1020
.
[PubMed]
Grossman
F
Potter
WZ
Brown
EA
Maislin
G
(
1999
).
A double-blind study comparing idazoxan and bupropion in bipolar depressed patients
.
Journal of Affective Disorders
 
56
,
237
243
.
[PubMed]
Grunze
H
Vieta
E
Goodwin
GM
Bowden
C
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 Journal of Biological Psychiatry
 
10
,
85
116
.
[PubMed]
Harrison
TS
Keating
GM
(
2005
).
Extended-release carbamazepine capsules in bipolar I disorder
.
CNS Drugs
 
19
,
709
716
.
[PubMed]
Higgins
JPT
Thompson
SG
(
2002
).
Quantifying heterogeneity in a meta-analysis
.
Statistics in Medicine
 
21
,
1539
1558
.
[PubMed]
Higgins
JPT
Thompson
SG
Deeks
JJ
Altman
DG
(
2003
).
Measuring inconsistency in meta-analyses
.
British Medical Journal
 
327
,
557
560
.
[PubMed]
Himmelhoch
JM
Thase
ME
Mallinger
AG
Houck
P
(
1991
).
Tranylcypromine versus imipramine in anergic bipolar depression
.
American Journal of Psychiatry
 
148
,
910
916
.
[PubMed]
Hirschfeld
RM
Keck
PE
Jr.
Kramer
M
Karcher
K
et al
(
2004
).
Rapid antimanic effect of risperidone monotherapy: a 3-week multicenter, double-blind, placebo-controlled trial
.
American Journal of Psychiatry
 
161
,
1057
1065
.
[PubMed]
Ichim
L
Berk
M
Brook
S
(
2000
)
Lamotrigine compared with lithium in mania: a double-blind randomized controlled trial
.
Annals of Clinical Psychiatry
 
12
,
5
10
.
[PubMed]
Jadad
AR
Moore
RA
Carroll
D
Jenkinson
C
et al
(
1996
).
Assessing the quality of reports of randomized clinical trials: is blinding necessary?
.
Controlled Clinical Trials
 
17
,
1
12
.
[PubMed]
Janicak
PG
Sharma
RP
Pandey
G
Davis
JM
(
1998
).
Verapamil for the treatment of acute mania: a double-blind, placebo-controlled trial
.
American Journal of Psychiatry
 
155
,
972
973
.
[PubMed]
Johnson
G
Gershon
S
Hekiman
LJ
(
1968
).
Controlled evaluation of lithium and chlorpromazine in the treatment of manic states: an interim report
.
Comprehensive Psychiatry
 
9
,
563
573
.
[PubMed]
Keck
PE
Jr.
Marcus
R
Tourkodimitris
S
Ali
M
et al
(
2003
a).
A placebo-controlled double-blind study of the efficacy and safety of aripiprazole in patients with acute bipolar mania
.
American Journal of Psychiatry
 
160
,
1651
1658
.
[PubMed]
Keck
PE
Jr.
Versiani
M
Potkin
S
West
SA
et al
(
2003
b).
Ziprasidone in the treatment of acute bipolar mania: a three-week, placebo-controlled, double-blind, randomized trial
.
American Journal of Psychiatry
 
160
,
741
748
.
[PubMed]
Keck
PE
Orsulak
PJ
Cutler
AJ
Sanchez
R
et al
(
2009
).
Aripiprazole monotherapy in the treatment of acute bipolar I mania: a randomized, double-blind, placebo- and lithium-controlled study
.
Journal of Affective Disorders
 
112
,
36
49
.
[PubMed]
Khanna
S
Vieta
E
Lyons
B
Grossman
F
et al
(
2005
).
Risperidone in the treatment of acute bipolar mania: a double-blind, placebo-controlled study
.
British Journal of Psychiatry
 
187
,
229
234
.
[PubMed]
Kowatch
RA
Suppes
T
Carmody
TJ
Bucci
JP
et al
(
2000
).
Effect size of lithium, divalproex sodium, and carbamazepine in children and adolescents with bipolar disorder
.
Journal of the American Academy of Child and Adolescent Psychiatry
 
39
,
713
720
.
[PubMed]
Kraemer
HC
Kupfer
DJ
(
2006
).
Size of treatment effects and their importance to clinical research and practice
.
Biological Psychiatry
 
59
,
990
996
.
[PubMed]
Kramlinger
KG
Post
RM
(
1989
).
The addition of lithium to carbamazepine. Antidepressant efficacy in treatment-resistant depression
.
Archives of General Psychiatry
 
