PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
J Clin Psychopharmacol. Author manuscript; available in PMC 2012 November 5.
Published in final edited form as:
PMCID: PMC3489178
NIHMSID: NIHMS398295

Antipsychotic-Induced Extrapyramidal Side Effects in Bipolar Disorder and Schizophrenia

A Systematic Review

Abstract

Objectives

Newer atypical antipsychotics have been reported to cause a lower incidence of extrapyramidal side effects (EPS) than conventional agents. This review is to compare antipsychotic-induced EPS relative to placebo in bipolar disorder (BPD) and schizophrenia.

Methods

English-language literature cited in Medline was searched with terms antipsychotics, placebo-controlled trial, and bipolar disorder or schizophrenia and then with antipsychotic (generic/brand name), safety, akathisia, EPS, or anticholinergic use, bipolar mania/depression, BPD, or schizophrenia, and randomized clinical trial. Randomized, double-blind, placebo-controlled, monotherapy studies with comparable doses in both BPD and schizophrenia were included. Absolute risk increase and number needed to treat to harm (NNTH) for akathisia, overall EPS, and anticholinergic use relative to placebo were estimated.

Results

Eleven trials in mania, 4 in bipolar depression, and 8 in schizophrenia were included. Haloperidol significantly increased the risk for akathisia, overall EPS, and anticholinergic use in both mania and schizophrenia, with a larger magnitude in mania, an NNTH for akathisia of 4 versus 7, EPS of 3 versus 5, and anticholinergic use of 2 versus 4, respectively Among atypical antipsychotics, only ziprasidone significantly increased the risk for overall EPS and anticholinergic use in both mania and schizophrenia, again with larger differences in mania, an NNTH for overall EPS of 11 versus 19, and anticholinergic use of 5 versus 9. In addition, risks were significantly increased for overall EPS (NNTH = 5) and anticholinergic use (NNTH = 5) in risperidone-treated mania, akathisia in aripiprazole-treated mania (NNTH = 9) and bipolar depression (NNTH = 5), and overall EPS (NNTH = 19) in quetiapine-treated bipolar depression.

Conclusions

Bipolar patients, especially in depression, were more vulnerable to having acute antipsychotic-induced movement disorders than those with schizophrenia.

The matter of bipolar disorder (BPD) as a risk factor for antipsychotic-induced movement disorders is still inconclusive. Some early studies showed that patients with BPD were more vulnerable to developing tardive dyskinesia (TD) as well as acute extrapyramidal side effects (EPS) than those with schizophrenia,1-3 but others found that they had a similar risk.4,5 More recently, in a pooled data analysis, Canvazoni et al6 reported that haloperidol-treated patients with BPD seemed to be more vulnerable to the development of EPS than those with schizophrenia, but not olanzapine-treated patients with BPD. It remains unclear if patients with BPD have a similar degree of vulnerability to developing acute EPS as those with schizophrenia when being treated with other antipsychotics.

Atypical agents have a lower liability for acute EPS and TD than typical agents,7 but TD has been observed even with the atypicals.8,9 A number of studies have reported that the development of acute EPS is a significant risk factor for later development of TD in schizophrenia.10-12 With the increasing use of atypical antipsychotics13,14 and continuous use of typical agents in BPD,15,16 the issue of antipsychotic-induced acute EPS in BPD is worth revisiting. In this review, we used randomized, double-blind, placebo-controlled studies of antipsychotics being carried out in both schizophrenia and BPD to compare the risk for antipsychotic-induced acute EPS relative to that of placebo.

METHODS

English-language literature published and cited in Medline through October 31, 2007 was searched using the terms antipsychotics, placebo-controlled trial, and BPD, or mania, or schizophrenia, and then with terms typical antipsychotics, atypical antipsychotics, fluphenazine, haloperidol, perphenazine, pimozide, thiothixene, trifluoperazine, loxapine, molindone, chlorpromazine, mesoridazine, thioridazine, fluspirilene, penfuridol, pipothiazine, flupenthixol, clozapine, olanzapine, risperidone, quetiapine, ziprasidone, or aripiprazole; with safety, tolerability, akathisia, EPS, or anticholinergic use; with bipolar mania or depression, BPD, manic-depressive illness, or schizophrenia; and with randomized, double-blind, controlled clinical trial. Recent studies, especially in BPD, presented at major scientific meetings were also included.

