- Research article
- Open Access
- Open Peer Review
This article has Open Peer Review reports available.
Mono- and combination drug therapies in hospitalized patients with bipolar depression. Data from the European drug surveillance program AMSP
© Haeberle et al.; licensee BioMed Central Ltd. 2012
Received: 30 April 2012
Accepted: 17 September 2012
Published: 21 September 2012
For the pharmacological treatment of bipolar depression several guidelines exist. It is largely unknown, to what extent the prescriptions in daily clinical routine correspond to these evidence based recommendations and which combinations of psychotropic drugs are frequently used.
The prescriptions of psychotropic drugs were investigated of all in-patients with bipolar depression (n = 2246; time period 1994–2009) from hospitals participating in the drug surveillance program AMSP. For the drug use in 2010, 221 cases were analysed additionally.
From 1994 to 2009, 85% of all patients received more than one class of psychotropic substances: 74% received antidepressants in combination therapy, 55% antipsychotics, 48% anticonvulsants and 33% lithium. When given in combination, lithium is the most often prescribed substance for bipolar depression (33%), followed by valproic acid (23%), mirtazapine and venlafaxine (16% each), quetiapine (15%), lamotrigine (14%) and olanzapine (13%). Both, lithium and valproic acid are often combined with selective serotonin reuptake inhibitors (SSRI), but also with mirtazapine und venlafaxine. Combinations of more than one antidepressant occur quite often, whereby combinations with bupropion, paroxetine, fluoxetine or fluvoxamine are very rare. In 2010, quetiapine (alone and combined) was the most frequently prescribed drug (39%); aripiprazole was administered in 10%.
Combinations of antidepressants (SSRI, mirtazapine, venlafaxine) with mood stabilizers (lithium, valproic acid, lamotrigine) and / or atypical antipsychotics (quetiapine, olanzapine) are common. Of most of those combinations the efficacy has not been studied. The use of aripiprazole and the concomitant use of two or three antidepressants contrast the guidelines.
For the treatment of bipolar depression a variety of partly controversial options exist. Several up to date guidelines provide clinicians with a framework of evidence based pharmacological treatments of bipolar depression [1–6].
The present study shows the prescriptions of psychopharmacological substances for bipolar depression in daily clinical routine. The data from a large European multicenter study (AMSP) [7, 8] allow a direct comparison between clinical routine and recommendations of the guidelines.
Previous analysis of these data have shown several important prescribing trends in the treatment of bipolar depression from 1994 until 2009: Antidepressants are prescribed in almost 80% of all in-patients, thus being by far the most important class of psychotropic drugs prescribed for bipolar depression; antipsychotics in about 60% with increasing trend, especially for quetiapine; anticonvulsants in about 50%, mostly valproic acid and lamotrigine and lithium in about 35% with a decreasing trend. Furthermore, a pronounced increase of polypharmacy was found .
For the first time, the present article investigates specifically the most frequently administered combinations of psychotropic substances and focuses on the use of single antidepressant drugs over the time of 15 years in hospitalized patients with bipolar depression.
All in-patients with a diagnosis of bipolar depression hospitalized in the participating hospitals of the AMSP project were selected (n = 2246; time period 1994–2009). For the years 2001 – 2009 patients with the diagnoses F 31.3 – 31.5 according to ICD 10 were selected, for the years 1994 – 2000 patients with the corresponding diagnosis in ICD 9 (manic-depressive psychosis, circular type, currently depressed) were included. A detailed description of the patient population can be found in Greil et al. 2012 . For the present analysis 15 patients with missing personal data not included in the previous analysis were added to the population. For the special calculation of drug use in 2010 additional 221 cases were analysed.
The present data were taken from the large data pool of the AMSP program (Arzneimittelsicherheit in der Psychiatrie) . This drug safety project was started in 1993 by the Psychiatric University Hospital Munich and serves to continuously record prescriptions of psychotropic drugs and their adverse side effects of in-patients of various hospitals in Germany, Switzerland and Austria (and temporarily also Hungary and Belgium). In 2009, 51 hospitals participated in the project. The data on prescription rates were gathered twice a year as follows: At two index dates per year each participating hospital / ward recorded for each patient hospitalized at that day age, sex, psychiatric diagnosis (ICD 9 and 10, respectively) and daily dosage of all drugs (psychotropic and non-psychotropic). These data were subsequently sent to the Psychiatric University Hospital Munich, where they were collected in an overall database.