46
,
794
800
.
[PubMed]
Kudo
Y
Ichimaru
S
Kawakita
Y
Saito
M
et al
(
1987
).
Comparison of therapeutic effect on mania of sultopride hydrochloride with haloperidol using double-blind hnique
.
Rinsho Hyoka
 
15
,
15
36
.
Kupfer
DJ
Frank
E
Grochocinski
VI
Cluss
PA
et al
(
2002
).
Demographic and clinical characteristics of individuals in a bipolar disorder case registry
.
Journal of Clinical Psychiatry
 
63
,
120
125
.
[PubMed]
Kushner
SF
Khan
A
Lane
R
Olson
WH
(
2006
).
Topiramate monotherapy in the management of acute mania: results of four double-blind placebo-controlled trials
.
Bipolar Disorders
 
8
,
15
27
.
[PubMed]
Lam
RW
Kennedy
SH
(
2005
).
Using metaanalysis to evaluate evidence: practical tips and traps
.
Canadian Journal of Psychiatry
 
50
,
167
174
.
Lerer
B
Moore
N
Meyendorff
E
Cho
SR
et al
(
1987
).
Carbamazepine versus lithium in mania: a double-blind study
.
Journal of Clinical Psychiatry
 
48
,
89
93
.
[PubMed]
Levine
J
Chengappa
KN
Brar
JS
Gershon
S
et al
(
2000
).
Psychotropic drug prescription patterns among patients with bipolar I disorder
.
Bipolar Disorders
 
2
,
120
130
.
[PubMed]
Lewis
J
Winokur
G
(
1982
).
The induction of mania: a natural history study with controls
.
Archives of General Psychiatry
 
39
,
303
306
.
[PubMed]
Li
H
Ma
C
Wang
G
Zhu
X
et al
(
2008
).
Response and remission rates in Chinese patients with bipolar mania treated for 4 weeks with either quetiapine or lithium: a randomized and double-blind study
.
Current Medical Research and Opinion
 
24
,
1
10
.
[PubMed]
Lyseng-Williamson
KA
Perry
CM
(
2004
).
Aripiprazole: in acute mania associated with bipolar I disorder
.
CNS Drugs
 
18
,
367
376
.
[PubMed]
MacFadden
W
Calabrese
J
Suppes
T
McCoy
R
et al
(
2005
).
Quetiapine in bipolar I depression: Double-blind, placebo-controlled study. Poster NR802, presented at the 158th APA Annual Meeting
 ,
Atlanta, GA
.
McElroy
SL
Keck
PE
Pope
HG
Hudson
JI
et al
(
1991
).
Correlates of antimanic response to valproate
.
Psychopharmacology Bulletin
 
27
,
127
133
.
[PubMed]
McElroy
SL
Keck
PE
Stanton
SP
Tugrul
KC
et al
(
1996
).
A randomized comparison of divalproex oral loading versus haloperidol in the initial treatment of acute psychotic mania
.
Journal of Clinical Psychiatry
 
57
,
142
146
.
[PubMed]
McIntyre
RS
Brecher
M
Paulsson
B
Huizar
K
et al
(
2005
).
Quetiapine or haloperidol as monotherapy for bipolar mania. A 12-week, double-blind, randomized, parallel-group, placebo-controlled trial
.
European Neuropsychopharmacology
 
15
,
573
585
.
[PubMed]
Mendels
J
(
1976
).
Lithium in the treatment of depression
.
American Journal of Psychiatry
 
133
,
373
378
.
[PubMed]
Mishory
A
Yaroslavsky
Y
Bersudsky
Y
Belmaker
RH
(
2000
).
Phenytoin as an antimanic anticonvulsant: a controlled study
.
American Journal of Psychiatry
 
157
,
463
465
.
[PubMed]
Moreno
RA
Hanna
MM
Tavares
SM
Wang
YP
(
2007
).
A double-blind comparison of the effect of the antipsychotics haloperidol and olanzapine on sleep in mania
.
Brazilian Journal of Medical and Biological Research
 
40
,
357
366
.
[PubMed]
Mukherjee
S
Rosen
AM
Caracci
G
Shukla
S
(
1986
).
Persistent tardive dyskinesia in bipolar patients
.
Archives of General Psychiatry
 
43
,
342
346
.
[PubMed]
Niufan
G
Tohen
M
Qiuqing
A
Fude
Y
et al
(
2008
).
Olanzapine versus lithium in the acute treatment of bipolar mania: a double-blind, randomized, controlled trial
.
Journal of Affective Disorders
 