Citations generated by the Medline search were examined for the original placebo-controlled trials of antipsychotics in BPD or schizophrenia. Only antipsychotics with studies in both BPD and schizophrenia were included for further examination. Studies designed for schizoaffective disorder or prodromal psychosis were excluded for analyses. With only a few maintenance studies of antipsychotics in BPD, maintenance studies were also excluded for further examination. Among acute treatment studies, dosing schedule and dosages of antipsychotics varied substantially. In acute schizophrenia studies, multiple fixed doses of antipsychotics were used. Some of these dosages, such as aripiprazole 2 mg/d, olanzapine 2.5 mg/d, risperidone 2 mg/d, quetiapine 75 mg/d, or ziprasidone 10 mg/d, were low and less likely to be clinically useful. On the other hand, most studies in BPD were flexibly dosed, but the mean doses of most of these atypical antipsychotics were targeted to the maximal doses recommended for schizophrenia. To make a comparison as fair as possible, the incidences of the movement disorders of the closest dose(s) of an antipsychotic in a schizophrenia study to the mean dose of a corresponding mania study was chosen: aripiprazole 30 mg/d for mania and 15–20 mg/d for bipolar depression, haloperidol 8 to 12 mg/d, olanzapine 12 to 16 mg/d, quetiapine 600 mg/d, risperidone 6 mg/d, and ziprasidone 120 to 160 mg/d. For quetiapine bipolar depression studies, 600 mg/d was used to match the quetiapine mania study. Studies in schizophrenia with either a lower or a higher dose than those defined above were excluded for analysis.

In terms of the outcome variables for EPS, the EPS was reported by the incidence of occurrence, the use of anticholinergic agents, and/or the change in rating scales. The occurrence of akathisia was reported separately in most studies. Therefore, comparisons of the risk for akathisia, overall EPS, and anticholinergic use would cover a spectrum of antipsychotic-induced movement disorders. For this review, the number needed to treat to benefit (NNTB) or harm (NNTH) and the absolute risk reduction (ARR) or increase (ARI) were used to measure the differences.17 The NNTB or NNTH = 1/ARR or ARI and the ARR or ARI = placebo event rate – antipsychotic event rate. The calculation was based on the assumption that an antipsychotic would cause a greater occurrence of the EPS than placebo. Therefore, a negative value was indicative of a higher risk of an antipsychotic than placebo, presented with an NNTH and an ARI. A positve value was indicative of a lower risk of an antipsychotic than placebo presented with an NNTB and an ARR.

The type I error rate for significance tests between antipsychotics and placebo was set at α = 0.05. Confidence intervals (CI) were presented as mean ± 1.96 standard error.18 For antipsychotic-placebo comparison, statistical significance was declared when a CI did not include zero. For between-condition comparisons, nonoverlapping CIs were considered to be an indicator of statistical significance. Overlapping CIs were interpreted to indicate lack of statistical significance. Although this conservative interpretation might miss statistical significance,19 the NNTB or NNTH and the degree overlap of CIs can help clinicians to determine the degree of clinical significance. For antipsychotics with more than one clinical trial of a similar study design, the values of these variables were recalculated based on a pooled sample.

RESULTS

The Medline search generated 1003 citations for schizophrenia and 128 for BPD. An initial examination of these citations revealed that only haloperidol, aripiprazole, olanzapine, quetiapine, risperidone, and ziprasidone had placebo-controlled studies in both BPD and schizophrenia. Among the acute treatment studies, 9 in schizophrenia,20-28 11 monotherapy trials in the acute treatment of mania,29-39 and 4 in bipolar depression40-43 met the inclusion criteria for analysis (Tables 1--33).