To statistically analyse the rates of psychopharmacological prescriptions, the percentage of patients per year was calculated, which received a particular agent. The number of patients receiving a particular agent in one year was divided by the total number of patients in this year = prescription rate, i.e. percentage of patients receiving the agent per year. Although the data were collected twice per calendar year, an average prescription rate was calculated using the data of one calendar year. Hence, we phrase “% of patients” referring to virtual single patients. For the analyses, the period 1994–2009 was segmented into four equal time periods due to low number of patients with single drugs.
The ethics committee of the Ludwig Maximilian University of Munich, the location of the AMSP main data center, had approved the analysis of the AMSP data with a waver of authorization. The permission to use the special data set of bipolar depression was given by the publication commission consisting of the presidents of the AMSP associations in Germany, Austria and Switzerland.
Frequency of prescriptions of drug classes in combination therapy
Frequency of prescriptions in mono- and combination therapy for classes of psychotropic substances
1994 - 1997
1998 - 2001
2002 - 2005
2006 - 2009
Number of patients
Number of patients monotherapy
Number of patients combination therapy
Monotherapy had a low prevalence (about 15% of the patients) and shows a decreasing trend. A remarkable decrease is seen for antidepressant monotherapy, from 13% to 5% in the time period from 1994 to 1997 as compared to the last period from 2006 to 2009. Hereby, monotherapy is defined as the use of either antidepressants or antipsychotics or anticonvulsants or lithium, but additional use of hypnotics and tranquilizers or the use of more than one drug within the respective class being allowed (see also ).
Psychotropic substances in mono- and combination therapy
Frequency of prescriptions of single psychotropic substances
1994 - 1997
1998 – 2001
2002 – 2005
2006 - 2009
2.4 + 42.3
2.9 + 33.5
1.8 + 28.7
1.2 + 33.1
1.9 + 32.8
2.4 + 15.3
3.5 + 22.4
2.4 + 29
2.0 + 28.6
2.5 + 26.0
0.4 + 4.8
1.8 + 19.8
1.5 + 28.4
1.3 + 24.4
1.4 + 22.8
2.6 + 12.1
2.1 + 20.7
2.0 + 18.8
2.0 + 16.3
2.0 + 4.4
1.1 + 10.4
1.3 + 21.5
1.1 + 18.3
1.2 + 16.2
0.3 + 12.7
1.4 + 28.1
0.6 + 14.6
0.7 + 2.9
0.1 + 17.7
0.4 + 22.2
0.3 + 14.4
0.9 + 9.5
0.7 + 18
1.1 + 13.6
0.8 + 12.7
2.0 + 21
1.8 + 18.7
0.4 + 10.4
0.2 + 5.5
0.8 + 11.4
0.7 + 10.1
1.1 + 14.4
0.6 + 8.5
0.8 + 4.8
1.3 + 8.1
0.8 + 9.8
0.2 + 7
0.7 + 7.9
0.2 + 5.9
0.1 + 7.3
0.2 + 7.6
0.2 + 6.5
0.9 + 6.4
0.4 + 5.1
0.5 + 4.0
0.5 + 4.4
0.8 + 8.5
1.3 + 5.3
0.1 + 2.5
0.4 + 3.7
0.8 + 5.6
0.4 + 5.3
0.2 + 3.2
1.1 + 2.9
0.1 + 4.2
0.2 + 3.0
0.4 + 3.0
0.8 + 11.3
0.4 + 4.0
0.7 + 1.3
0.4 + 3.0
0.1 + 1.5
0.1 + 6.6
0.1 + 2.9
0.2 + 3.3
0.4 + 3.7
0.2 + 2.9
0.8 + 5.6
0.2 + 3.1
0.1 + 1.4
0.5 + 1.7
0.4 + 2.3
0.1 + 4.7
0.2 + 2.2
0.3 + 1.7
0.1 + 1.8
0.2 + 2.0
0.8 + 1.6
0.4 + 1.5
0.2 + 0.8
0.3 + 1.5
The analysis of the prescription data from 2010 (patients with bipolar depression, n = 221) shows the following results for the most often used single drugs: Quetiapine (alone and in combination) is prescribed in 38.9% of the patients, followed by valproic acid (33.5%), lithium (26.7%), escitalopram (19.5%), lamotrigine (18.6%), venlafaxine (17.7%) and mirtazapine (14.5%). Interestingly, aripiprazole (10.0%) is prescribed more often than olanzapine (9.1%). The group of SSRI is prescribed in 30.9%.