105
,
101
118
.
[PubMed]
Nolen
WA
Bloemkolk
D
(
2000
).
Treatment of bipolar depression, a review of the literature and a suggestion for an algorithm
.
Neuropsychobiology
 
1
(
Suppl.
),
11
17
.
Noyes
R
Jr.
Dempsey
GM
Blum
A
Cavanaugh
GL
(
1974
).
Lithium treatment of depression
.
Comprehensive Psychiatry
 
15
,
187
193
.
[PubMed]
Okuma
T
Inanaga
K
Otsuki
S
Sarai
K
et al
(
1979
).
Comparison of the antimanic efficacy of carbamazepine and chlorpromazine: a double-blind controlled study
.
Psychopharmacology
 
66
,
211
217
.
[PubMed]
Okuma
T
Yamashita
I
Takahashi
R
Itoh
H
et al
(
1990
).
Comparison of the antimanic efficacy of carbamazepine and lithium carbonate by double-blind controlled study
.
Pharmacopsychiatry
 
23
,
143
150
.
[PubMed]
Ortega
HA
Hernandez
CA
Jasso
A
Hasfura
CA
(
1993
).
Carbamazepine vs. haloperidol in the treatment of manic episodes: a controlled clinical trial
.
Salud Mental
 
16
,
44
50
.
Perlis
RH
Baker
RW
Zarate
CA
Jr.
Brown
EB
et al
(
2006
).
Olanzapine versus risperidone in the treatment of manic or mixed States in bipolar I disorder: a randomized, double-blind trial
.
Journal of Clinical Psychiatry
 
67
,
1747
1753
.
[PubMed]
Petitti
DB
(
2000
).
Meta-Analysis, Meta-Analysis, Decision Analysis, and Cost-Effectiveness Analysis: Methods for Quantitative Synthesis in Medicine
 ,
2nd edn
(pp.
83
85
,
95
99
),
New York
:
Oxford University Press
.
Platman
SR
(
1970
).
A comparison of lithium carbonate and chlorpromazine in mania
.
American Journal of Psychiatry
 
127
,
351
353
.
[PubMed]
Pope
HG
Jr.
McElroy
SL
Keck
PE
Jr.
Hudson
JI
(
1991
).
Valproate in the treatment of acute mania. A placebo-controlled study
.
Archives of General Psychiatry
 
48
,
62
68
.
[PubMed]
Post
RM
Altshuler
LL
Leverich
GS
Frye
MA
et al
(
2006
).
Mood switch in bipolar depression: comparison of adjunctive venlafaxine, bupropion and sertraline
.
British Journal of Psychiatry
 
189
,
124
131
.
[PubMed]
Post
RM
Uhde
TW
Roy-Byrne
PP
Joffe
RT
(
1986
).
Antidepressant effects of carbamazepine
.
American Journal of Psychiatry
 
3
,
29
34
.
Post
RM
Uhde
TW
Roy-Byrne
PP
Joffe
RT
(
1987
).
Correlates of antimanic response to carbamazepine
.
Psychiatry Research
 
21
,
71
83
.
[PubMed]
Potkin
SG
Keck
PE
Jr.
Segal
S
Ice
K
et al
(
2005
).
Ziprasidone in acute bipolar mania. A 21-day randomized, double-blind, placebo-controlled replication trial
.
Journal of Clinical Psychopharmacology
 
25
,
301
310
.
[PubMed]
Prien
RF
Caffey
EM
Jr.
Klett
CJ
(
1972
).
Comparison of lithium carbonate and chlorpromazine in the treatment of mania. Report of the Veterans Administration and National Institute of Mental Health Collaborative Study Group
.
Archives of General Psychiatry
 
26
,
146
153
.
[PubMed]
Richy
F
Ethgen
O
Bruyere
O
Deceulaer
F
et al
(
2004
).
From sample size to effect-size: small study effect investigation (SSEi)
.
The Internet Journal of Epidemiology
 
1
.
Sachs
G
Sanchez
R
Marcus
R
Stock
E
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
.
Journal of Psychopharmacology
 
20
,
536
546
.
[PubMed]
Sachs
GS
Nierenberg
AA
Calabrese
JR
Marangell
LB
et al
(
2007
).
Effectiveness of adjunctive antidepressant treatment for bipolar depression
.
New England Journal of Medicine
 
