randomized controlled trials of antidepressants for bipolar disorder


(Updated 6/14/05; note that placebo-controlled trials have been placed in the right column.)

Fagiolini A, Frank E, Cherry CR, Houck PR, Novick DM, Buysse DJ, Kupfer DJ.
Department of Psychiatry University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, Pittsburgh, PA 15213, USA.
Clinical indicators for the use of antidepressants in the treatment of bipolar I depression.
Bipolar Disord. 2002 Oct;4(5):277-82.
"OBJECTIVES: Current guidelines provide little practical information on the clinical characteristics of bipolar I patients who are likely to benefit from the combination of a mood stabilizer and an antidepressant. Rather, guidelines simply state that an adjunctive antidepressant is recommended in cases of 'severe' depression. Our objective was to evaluate the clinical and demographic differences between patients who remitted on a mood stabilizer alone and patients who subsequently required an adjunctive antidepressant to achieve stabilization. METHODS: We retrospectively compared the pharmacological treatment strategies of 39 patients with bipolar I disorder who were in a current depressive episode. Patients who did not respond to mood stabilizer monotherapy were prescribed an adjunctive antidepressant. We evaluated the clinical differences at baseline and week 1, 2 and 3 of treatment between patients stabilizing on a mood stabilizer alone and patients that did not remit until they subsequently received an adjunctive antidepressant. RESULTS: Patients who required an adjunctive antidepressant had significantly higher total Hamilton Depression Rating (HRS-D) scores at week 1, 2 and 3 of treatment, but not at baseline. Patients who remitted on mood stabilizer monotherapy were more likely to be married, achieved stabilization in less time, presented with higher Young Mania Rating Scale (YMRS) scores, and experienced the previous episode of depression more recently than patients who required an antidepressant. CONCLUSIONS: Our findings suggest that rapid improvement after achieving a therapeutic dose of a mood stabilizer is clinically significant and represents a surrogate endpoint in the treatment of bipolar I depression. Larger, prospective, and controlled studies are needed to verify our results and to identify additional indicators for a mood stabilizer and antidepressant combination treatment strategy." [Abstract]

McIntyre RS, Mancini DA, McCann S, Srinivasan J, Sagman D, Kennedy SH.
Department of Psychiatry, University of Toronto, Mood and Anxiety Disorders Program, Center for Addiction and Mental Health, Clarke Site, Ontario, Canada. roger_mcintyre@camh.net
Topiramate versus bupropion SR when added to mood stabilizer therapy for the depressive phase of bipolar disorder: a preliminary single-blind study.
Bipolar Disord. 2002 Jun;4(3):207-13.
"OBJECTIVE: Antiepileptic drugs (AEDs) are commonly employed in the treatment of bipolar disorder. The efficacy and tolerability of topiramate, a novel anticonvulsant, and bupropion SR when added to mood stabilizer therapy were compared under single-blind conditions (rater-blinded) in patients meeting DSM-IV criteria for bipolar I/II depression. METHODS: A total of 36 out-patients with Hamilton Depression Rating Scale (HDRS-17) scores > or = 16 were randomized to receive escalating doses of either topiramate (50-300 mg/day) or bupropion SR (100-400 mg/day) for 8 weeks. Data were analyzed on an intent-to-treat basis using the last observation carried forward method. RESULTS: The percentage of patients meeting a priori response criteria (> or = 50% decrease from baseline in mean HDRS-17 total score) was significant for both topiramate (56%) and bupropion SR (59%) [t(17) = 2.542, p = 0.04 and t(17) = 2.661, p = 0.03, respectively]. Baseline demographic and clinical parameters were comparable between the two treatment groups. The mean doses of study medication were 176 mg/day (SD = 102 mg/day) for the topiramate-treated group and 250 mg/day (SD = 133 mg/day) for the bupropion SR-treated group. A significant and comparable reduction in depressive symptoms was observed from baseline to endpoint following topiramate and bupropion SR treatment, according to a > or = 50% reduction in the HDRS-17. Total mean HDRS-17 scores significantly decreased from baseline to endpoint in both groups (p = 0.001), however, differences between the topiramate-treated group and the bupropion SR-treated group were not significant [t(36) = 1.754, p = 0.097]. Both topiramate and bupropion SR were generally well tolerated. Thirteen patients discontinued the study: 2 because of lack of efficacy, 1 due to withdrawal of consent and 10 following side-effects (six in the topiramate and four in the bupropion SR-treated group). There were no cases of affective switch in either arm. Weight loss was experienced by patients in both groups (mean weight loss at endpoint was 1.2 kg in bupropion SR and 5.8 kg in topiramate) [t(17) = 2.325, p = 0.061 and t(17) = 2.481, p = 0.043, respectively]. CONCLUSIONS: These preliminary data suggest that adjunctive topiramate may reduce depressive symptom severity in acute bipolar depression. The antidepressant efficacy of this compound requires confirmation via double-blind placebo controlled investigation." [Abstract]