TABLE 1
Comparison of Akathisia Between Antipsychotics and Placebo in the Acute Treatment of Schizophrenia, Mania, or Bipolar Depression
TABLE 3
Comparison of Anticholinergic Use Between Antipsychotics and Placebo in the Acute Treatment of Schizophrenia, Mania, or Bipolar Depression

Akathisia in Schizophrenia, Mania, or Bipolar Depression

In schizophrenia, there was a higher risk for akathisia with haloperidol than placebo with an NNTH of 7 (95% CI: −12 to −5). There was no higher risk for akathisia with aripiprazole, olanzapine, quetiapine, or ziprasidone compared with their respective placebo (Table 1). In mania, there is also no higher risk with quetiapine or ziprasidone compared with placebo, but there was higher risk with haloperidol or aripiprazole compared with placebo with an NNTH of 4 (95% CI: −6 to −3) for haloperidol and 9 (95% CI: −16 to −6) for aripiprazole. In bipolar depression, there was a significantly higher risk with aripiprazole compared with placebo with an NNTH of 5 (95% CI: −6 to −4). There was no overlap between the ARIs of aripiprazole in bipolar depression and aripiprazole 15 to 20 mg/d in schizophrenia. However, the CIs of other antipsychotics in BPD and schizophrenia or the CIs of aripiprazole in mania and bipolar depression overlapped (Table 1).

Overall EPS in Schizophrenia, Mania, or Bipolar Depression

In schizophrenia, there was no higher risk with aripiprazole, quetiapine, or risperidone compared with placebo. However, there was higher risk with haloperidol and ziprasidone compared with placebo with an NNTH of 5 (95% CI: −8 to −3) for haloperidol and 19 (95% CI: −203 to −10) for ziprasidone (Table 2). In mania, the higher risk with haloperidol and ziprasidone compared with placebo continued with an NNTH of 3 (95% CI: −4 to −3) for haloperidol and 11 (95% CI: −67 to −6) for ziprasidone. In addition, there was also higher risk with risperidone compared with placebo with an NNTH of 5 (95% CI: −8 to −4). In depression, there was higher risk with quetiapine compared with placebo with an NNTH of 19 (95% CI: −72 to −11) (Table 2). There was no overlap between the CI of ARI of risperidone in schizophrenia and the CI in mania. All other CIs of overall EPS overlapped (Table 2).

TABLE 2
Comparison of Overall EPS Between Antipsychotics and Placebo in the Acute Treatment of Schizophrenia, Mania, or Bipolar Depression

Anticholinergic Use in Schizophrenia, Mania, or Bipolar Depression

In schizophrenia, there was a higher risk with haloperidol compared with placebo in anticholinergic use with an NNTH of 4 (95% CI: −7 to −3). There was also a higher risk with olanzapine and ziprasidone compared with their respective placebo with an NNTH of 9 (95% CI: −33 to −5) for ziprasidone and 8 (95% CI: −78 to −4) for olanzapine. In mania, the higher risks with haloperidol and ziprasidone compared with placebo continued with an NNTH of 2 (95% CI: −4 to −2) for haloperidol and 5 (95% CI: −12 to −4) for ziprasidone. In addition, there was a higher risk with risperidone compared with placebo with an NNTH of 5 (95% CI: −7 to −4). All CIs of ARI in mania and schizophrenia overlapped. The CIs overlap was small with haloperidol as well as with risperidone (Table 3).

DISCUSSION

This first systematic review of the antipsychotic-induced acute EPS in BPD and schizophrenia has found that patients with BPD were more vulnerable to developing akathisia and other EPS than those with schizophrenia. Although only a few comparisons between these 2 disorders reached the conservative interpretation of statistical significance, the NNTH for akathisia, overall EPS, and/or anticholinergic use of each antipsychotic in BPD was much smaller than that in schizophrenia. In addition, the lower doses of haloperidol, risperidone, and ziprasidone used in BPD than those in schizophrenia further support these findings (Tables 1--33).

Seemingly, bipolar depressed patients were even more sensitive to antipsychotics than those in mania, which was at least supported by quetiapine and aripiprazole studies.20,21,31,32,40-42 A naturalistic report of aripiprazole augmentation in refractory bipolar depression also found that 42% (5/12) of patients developed akathisia.44 However, olanzapine did not show a higher risk for overall EPS than placebo in depression43 as well as in mania, although a higher risk was observed in schizophrenia.24 It remains unclear whether the increased EPS in quetiapine-treated bipolar depression is a state-dependent phenomenon or an individual antipsychotic-dependent phenomenon or both.