356
,
1711
1722
.
[PubMed]
Segal
J
Berk
M
Brook
S
(
1998
).
Risperidone compared with both lithium and haloperidol in mania: a double-blind randomized controlled trial
.
Clinical Neuropharmacology
 
21
,
176
180
.
[PubMed]
Shopsin
B
Gershon
S
Thompson
H
Collins
P
(
1975
).
Psychoactive drug in mania. A controlled comparison of lithium carbonate, chlorpromazine, and haloperidol
.
Archives of General Psychiatry
 
32
,
34
42
.
[PubMed]
Silverstone
T
on behalf of the Moclobemide Bipolar Study Group
(
2001
).
Moclobemide vs. imipramine in bipolar depression: a multicentre double-blind clinical trial
.
Acta Psychiatrica Scandinavica
 
104
,
104
109
.
[PubMed]
Singh
GP
(
2008
).
A double blind comparative study of clinical efficacy of verapamil versus lithium in acute mania
.
International Journal of Psychiatry in Clinical Practice
 
12
,
303
308
.
Small
JG
Klapper
MH
Milstein
V
Kellams
JJ
et al
(
1991
).
Carbamazepine compared with lithium in the treatment of mania
.
Archives of General Psychiatry
 
48
,
915
921
.
[PubMed]
Smeraldi
E
Benedetti
F
Barbini
B
Campori
E
et al
(
1999
).
Sustained antidepressant effect of sleep deprivation combined with pindolol in bipolar depression: a placebo-controlled trial
.
Neuropsychopharmacology
 
20
,
380
385
.
[PubMed]
Smith
LA
Cornelius
V
Warnock
A
Tacchi
MJ
et al
(
2007
).
Acute bipolar mania: a systematic review and meta-analysis of co-therapy vs. monotherapy
.
Acta Psychiatrica Scandinavica
 
115
,
12
20
.
[PubMed]
Smulevich
AB
Khanna
S
Eerdekens
M
Karcher
K
et al
(
2005
).
Acute and continuation risperidone monotherapy in bipolar mania: a 3-week placebo-controlled trial followed by a 9-week double-blind trial of risperidone and haloperidol
.
European Neuropsychopharmacology
 
15
,
75
84
.
[PubMed]
Spring
G
Schweid
D
Gray
C
Steinberg
J
et al
(
1970
).
A double-blind comparison of lithium and chlorpromazine in the treatment of manic states
.
American Journal of Psychiatry
 
126
,
1306
1309
.
[PubMed]
Stokes
PE
Shamoian
CA
Stoll
PM
Patton
MJ
(
1971
).
Efficacy of lithium as acute treatment of manic-depressive illness
.
Lancet
 
1
,
1319
1325
.
[PubMed]
Storosum
JG
Wohlfarth
T
Schene
A
Elferink
A
et al
(
2007
).
Magnitude of effect of lithium in short-term efficacy studies of moderate to severe manic episode
.
Bipolar Disorders
 
9
,
793
798
.
[PubMed]
Takahashi
R
Sakuma
A
Itoh
K
Itoh
H
et al
(
1975
).
Comparison of efficacy of lithium carbonate and chlorpromazine in mania
.
Archives of General Psychiatry
 
32
,
1310
1318
.
[PubMed]
Tamayo
JM
Sutton
VK
Mattei
MA
Diaz
B
et al
(
2009
).
Effectiveness and safety of the combination of fluoxetine and olanzapine in outpatients with bipolar depression. An open-label, randomized, flexible-dose study in Puerto Rico
.
Journal of Clinical Psychopharmacology
 
29
,
358
361
.
[PubMed]
Thase
ME
MacFadden
W
Weisler
RH
Chang
W
et al
(
2006
).
Efficacy of quetiapine monotherapy in bipolar I and II depression: a double-blind, placebo-controlled study (the BOLDER II study)
.
Journal of Clinical Psychopharmacology
 
26
,
600
609
.
[PubMed]
Thase
ME
Mallinger
AG
Mcknight
D
Himmelhoch
JM
(
1992
).
Treatment of imipramine-resistant recurrent depression, IV: a double-blind crossover study of tranylcypromine for anergic bipolar depression
.
American Journal of Psychiatry
 
149
,
195
198
.
[PubMed]
Thase
ME
Sachs
GS
(
2000
).
Bipolar depression: pharmacotherapy and related therapeutic strategies
.
Biological Psychiatry
 