Frequent combinations of psychotropic substances
a and b Most frequent combinations of at least two and three substances
Frequent combinations of classes of substances
Most frequent combinations of classes of psychotropic drugs
Antidepressants (SSRI, Mir, Ven)
atypical Neuroleptics (Quet, Ola, Ri)
Antidepressants (SSRI, Mir, Ven)
Antidepressants (SSRI, Mir, Ven)
atypical Neuroleptics (Quet, Ola, Ri)
Anticonvulsives (Val, Lam)
atypical Neuroleptics (Quet, Ola, Ri)
Anticonvulsives (Val, Lam)
Anticonvulsives (Val, Lam)
The present study focuses on the psychopharmacological combination treatment of bipolar depression in hospitalized patients in the time period 1994–2009. It shows that lithium given in about one third of the patients is the most frequently administered single substance given at all and concomitantly with other psychotropic drugs. This is also found for the time period 2006–2009, even though the trend to prescribe lithium has decreased over the last 15 years . The data, however, do not allow a specification whether lithium is given due to its antidepressant property, as an augmentation strategy or for preventive purpose.
Clinical studies on the efficacy of lithium show a modest antidepressant effect of lithium in bipolar depression, at best [10–13]. Nevertheless, several guidelines include lithium as a fist-line treatment option alone [4, 6] or in combination with other substances, e.g. lamotrigine . The combinations of lithium with other psychotropic drugs found in the present data only include substances that do not interfere with the pharmacokinetics of lithium. Only the risk of serotonergic syndrome may be increased in combinations of lithium with SSRI and / or venlafaxine.
The data also emphasize, that antidepressants are the most frequently prescribed class of drugs given in combination, although the use of antidepressants in bipolar depression is controversial. Since 2002, in US guidelines it is generally recommended to avoid antidepressants in bipolar depression . Especially for mirtazapine and venlafaxine, both found in the present study to be combined often with lithium and valproic acid respectively, there is no data that supports the efficacy of these combinations.
In 2002, international  and US guidelines  proposed the combination of a non-tricyclic antidepressant (SSRI or bupropion) with mood stabilizer (lithium or lamotrigine) as a treatment option. In accordance with these recommendations and with modern guidelines, that in bipolar depression antidepressants should be prescribed in combination with mood stabilizing and antimanic drugs only we observed that antidepressants are combined mainly with lithium, valproic acid, quetiapine and lamotrigine. However, the evidence based combination recommended by the guidelines, olanzapine plus fluoxetine (OFC), was found to be prescribed only in very few patients (cf. ). Bupropion, listed in international guidelines as an antidepressant specifically recommended for bipolar depression, is administered very rarely. Moreover, antidepressants with a high potential for pharmacokinetic interactions, i.e. paroxetine, fluoxetine and fluvoxamine, are not used within the usual combinations. Hence, critical drug-drug interactions are avoided despite increasing polypharmacy (cf. ). A trend to polypharmacy has already been described in the treatment of bipolar disorder generally [17–19], a systematic description of this trend for the treatment of bipolar depression is - to our knowledge - given for the first time in our previous  and present analysis.
Within the time period of 2006 – 2009, the anticonvulsants valproic acid and lamotrigine were the third and fourth most frequently given substances for bipolar depression and more than every fifth patient receives valproic acid or lamotrigine in combination with other drugs. The efficacy of valproic acid has been validated in clinical studies and recent meta-analyses , whereby the efficacy of lamotrigine is still a controversial issue and only a modest antidepressant effect can be expected . In 2004, an international consensus group on Bipolar I Depression Treatment Guidelines recommended lamotrigine with category 1 evidence .