The impact of this higher vulnerability to antipsychotic-induced acute EPS on the development of TD in BPD is yet to be determined. However, the uncertainty of the effect of acute EPS on TD in BPD should not minimize the importance of reducing the occurrence of acute EPS. One strategy is to select an antipsychotic with low EPS liability. From this review, haloperidol had the highest risk for movement disorders. These results are consistent with head-to-head comparison studies of haloperidol versus atypical agents in BPD45,46 and schizophrenia.47,48 However, it is also possible that the unnecessarily high doses of haloperidol being used in these studies might play a role. Neuroimaging studies have shown that the occurrence of EPS was positively correlated to doses of haloperidol.49,50 The doses of haloperidol in bipolar studies varied from 3 to 15 mg/d (most around 10 mg/d), and those in schizophrenia were even higher, mostly 10 to 20 mg/d.

Among the atypical antipsychotics, aripiprazole, ziprasidone, and risperidone were more likely to cause EPS (Tables 1--3).3). However, the results have been challenged by an observational study, in which Ghaemi et al51 assessed 51 individual patient trials of atypical antipsychotics in 37 patients with BPD and found that 63% of trials resulted in moderate to severe EPS. The EPS and discontinuation frequencies were similar between high-potency (risperidone/ziprasidone/aripiprazole) and low-potency (quetiapine/olanzapine) agents.

Another strategy is to use lower doses of antipsychotics. However, most studies in BPD are flexibly dosed and the dose-efficacy or dose–side effect data are not available. Therefore, the balance between efficacy and side effects including EPS in the treatment of BPD should be evaluated individually.

Limitations

First, the ideal for indirect comparison should be to compare interventions of equivalent intensity or dose, in the same condition, at similar disease severity, using the same outcomes, and during the same period of time.52 Clearly, these requirements were not met in this review. Second, for each antipsychotic, the studies were pooled based on the diagnosis. Although incidences of EPS at the closest dose from each study were used, the heterogeneity within and between the original studies could not be controlled. The results could be biased by original study designs, including inclusion and exclusion criteria, sample sizes, study durations, medication doing schedule and dosages, or concomitant treatments such as benzodiazepines that could mask or prevent EPS from emerging. Third, only published studies were reviewed. Although the occurrence of EPS was unlikely to cause publication bias, it remains unclear whether the efficacy-related publication bias had any effect on the outcomes of adverse events including EPS. Fourth, the severity of EPS and doses or number of times an anticholinergic drug was administered could not be systematically reviewed because most studies did not report these results.

CONCLUSIONS

Overall, patients with BPD, especially when in a depressive phase, are more vulnerable to developing antipsychotic-induced acute EPS than those with schizophrenia. Compared with haloperidol, atypical antipsychotics are less liable for inducing acute EPS in BPD, although each individual antipsychotic has a differential liability. The relationship between acute EPS and TD in BPD is worthy of further exploration.

Acknowledgments

AUTHOR DISCLOSURE INFORMATION

Dr Calabrese has also received grant support and honoraria from Abbott, AstraZeneca, Bristol Myers Squibb, GlaxoSmithKline, Lilly, Pfizer, and Janssen. Dr Gao received honoraria and/or grant support from Abbott, AstraZeneca, GSK, and NARSAD. Dr Gajwani received grant support and/or honoraria from Abbott Laboratories, AstraZeneca, Bristol Myers Squibb, Cyberonics, Forest Pharmaceuticals, GlaxoSmithKline, and Pfizer. Dr Kemp received educational grants from Abbott and Bristol-Myers Squibb and research support from GlaxoSmithKline.

Support for this study included NIMH P20 MH-66054 (J.R.C.).