48
,
558
572
.
[PubMed]
Thase
ME
Jonas
A
Khan
A
Bowden
CL
et al
(
2008
).
Aripiprazole monotherapy in nonpsychotic bipolar I depression: results of 2 randomized, placebo-controlled studies
.
Journal of Clinical Psychopharmacology
 
28
,
13
20
.
[PubMed]
Tohen
M
Baker
RW
Altshuler
LL
Zarate
C
et al
(
2002
).
Olanzapine versus divalproex in the treatment of acute mania
.
American Journal of Psychiatry
 
159
,
1011
1017
.
[PubMed]
Tohen
M
Frank
E
Bowden
CL
Colom
F
et al
(
2009
).
The International Society for Bipolar Disorders (ISBD) task force report on the nomenclature of course and outcome in bipolar disorders
.
Bipolar Disorders
 
11
,
453
473
.
[PubMed]
Tohen
M
Goldberg
JF
Gonzalez-Pinto
AM
Azorin
JM
et al
(
2003
a).
A 12-week, double-blind comparison of olanzapine vs haloperidol in the treatment of acute mania
.
Archives of General Psychiatry
 
60
,
1218
1226
.
[PubMed]
Tohen
M
Jacobs
TG
Grundy
SL
McElroy
SL
et al
(
2000
).
Efficacy of olanzapine in acute bipolar mania: a double-blind, placebo-controlled study
.
Archives of General Psychiatry
 
57
,
841
849
.
[PubMed]
Tohen
M
Kryzhanovskaya
L
Carlson
G
DelBello
M
et al
(
2007
).
Olanzapine versus placebo in the treatment of adolescents with bipolar mania
.
American Journal of Psychiatry
 
164
,
1547
1556
.
[PubMed]
Tohen
M
Sanger
TM
McElroy
SL
Tollefson
GD
et al
(
1999
).
Olanzapine versus placebo in the treatment of acute mania
.
American Journal of Psychiatry
 
156
,
702
709
.
[PubMed]
Tohen
M
Vieta
E
Calabrese
J
Ketter
TA
et al
(
2003
b).
Efficacy of olanzapine and olanzapine-fluoxetine combination in the treatment of bipolar I depression
.
Archives of General Psychiatry
 
60
,
1079
1088
.
[PubMed]
Tohen
M
Vieta
E
Goodwin
GM
Sun
B
et al
(
2008
).
Olanzapine versus divalproex versus placebo in the treatment of mild to moderate mania: a randomized, 12-week, double-blind study
.
Journal of Clinical Psychiatry
 
69
,
1776
1789
.
[PubMed]
Tohen
M
Zhang
F
Taylor
CC
Burns
P
et al
(
2001
).
A meta-analysis of the use of typical antipsychotic agents in bipolar disorder
.
Journal of Affective Disorders
 
65
,
85
93
.
[PubMed]
Trial 3077a (S1 and S2)
(
2008
).
Placebo-controlled olanzapine monotherapy in the treatment of bipolar I depression (http://www.clinicalstudyresults.org)
 . Accessed 3 December 2008.
Trials CN138-096, CN138-146
(
2008
).
Placebo-controlled aripiprazole monotherapy in the treatment of bipolar depression (http://www.clinicalstudyresults.org)
 . Accessed 3 December 2008.
Trials SCAA2010, SCA40910, SCA30924
(
2008
).
Placebo-controlled lamotrigine monotherapy in the treatment of bipolar depression (http://www.clinicalstudyresults.org)
 . Accessed 3 December 2008.
Vasudev
K
Goswami
U
Kohli
K
(
2000
).
Carbamazepine and valproate monotherapy: feasibility, relative safety and efficacy, and therapeutic drug monitoring in manic disorder
.
Psychopharmacology
 
150
,
15
23
.
[PubMed]
Vestergaard
P
(
1992
).
Treatment and prevention of mania: a Scandinavian perspective
.
Neuropsychopharmacology
 
7
,
249
259
.
[PubMed]
Vieta
E
Bourin
M
Sanchez
R
Marcus
R
et al
(
2005
).
Effectiveness of aripiprazole vs. haloperidol in acute bipolar mania. Double-blind, randomized, comparative 12-week trial
.
British Journal of Psychiatry
 
187
,
235
242
.
[PubMed]
Vieta
E
Carné
X
(
2005
).
The use of placebo in clinical trials on bipolar disorder: a new approach for an old debate
.
Psychotherapy and Psychosomatics
 