Quetiapine was found in the present study to be the second most frequently prescribed substance for bipolar depression during the period from 2006 to 2009, whereby the number of prescriptions has increased rapidly in the last ten years . In 2010, quetiapine was even the most often prescribed single substance, followed by valproic acid and lithium. Evidence for the efficacy of quetiapine in the treatment of bipolar depression is ample [13, 23–26]. Therefore, all international guidelines explicitly recommend quetiapine as first line treatment, usually proposed as monotherapy [1–6]. Already in 2005, in the Texas algorithms for treatment of bipolar I depression quetiapine was proposed besides lamotrigine and olanzapine / fluoxetine combination  and in 2007, quetiapine was recommended as first line treatment option by the international CANMAT guidelines . However, monotherapy of quetiapine is very unusual in our data and quetiapine was found to be combined frequently with SSRI and mood stabilizers (lithium, valproic acid or lamotrigine). Note that aripiprazole was prescribed in 2010 in 10% of the patients despite negative trials for bipolar depression .
The present study bears some limitations, a detailed description of which is given in Greil et al. 2012 . Most importantly, the study is based on data from hospitalized patients, which suffer from severe depression usually and may be treatment resistant as well. Thus, this population may need a higher number of psychotropic drugs concomitantly as compared to out-patients. Moreover, polypharmacy in our population may be overestimated due to tapering off ineffective drugs and starting new medications.
Overall, the study shows, that multiple combinations of psychotropic substances for therapy of bipolar depression are daily clinical routine. Combinations of antidepressants (SSRI, mirtazapine, venlafaxine) with mood stabilizers (lithium, valproic acid, lamotrigine) and/or atypical neuroleptics (quetiapine, olanzapine, risperidone) are common and combinations of more than one antidepressant substance occur quite often.
The efficacy of these frequent combinations applied has not yet been investigated thoroughly. There is a general agreement, that mood stabilizers (lithium, valpoic acid, lamotrigine) combined with atypical neuroleptics may be efficacious in acute bipolar depression [29–32]. In contrast, the efficacy of combinations with antidepressants, especially with mirtazapine and venlafaxine and the efficacy of combinations involving multiple antidepressant substances are not supported by research data. No studies on the efficacy of mirtazapine for bipolar disorder exist. Concerning venlafaxine, its efficacy in the treatment of bipolar II depression has been shown in small sample sizes only [33–35] and one study shows that venlafaxine may trigger switches to mania . Recent reviews and studies on the efficacy of antidepressants alone or in combination in the treatment of bipolar depression do not find stable effects for their efficacy [37–42]. Indicating awareness of drug safety, combinations with substances that have high interaction properties such as paroxetine, fluoxetine and fluvoxamine were found to be scarce in our data.
The present study shows that administration of combinations of psychotropic drugs is an every day phenomenon in clinical routine, although profound knowledge about their efficacy is missing. Corresponding recommendations in international guidelines based on clinical trials on the treatment of bipolar depression would constitute great assistance for physicians, but they are not yet available.
The authors thank all hospitals and staff participating in the AMSP project for their contribution to data collection. For collecting the relevant literature and maintaining the literature data base we appreciate the thorough work of Christel Apfelbaum.