References

1. Hunt N, Silverstone T. Tardive dyskinesia in bipolar affective disorder: a catchment care study. Int Clin Psychopharmacol. 1991;6:45–50. [PubMed]
2. Hamra BJ, Nasrallah HA, Clancy J, et al. Psychiatric diagnosis and risk for tardive dyskinesia. Arch Gen Psychiatry. 1983;40:346–347. [PubMed]
3. Nasrallah HA, Churchill CM, Hamdan-Allan GA. Higher frequency of neuroleptic-induced dsytonia in mania than in schizophrenia. Am J Psychiatry. 1988;145:1455–1456. [PubMed]
4. Kane JM. Tardive dyskinesia in affective disorders. J Clin Psychiatry. 1999;60(suppl 5):43–47. [PubMed]
5. Khanna R, Das A, Damodaran SS. Prospective study of neuroleptic-induced dystonia in mania and schizophrenia. Am J Psychiatry. 1992;149:511–513. [PubMed]
6. Cavazzoni PA, Berg PH, Kryzhanovskaya LA, et al. Comparison of treatment-emergent extrapyramidal symptoms in patients with bipolar mania or schizophrenia during olanzapine clinical trials. J Clin Psychiatry. 2006;67:107–113. [PubMed]
7. Correll CU, Leucht S, Kane JM. Lower risk for tardive dyskinesia associated with second-generation antipsychotics: a systematic review of 1-year studies. Am J Psychiatry. 2004;161:414–425. [PubMed]
8. Jeste DV. Tardive dyskinesia rates with atypical antipsychotics in older adults. J Clin Psychiatry. 2004;65(suppl 9):21–24. [PubMed]
9. Kane JM. Tardive dyskinesia rates with atypical antipsychotics in adults: prevalence and incidence. J Clin Psychiatry. 2004;65(suppl 9):16–20. [PubMed]
10. Keepers GA, Casey DE. Use of neuroleptic-induced extrapyramidal symptoms to predict future vulnerability to side effects. Am J Psychiatry. 1991;148:85–89. [PubMed]
11. Muscettola G, Barbato G, Pampallona S, et al. Extrapyramidal syndromes in neuroleptic-treated patients: prevalence, risk factors, and association with tardive dyskinesia. J Clin Psychopharmacol. 1999;19:203–208. [PubMed]
12. Tenback DE, van Harten PN, Slooff CJ, et al. Evidence that early extrapyramidal syndromes predict later tardive dyskinesia: a prospective analysis of 10,000 patients in the European Schizophrenia Outpatient Health Outcome (SOHO) study. Am J Psychiatry. 2006;163:1438–1440. [PubMed]
13. Gao K, Gajwani P, Muzina D, et al. Typical and atypical antipsychotics in bipolar depression. J Clin Psychiatry. 2005;66:1376–1385. [PubMed]
14. Gao K, Gajwani P, Muzina D, et al. The effects of antipsychotics on mood. Adv Schizophr Clin Psychiatry. 2006;2:120–127.
15. Bech P, Baastrup PC, de Bleeker E, et al. Dimensionality, responsiveness and standardization of the Bech-Rafaelsen Mania Scale in the ultra-short therapy with antipsychotics in patients with severe manic episodes. Acta Psychiatr Scand. 2001;104:25–30. [PubMed]
16. Samellas D, Read P, Cookson JC. Antipsychotic drugs in mania: factors predicting use of antipsychotic medication following inpatient treatment of mania. Int Clin Psychopharmacol. 2004;19:291–297. [PubMed]
17. McQuay HJ, Moore AR. Using numerical results from systematic reviews in clinical practice. Ann Intern Med. 1997;126:712–720. [PubMed]
18. Altman DG. Confidence intervals for the number needed to treat. BMJ. 1998;317:1309–1312. [PMC free article] [PubMed]
19. Cumming G, Finch S. Confidence Inference by eye: confidence intervals and how to read pictures of data. Am Psychol. 2005;60:170–180. [PubMed]
20. Kane JM, Carson WH, Saha AR, et al. Efficacy and safety of aripiprazole and haloperidol versus placebo in patients with schizophrenia and schizoaffective disorder. J Clin Psychiatry. 2002;63:763–771. [PubMed]