74
,
10
16
.
[PubMed]
Vieta
E
Ramey
T
Keller
D
English
P
et al
(
2008
).
Ziprasidone in the treatment of acute mania: a 12-week, placebo-controlled, haloperidol-referenced study
.
Journal of Psychopharmacology
  Published online: 12 December 2008. doi:10.1177/0269881108099418.
[PubMed]
Wagner
KD
Kowatch
RA
Emslie
GJ
Findling
RL
et al
(
2006
).
A double-blind, randomized, placebo-controlled trial of oxcarbazepine in the treatment of bipolar disorder in children and adolescents
.
American Journal of Psychiatry
 
163
,
1179
1186
.
[PubMed]
Wagner
KD
Redden
L
Kowatch
RA
Wilens
TE
et al
(
2009
).
A double-blind, randomized, placebo-controlled trial of divalproex extended-release in the treatment of bipolar disorder in children and adolescents
.
Journal of American Academy of Child and Adolescent Psychiatry
 
48
,
519
532
.
Walton
SA
Berk
M
Brook
S
(
1996
).
Superiority of lithium over verapamil in mania: a randomized, controlled, single-blind trial
.
Journal of Clinical Psychiatry
 
57
,
543
546
.
[PubMed]
Wehr
TA
Goodwin
FK
(
1979
).
Rapid cycling in manic-depressives induced by tricyclic antidepressants
.
Archives of General Psychiatry
 
36
,
555
559
.
[PubMed]
Weisler
RH
Calabrese
JR
Thase
ME
Arvekvist
R
et al
(
2008
).
Efficacy of quetiapine monotherapy for the treatment of depressive episodes in bipolar I disorder: a post hoc analysis of combined results from 2 double-blind, randomized, placebo-controlled studies
.
Journal of Clinical Psychiatry
 
69
,
769
782
.
[PubMed]
Weisler
RH
Kalali
AH
Ketter
TA
and the SPD417 Study Group
(
2004
).
A multicenter, randomized, double-blind, placebo-controlled trial of extended-release carbamazepine capsules as monotherapy for bipolar disorder patients with manic or mixed episodes
.
Journal of Clinical Psychiatry
 
65
,
478
484
.
[PubMed]
Weisler
RH
Keck
PE
Swann
AC
Cutler
AJ
et al
(
2005
).
Extended-release carbamazepine capsules as monotherapy for acute mania in bipolar disorder: a multicenter, randomized, double-blind, placebo-controlled trial
.
Journal of Clinical Psychiatry
 
66
,
323
330
.
[PubMed]
Wolfsperger
M
Greil
W
Rössler
W
Grohmann
R
(
2007
).
Pharmacological treatment of acute mania in psychiatric in-patients between 1994 and 2004
.
Journal of Affective Disorders
 
99
,
9
17
.
[PubMed]
Yildiz
A
Guleryuz
S
Ankerst
DP
Ongur
D
et al
(
2008
).
Protein kinase C inhibition in the treatment of mania. A double-blind, placebo-controlled trial of tamoxifen
.
Archives of General Psychiatry
 
65
,
255
263
.
[PubMed]
Young
AH
Oren
DA
Lowy
A
McQuade
RD
et al
(
2009
).
Aripiprazole monotherapy in acute mania: 12-week randomised placebo- and haloperidol- controlled study
.
British Journal of Psychiatry
 
194
,
40
48
.
[PubMed]
Young
LT
Joffe
RT
Robb
JC
Macqueen
GM
et al
(
2000
).
Double-blind comparison of addition of a second mood stabilizer versus an antidepressant to an initial mood stabilizer for treatment of patients with bipolar depression
.
American Journal of Psychiatry
 
157
,
124
126
.
[PubMed]
Zajecka
JM
Weisler
R
Sachs
G
Swann
AC
et al
(
2002
).
A comparison of the efficacy, safety, and tolerability of divalproex sodium and olanzapine in the treatment of bipolar disorder
.
Journal of Clinical Psychiatry
 
63
,
1148
1155
.
[PubMed]
Zarate
CA
Jr.
Singh
JB
Carlson
PJ
Quiroz
J
et al
(
2007
).
Efficacy of a protein kinase C inhibitor (tamoxifen) in the treatment of acute mania: a pilot study
.
Bipolar Disorders
 
9
,
561
570
.
[PubMed]
Zarate
C
Jr.
Tohen
M
(
2004
).
Double-blind comparison of the continued use of antipsychotic treatment versus its discontinuation in remitted manic patients
.
American Journal of Psychiatry
 
161
,
169
171
.
[PubMed]