- Malhi GS, Adams D, Lampe L, Paton M, O'Connor N, Newton LA, Walter G, Taylor A, Porter R, Mulder RT, et al: Clinical practice recommendations for bipolar disorder. Acta Psychiatr Scand Suppl. 2009, 439: 27-46.View ArticlePubMedGoogle Scholar
- Grunze H, Vieta E, Goodwin GM, Bowden C, Licht RW, Moller HJ, Kasper S: The world federation of societies of biological psychiatry (WFSBP) Guidelines for the biological treatment of bipolar disorders: update 2010 on the treatment of acute bipolar depression. World J Biol Psychiatry. 2010, 11: 81-109. 10.3109/15622970903555881.View ArticlePubMedGoogle Scholar
- NICE: Review of Clinical Guidelines (CG38) - Bipolar; the management of bipolar disorder in adults, children and adolescents, in primary and secondary care. National Institute for Health and Clinical Excellence, centre for Clinical Practice. 2012, http://publications.nice.org.uk/bipolar-disorder-cg38,Google Scholar
- Goodwin GM: Evidence-based guidelines for treating bipolar disorder: revised second edition–recommendations from the British Association for Psychopharmacology. J Psychopharmacol. 2009, 23: 346-388. 10.1177/0269881109102919.View ArticlePubMedGoogle Scholar
- Kasper S: International Consensus Group on the evidence-based pharmacologic treatment of bipolar I and II depression. J Clin Psychiatry. 2008, 69: 1632-1646.View ArticleGoogle Scholar
- Yatham LN, Kennedy SH, Schaffer A, Parikh SV, Beaulieu S, O'Donovan C, MacQueen G, McIntyre RS, Sharma V, Ravindran A, et al: Canadian network for mood and anxiety treatments (CANMAT) and international society for bipolar disorders (ISBD) collaborative update of CANMAT guidelines for the management of patients with bipolar disorder: update 2009. Bipolar Disord. 2009, 11: 225-255. 10.1111/j.1399-5618.2009.00672.x.View ArticlePubMedGoogle Scholar
- Grohmann R, Engel RR, Ruther E, Hippius H: The AMSP drug safety program: methods and global results. Pharmacopsychiatry. 2004, 37 (Suppl 1): S4-S11.PubMedGoogle Scholar
- Engel RR, Grohmann R, Ruther E, Hippius H: Research methods in drug surveillance. Pharmacopsychiatry. 2004, 37 (Suppl 1): S12-S15.PubMedGoogle Scholar
- Greil W, Haberle A, Haueis P, Grohmann R, Russmann S: Pharmacotherapeutic trends in 2231 psychiatric inpatients with bipolar depression from the International AMSP Project between 1994 and 2009. J Affect Disord. 2012, 136: 534-542. 10.1016/j.jad.2011.10.033.View ArticlePubMedGoogle Scholar
- Amsterdam JD, Shults J: Comparison of short-term venlafaxine versus lithium monotherapy for bipolar II major depressive episode: a randomized open-label study. J Clin Psychopharmacol. 2008, 28: 171-181. 10.1097/JCP.0b013e318166c4e6.View ArticlePubMedGoogle Scholar
- Suppes T, Marangell LB, Bernstein IH, Kelly DI, Fischer EG, Zboyan HA, Snow DE, Martinez M, Al JR, Shivakumar G, et al: A single blind comparison of lithium and lamotrigine for the treatment of bipolar II depression. J Affect Disord. 2008, 111: 334-343. 10.1016/j.jad.2008.02.004.View ArticlePubMedPubMed CentralGoogle Scholar
- van der Loos ML, Mulder PG, Hartong EG, Blom MB, Vergouwen AC, de Keyzer HJ, Notten PJ, Luteijn ML, Timmermans MA, Vieta E, et al: Efficacy and safety of lamotrigine as add-on treatment to lithium in bipolar depression: a multicenter, double-blind, placebo-controlled trial. J Clin Psychiatry. 2009, 70: 223-231. 10.4088/JCP.08m04152.View ArticlePubMedGoogle Scholar
- Young AH, McElroy SL, Bauer M, Philips N, Chang W, Olausson B, Paulsson B, Brecher M: A double-blind, placebo-controlled study of quetiapine and lithium monotherapy in adults in the acute phase of bipolar depression (EMBOLDEN I). J Clin Psychiatry. 2010, 71: 150-162. 10.4088/JCP.08m04995gre.View ArticlePubMedGoogle Scholar
- American Psychiatric Association: Practice guideline for the treatment of patients with bipolar disorder (revision). Am J Psychiatry. 2002, 159: 1-50. 10.1176/appi.ajp.159.1.1.View ArticleGoogle Scholar