21. Arvanitis LA, Miller BG. the Seroquel Trial 13 Study Group. Multiple fixed doses of “Seroquel” (quetiapine) in patients with acute exacerbation of schizophrenia: a comparison with haloperidol and placebo. Biol Psychiatry. 1997;42:233–246. [PubMed]
22. Zimbroff DL, Kane JM, Tamminga CA, et al. Controlled, dose-response study of sertindole and haloperidol in the treatment of schizophrenia. Am J Psychiatry. 1997;154:782–791. [PubMed]
23. Potkin SG, Saha AR, Kujawa MJ, et al. Aripiprazole, an antipsychotic with a novel mechanism of action, and risperidone vs. placebo in patients with schizophrenia and schizoaffective disorder. Arch Gen Psychiatry. 2003;60:681–690. [PubMed]
24. Beasley CM, Tollefson G, Tran P, et al. Olanzapine versus placebo and haloperidol: acute phase results of the North American double-blinded olanzapine trial. Neuropsychopharmacology. 1996;14:111–123. [PubMed]
25. Chouinard G, Jones B, Remington G, et al. A Canadian multicenter placebo-controlled study of fixed doses of risperidone and haloperidol in the treatment of chronic schizophrenic patients. J Clin Psychopharmacol. 1993;13:25–40. [PubMed]
26. Marder SR, Meibach RC. Risperidone in the treatment of schizophrenia. Am J Psychiatry. 1994;15l:825–835. [PubMed]
27. Keck P, Jr, Buffenstein A, Ferguson J, et al. Ziprasidone 40 and 120 mg/day in the acute exacerbation of schizophrenia and schizoaffective disorder: a 4-week placebo-controlled trial. Psychopharmacology (Berl) 1998;140:173–184. [PubMed]
28. Daniel DG, Zimbroff DL, Potkin SG, et al. Ziprasidone 80 mg/day and 160 mg/day in the acute exacerbation of schizophrenia and schizoaffective disorder: a 6-week placebo-controlled trial. Ziprasidone Study Group. Neuropsychopharmacology. 1999;20:491–505. [PubMed]
29. McIntyre RS, Brecher M, Paulsson B, et al. Quetiapine or haloperidol as monotherapy for bipolar mania—a 12-week, double-blind, randomized, parallel-group, placebo-controlled trial. Eur Neuropsychopharmacol. 2005;15:573–585. [PubMed]
30. Keck PE, Jr, Marcus R, Tourkodimitris S, et al. A placebo-controlled, double-blind study of the efficacy and safety of aripiprazole in patients with acute bipolar mania. Am J Psychiatry. 2003;160:1651–1658. [PubMed]
31. Sachs G, Sanchez R, Marcus R, et al. Aripiprazole in the treatment of acute manic or mixed episodes in patients with bipolar disorder: a 3-week placebo-controlled study. J Psychopharmacol. 2006;20:536–546. [PubMed]
32. Vieta E, Mullen J, Brecher M, et al. Quetiapine monotherapy for mania associated with bipolar disorder: combined analysis of two international, double-blind, randomized, placebo-controlled studies. Curr Med Res Opin. 2005;21:923–934. [PubMed]
33. Tohen M, Sanger TM, McElroy SL, et al. Olanzapine versus placebo in the treatment of acute mania. Am J Psychiatry. 1999;156:702–709. [PubMed]
34. Tohen M, Jacobs TG, Grundy SL, et al. Efficacy of olanzapine in acute bipolar mania: a double blind, placebo-controlled study. Arch Gen Psychiatry. 2000;57:841–849. [PubMed]
35. Smulevich AB, Khanna S, Eerdekens M, et al. Acute and continuation risperidone monotherapy in bipolar mania: a 3-weel placebo-controlled trial followed by a 9-week double-blind trial of risperidone and haloperidol. Eur Neuropsychopharmacol. 2005;15:75–84. [PubMed]
36. Hirschfeld RMA, Keck PE, Jr, Kramer M, et al. Rapid antimanic effect of risperidone monotherapy: a 3-week multicenter, double-blind, placebo-controlled trial. Am J Psychiatry. 2004;161:1057–1065. [PubMed]
37. Khanna S, Vieta E, Lyons B, et al. Risperidone in the treatment of acute mania. Br J Psychiatry. 2005;187:229–334. [PubMed]