Vieta E, Martinez-Aran A, Goikolea JM, Torrent C, Colom F, Benabarre A, Reinares M.
Bipolar Disorders Program, Barcelona Stanley Foundation Research Center, IDIBAPS, Hospital Clinic, University of Barcelona, Spain. evieta@clinic.ub.es
A randomized trial comparing paroxetine and venlafaxine in the treatment of bipolar depressed patients taking mood stabilizers.
J Clin Psychiatry. 2002 Jun;63(6):508-12.
"BACKGROUND: The treatment of depressive episodes occurring in bipolar patients taking mood stabilizers is an understudied area of research with outstanding clinical consequences. This study was aimed to assess and compare the efficacy and safety of 2 different antidepressant drugs, paroxetine and venlafaxine, in this indication. METHOD: Sixty DSM-IV bipolar patients. each presenting with a major depressive episode while receiving mood stabilizers, were randomly assigned to either paroxetine (N = 30) or venlafaxine (N = 30) for 6 weeks in a single-blind manner. They had to score higher than 17 on the 17-item Hamilton Rating Scale for Depression (HAM-D-17) and have their mood stabilizer blood levels within the therapeutic range. Efficacy was measured by the HAM-D. Reports of side effects were collected at each visit; switch to mania or hypomania was specifically assessed by the Young Mania Rating Scale at 5 of 7 visits. RESULTS: Significant improvements in HAM-D scores were observed in both paroxetine- and venlafaxine-treated patients (Wilcoxon p < .0001). There were no significant differences in either efficacy or safety measures between the 2 drugs. By intention-to-treat analysis, 43% (N = 13) of patients taking paroxetine and 48% (N = 14) taking venlafaxine were considered to be responders. Only 3% (N = 1) of patients switched to hypomania or mania in the paroxetine group, whereas 13% (N = 4) switched in the venlafaxine group. CONCLUSION: Paroxetine and venlafaxine are both effective and safe in the treatment of depressive breakthrough episodes in bipolar disorder. There was a suggestion of a slightly higher risk for switch to mania or hypomania with venlafaxine." [Abstract]

Silverstone T.
Department of Psychological Medicine, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand.
Moclobemide vs. imipramine in bipolar depression: a multicentre double-blind clinical trial.
Acta Psychiatr Scand. 2001 Aug;104(2):104-9.
"OBJECTIVE: To determine the relative efficacy, tolerability and risk of precipitating mania of moclobemide and imipramine in the treatment of bipolar depression. METHOD: A randomized, double-blind, parallel group, multicentre study of moclobemide (MCB) (450-750 mg daily) and imipramine (IMI) (150-250 mg daily) in 21 centres in nine countries; 156 patients (65 males, 91 females) aged 18-65 with bipolar depression (17-item Hamilton Depression Rating Scale (HAMD) score chi16) participated. Clinical status was assessed using standardized rating scales before treatment and at 1,2,3,4,6 and 8 weeks. The data were analysed on an intention to treat basis with the last observation carried forward. RESULTS: In the MCB group, the mean HAMD fell from 23.0 to 13.1, in the IMI group it fell from 22.5 to 9.5; the mean score on the Montgomery-Asberg Depression Rating Scale (MADRS) fell from 29.5 to 16.3 on MCB and from 29.2 to 11.6 on IMI. There were no statistically significant differences between the two groups on any efficacy measures. Anticholinergic side-effects were three times more common with IMI than MCB and weight gain was also greater on IMI. Two patients (3.7%) on MCB and six patients (11%) on IMI were withdrawn because of manic symptoms, with manic symptoms occurring earlier on IMI, although these differences did not reach statistical significance. CONCLUSION: No differences in efficacy were detected between MCB and IMI in the treatment of bipolar depression. The data suggests that MCB is less likely than IMI to precipitate mania." [Abstract]

Loo H, Saiz-Ruiz J, Costa e Silva JACE, Ansseau M, Herrington R, Vaz-Serra A, Dilling H, de Risio S.
Service Hospitalo Universitaire de Sante Mentale et de Therapeutique, Sainte-Anne Hospital, Paris, France.
Efficacy and safety of tianeptine in the treatment of depressive disorders in comparison with fluoxetine.
J Affect Disord. 1999 Dec;56(2-3):109-18.
"BACKGROUND: Depression is treated by a great variety of antidepressant treatments. SSRIs (such as fluoxetine) are well known: it is, however, sure that further progress is needed and the search for antidepressants with other mechanisms of action (such as tianeptine) or different efficacy is still of interest. METHODS: A multinational study compared tianeptine with fluoxetine in 387 patients with Depressive Episode, or Recurrent Depressive Disorder, or Bipolar Affective Disorder (ICD-10), in a double-blind parallel group design. They were treated for six weeks. RESULTS: At inclusion, no significant difference between groups was shown. Final MADRS scores were 15.7 and 15.8 with tianeptine and fluoxetine, respectively (ITT population) (p = 0.944). MADRS responders were 58% and 56% with tianeptine and fluoxetine, respectively (p = 0.710). No statistical difference was observed for the other efficacy parameters. Thirty-six withdrawals occurred in each group, without any difference for the reasons of discontinuation. There was no major difference between groups for the other safety parameters. CONCLUSIONS: In this study, both tianeptine and fluoxetine exhibited a good efficacy and safety." [Abstract]