- Grunze H, Kasper S, Goodwin G, Bowden C, Baldwin D, Licht R, Vieta E, Moller HJ: World federation of societies of biological psychiatry (WFSBP) guidelines for biological treatment of bipolar disorders. Part I: Treatment of bipolar depression. World J Biol Psychiatry. 2002, 3: 115-124. 10.3109/15622970209150612.View ArticlePubMedGoogle Scholar
- Haueis P, Greil W, Huber M, Grohmann R, Kullak-Ublick GA, Russmann S: Evaluation of drug interactions in a large sample of psychiatric inpatients: a data interface for mass analysis with clinical decision support software. Clin Pharmacol Ther. 2011, 90: 588-596. 10.1038/clpt.2011.150.View ArticlePubMedGoogle Scholar
- Frye MA, Ketter TA, Leverich GS, Huggins T, Lantz C, Denicoff KD, Post RM: The increasing use of polypharmacotherapy for refractory mood disorders: 22 years of study. J Clin Psychiatry. 2000, 61: 9-15. 10.4088/JCP.v61n0104.View ArticlePubMedGoogle Scholar
- Goldberg JF, Brooks JO, Kurita K, Hoblyn JC, Ghaemi SN, Perlis RH, Miklowitz DJ, Ketter TA, Sachs GS, Thase ME: Depressive illness burden associated with complex polypharmacy in patients with bipolar disorder: findings from the STEP-BD. J Clin Psychiatry. 2009, 70: 155-162. 10.4088/JCP.08m04301.View ArticlePubMedGoogle Scholar
- Brooks JO, Goldberg JF, Ketter TA, Miklowitz DJ, Calabrese JR, Bowden CL, Thase ME: afety and tolerability associated with second-generation antipsychotic polytherapy in bipolar disorder: findings from the Systematic Treatment Enhancement Program for Bipolar Disorder. J Clin Psychiatry. 2011, 72: 240-247. 10.4088/JCP.09m05214yel.View ArticlePubMedGoogle Scholar
- Smith LA, Cornelius VR, Azorin JM, Perugi G, Vieta E, Young AH, Bowden CL: Valproate for the treatment of acute bipolar depression: systematic review and meta-analysis. J Affect Disord. 2010, 122: 1-9. 10.1016/j.jad.2009.10.033.View ArticlePubMedGoogle Scholar
- Calabrese JR, Huffman RF, White RL, Edwards S, Thompson TR, Ascher JA, Monaghan ET, Leadbetter RA: Lamotrigine in the acute treatment of bipolar depression: results of five double-blind, placebo-controlled clinical trials. Bipolar Disord. 2008, 10: 323-333. 10.1111/j.1399-5618.2007.00500.x.View ArticlePubMedGoogle Scholar
- Calabrese JR, Kasper S, Johnson G, Tajima O, Vieta E, Yatham LN, Young AH: International consensus group on bipolar I depression treatment guidelines. J Clin Psychiatry. 2004, 65: 571-579. 10.4088/JCP.v65n0520a.View ArticlePubMedGoogle Scholar
- Calabrese JR, Keck PE, Macfadden W, Minkwitz M, Ketter TA, Weisler RH, Cutler AJ, McCoy R, Wilson E, Mullen J: 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. 10.1176/appi.ajp.162.7.1351.View ArticlePubMedGoogle Scholar
- Thase ME, Macfadden W, Weisler RH, Chang W, Paulsson B, Khan A, Calabrese JR: 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. 10.1097/01.jcp.0000248603.76231.b7.View ArticlePubMedGoogle Scholar
- McElroy SL, Weisler RH, Chang W, Olausson B, Paulsson B, Brecher M, Agambaram V, Merideth C, Nordenhem A, Young AH: A double-blind, placebo-controlled study of quetiapine and paroxetine as monotherapy in adults with bipolar depression (EMBOLDEN II). J Clin Psychiatry. 2010, 71: 163-174. 10.4088/JCP.08m04942gre.View ArticlePubMedGoogle Scholar
- Suppes T: Effectiveness of the extended release formulation of quetipaine as monotherapy for the treatment of acute bipolar depression. J Affect Disord. 2010, 121: 106-115. 10.1016/j.jad.2009.10.007.View ArticlePubMedGoogle Scholar
- Suppes T, Dennehy EB, Hirschfeld RM, Altshuler LL, Bowden CL, Calabrese JR, Crismon ML, Ketter TA, Sachs GS, Swann AC: The Texas implementation of medication algorithms: update to the algorithms for treatment of bipolar I disorder. J Clin Psychiatry. 2005, 66: 870-886. 10.4088/JCP.v66n0710.View ArticlePubMedGoogle Scholar