38. Keck PE, Jr, Versiani M, Potkin S, et al. Ziprasidone in the treatment of acute bipolar mania: a three-week, placebo-controlled, double-blind, randomized trial. Am J Psychiatry. 2003;160:741–748. [PubMed]
39. Potkin SG, Keck PE, Jr, Segal S, et al. Ziprasidone in acute bipolar mania: a 21-day randomized, double-blind, placebo-controlled replication trial. J Clin Psychopharmacol. 2005;25:301–310. [PubMed]
40. Marcus RN, Owen R, Swanink R, et al. Two studies to evaluate the safety and efficacy of aripiprazole monotherapy in quetiapine with bipolar I disorder with a major depressive episode without psychotic feature (Studies CN138-096 and CN138-146). New Research Abstracts of the 160th Annual Meeting of the American Psychiatric Association; May 19–24, 2007; San Diego, CA. NR 311.
41. Calabrese JR, Keck PE, Jr, Macfadden W, et al. for the BOLDER Study Group. A randomized, double-blind, placebo-controlled trial of quetiapine, in the treatment of bipolar I or II depression. Am J Psychiatry. 2005;162:1351–1360. [PubMed]
42. Thase ME, Macfadden W, Weisler RH, et al. Efficacy of quetiapine monotherapy in bipolar I and II depression: a double-blind, placebo-controlled study (the BOLDER II Study) J Clin Psychopharmacol. 2006;26:600–609. [PubMed]
43. Tohen M, Vieta E, Calabrese JR, et al. Efficacy of olanzapine and olanzapine-fluoxetine combination in the treatment of bipolar depression. Arch Gen Psychiatry. 2003;60:1079–1088. [PubMed]
44. Kemp DE, Gilmer WS, Fleck J, et al. Aripiprazole augmentation in treatment-resistant bipolar depression: early response and development of akathisia. Prog Neuropsychopharmacol Biol Psychiatry. 2007;31:574–577. [PubMed]
45. Tohen M, Goldberg JF, Gonzalez-Pinto Arrillaga AM, et al. A 12-week, double-blind comparison of olanzapine vs. haloperidol in the treatment of acute mania. Arch Gen Psychiatry. 2003;60:1218–1226. [PubMed]
46. Vieta E, Bourin M, Sanchez R, et al. Effectiveness of aripiprazole v. haloperidol in acute bipolar disorder. Br J Psychiatry. 2005;187:235–242. [PubMed]
47. Dossenbach M, Arango-Davila C, Ibarra HS, et al. Responses and relapse in patients with schizophrenia treated with olanzapine, risperidone, quetiapine, or haloperidol: 12-month follow-up of the intercontinental schizophrenia outpatient health outcomes (IC-SOHO) study. J Clin Psychiatry. 2005;66:1021–1030. [PubMed]
48. Goff DC, Posever T, Herz L, et al. An exploratory haloperidol-controlled dose-finding study of ziprasidone in hospitalized patients with schizophrenia or schizoaffective disorder. J Clin Psychopharmacol. 1998;18:296–304. [PubMed]
49. Kapur S, Remington G, Jones C, et al. High levels of dopamine D2 receptor occupancy with low dose of haloperidol treatment: a PET study. Am J Psychiatry. 1996;153:948–950. [PubMed]
50. Tauscher J, Kufferle B, Asenbaum S, et al. Striatal dopamine-2 receptor occupancy as measured with [1231]iodobenzamide and SPECT predicted the occurrence of EPS in patients treated with atypical antipsychotics and haloperidol. Psychopharmacology (Berl) 2002;162:42–49. [PubMed]
51. Ghaemi SN, Hsu DJ, Rosenquist KJ, et al. Extrapyramidal side effects with atypical antipsychotics in bipolar disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2006;30:209–213. [PubMed]
52. Moore RA, Derry S, McQuay HJ. Indirect comparison of interventions using published randomized trials: systematic review of PDE-5 inhibitors for erectile dysfunction. BMC Urol. 2005;5:18. [PMC free article] [PubMed]