- Yatham LN, Kennedy SH, O'Donovan C, Parikh SV, MacQueen G, McIntyre RS, Sharma V, Beaulieu S: Canadian network for mood and anxiety treatments (CANMAT) guidelines for the management of patients with bipolar disorder: update 2007. Bipolar Disord. 2006, 8: 721-739. 10.1111/j.1399-5618.2006.00432.x.View ArticlePubMedGoogle Scholar
- Fountoulakis KN, Grunze H, Panagiotidis P, Kaprinis G: Treatment of bipolar depression: an update. J Affect Disord. 2008, 109: 21-34. 10.1016/j.jad.2007.10.016.View ArticlePubMedGoogle Scholar
- Baldessarini RJ, Vieta E, Calabrese JR, Tohen M, Bowden CL: Bipolar depression: overview and commentary. Harv Rev Psychiatry. 2010, 18: 143-157. 10.3109/10673221003747955.View ArticlePubMedGoogle Scholar
- Ittasakul P, Johnson KR, Srivastava S, Childers ME, Brooks JO, Hoblyn JC, Ketter TA: Effectiveness of quetiapine plus lamotrigine maintenance therapy in challenging bipolar disorder patients. J Affect Disord. 2012, 137: 139-145. 10.1016/j.jad.2011.12.024.View ArticlePubMedGoogle Scholar
- Chiesa A, Chierzi F, De RD, Serretti A: Quetiapine for bipolar depression: a systematic review and meta-analysis. Int Clin Psychopharmacol. 2012, 27: 76-90. 10.1097/YIC.0b013e32834e4c56.View ArticlePubMedGoogle Scholar
- Amsterdam JD, Wang CH, Shwarz M, Shults J: Venlafaxine versus lithium monotherapy of rapid and non-rapid cycling patients with bipolar II major depressive episode: a randomized, parallel group, open-label trial. J Affect Disord. 2009, 112: 219-230. 10.1016/j.jad.2008.03.029.View ArticlePubMedGoogle Scholar
- Amsterdam JD, Shults J: Efficacy and safety of long-term fluoxetine versus lithium monotherapy of bipolar II disorder: a randomized, double-blind, placebo-substitution study. Am J Psychiatry. 2010, 167: 792-800. 10.1176/appi.ajp.2009.09020284.View ArticlePubMedPubMed CentralGoogle Scholar
- Amsterdam JD, Wang G, Shults J: Venlafaxine monotherapy in bipolar type II depressed patients unresponsive to prior lithium monotherapy. Acta Psychiatr Scand. 2010, 121: 201-208. 10.1111/j.1600-0447.2009.01462.x.View ArticlePubMedGoogle Scholar
- Leverich GS, Altshuler LL, Frye MA, Suppes T, McElroy SL, Keck PE, Kupka RW, Denicoff KD, Nolen WA, Grunze H, et al: Risk of switch in mood polarity to hypomania or mania in patients with bipolar depression during acute and continuation trials of venlafaxine, sertraline, and bupropion as adjuncts to mood stabilizers. Am J Psychiatry. 2006, 163: 232-239. 10.1176/appi.ajp.163.2.232.View ArticlePubMedGoogle Scholar
- Altshuler L, Suppes T, Black D, Nolen WA, Keck PE, Frye MA, McElroy S, Kupka R, Grunze H, Walden J, et al: Impact of antidepressant discontinuation after acute bipolar depression remission on rates of depressive relapse at 1-year follow-up. Am J Psychiatry. 2003, 160: 1252-1262. 10.1176/appi.ajp.160.7.1252.View ArticlePubMedGoogle Scholar
- Sachs GS, Nierenberg AA, Calabrese JR, Marangell LB, Wisniewski SR, Gyulai L, Friedman ES, Bowden CL, Fossey MD, Ostacher MJ, et al: Effectiveness of adjunctive antidepressant treatment for bipolar depression. N Engl J Med. 2007, 356: 1711-1722. 10.1056/NEJMoa064135.View ArticlePubMedGoogle Scholar
- Salvi V, Fagiolini A, Swartz HA, Maina G, Frank E: The use of antidepressants in bipolar disorder. J Clin Psychiatry. 2008, 69: 1307-1318. 10.4088/JCP.v69n0816.View ArticlePubMedGoogle Scholar
- Sidor MM, MacQueen GM: Antidepressants for the acute treatment of bipolar depression: a systematic review and meta-analysis. J Clin Psychiatry. 2011, 72: 156-167. 10.4088/JCP.09r05385gre.View ArticlePubMedGoogle Scholar
- Amit BH, Weizman A: Antidepressant treatment for acute bipolar depression: an update. Depress Res Treat. 2012, 684725-Google Scholar
- Ghaemi SN: Antidepressants in bipolar depression: The clinical debate. Aust.N.Z.J Psychiatry. 2012, 46: 289-301. 10.1177/0004867412445131.View ArticleGoogle Scholar
- The pre-publication history for this paper can be accessed here:http://0-www.biomedcentral.com.brum.beds.ac.uk/1471-244X/12/153/prepub
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.