Bennie EH, Mullin JM, Martindale JJ.
Leverndale Hospital, Glasgow, UK.
A double-blind multicenter trial comparing sertraline and fluoxetine in outpatients with major depression.
J Clin Psychiatry. 1995 Jun;56(6):229-37.
"BACKGROUND: Sertraline and fluoxetine have pharmacokinetic and pharmacologic differences, which may be of clinical relevance. METHOD: A randomized, double-blind, parallel-group study of 6 weeks' duration comparing the efficacy and safety of sertraline (50-100 mg/day) with those of fluoxetine (20-40 mg/day) was conducted in 286 psychiatric outpatients with DSM-III-R major depression or bipolar disorder (depressed). Primary efficacy measurements consisted of the 17-item Hamilton Rating Scale for Depression (HAM-D) and the Clinical Global Impressions (CGI) scale. Secondary measurements included the Hamilton Rating Scale for Anxiety (HAM-A), the Raskin Depression Scale, the Covi Anxiety Scale, and the Leeds Sleep Questionnaire. Additionally, scores for two items and five factors from the HAM-D were analyzed. RESULTS: Efficacy was based on 124 evaluable patients in each treatment group. As measured by HAM-D and CGI-Severity scores, there was a significant (p < .001) improvement from baseline to each follow-up visit in both treatment groups with no statistically significant difference between groups. There was also no significant difference in the proportion of responders in each group. CGI-Improvement responder rates were 69% for sertraline and 67% for fluoxetine. Results of secondary efficacy measurements followed the same trend, although from the second week of treatment there was a numerical advantage (not statistically significant) for sertraline over fluoxetine in improving anxiety symptoms as measured by the total HAM-A score. Headache and nausea were the most frequently reported events for both drugs. The incidence of early patient withdrawals due to treatment-emergent adverse events was 14% for sertraline and 13% for fluoxetine. The starting dosage (sertraline 50 mg/day, fluoxetine 20 mg/day) was the final dosage in 76% of patients in both treatment groups. CONCLUSION: Sertraline and fluoxetine were equally effective and well tolerated in patients with major depression and associated anxiety." [Abstract]

Himmelhoch JM, Thase ME, Mallinger AG, Houck P.
Department of Psychiatry, University of Pittsburgh School of Medicine, PA.
Tranylcypromine versus imipramine in anergic bipolar depression.
Am J Psychiatry. 1991 Jul;148(7):910-6.
"OBJECTIVE: This investigation compared the efficacy of the monoamine oxidase inhibitor (MAOI) tranylcypromine with that of the tricyclic imipramine in the treatment of anergic bipolar depressive illness. METHOD: A controlled, double-blind comparison was used to study 56 outpatients who met operationalized criteria for anergic bipolar depression. Patients with bipolar I and II depression were equally distributed between comparison groups. Outcome was measured by the patient-rated Beck Depression Inventory and the clinician-rated Hamilton Rating Scale for Depression, Raskin Mania and Depression Scales, Clinical Global Impression Scale, and the Pittsburgh Reversed Vegetative Symptom Scale. Twenty-eight patients were treated with tranylcypromine and 28 with imipramine. Seventy-three percent of bipolar depressive patients screened for the study met criteria for anergic depression, consistent with previous findings from studies in bipolar illness that stretch back over 100 years. RESULTS: Tranylcypromine produced statistically significant superior outcome in terms of lower attrition, greater symptomatic improvement, and higher global response without increased risk of treatment-emergent hypomania or mania. CONCLUSIONS: The authors propose that the apparently superior efficacy of tranylcypromine in bipolar depression is specifically linked to anergia and reversed neurovegetative symptoms. Bipolar I and bipolar II patients had comparable outcomes, but bipolar I patients had a significantly greater risk of treatment-emergent mood swings. Although the relatively poor showing of imipramine warrants close scrutiny, these findings provide further documentation of the utility of MAOIs in patients presenting with anergia, motor retardation, hyperphagia, and/or hypersomnia." [Abstract]

Bocchetta A, Bernardi F, Burrai C, Pedditzi M, Del Zompo M.
Department of Neuroscience Bernard B. Brodie, University of Cagliari, Italy.
A double-blind study of L-sulpiride versus amitriptyline in lithium-maintained bipolar depressives.
Acta Psychiatr Scand. 1993 Dec;88(6):434-9.
"A double-blind group comparison study of L-sulpiride and amitriptyline was carried out in 30 bipolar outpatients on maintenance treatment with lithium suffering from a major depressive recurrence. L-sulpiride showed equivalent antidepressant activity to amitriptyline at 4 weeks using the Hamilton Rating Scale for Depression. However, the onset of action was faster in the L-sulpiride group, showing a significant improvement at 1 week in both anxiety-somatization and specific depression items, including depressed mood, feelings of guilt, work & activities and retardation. The incidence of anticholinergic side effects was significantly higher in the amitriptyline treatment group." [Abstract]

Amsterdam JD, Garcia-Espana F, Fawcett J, Quitkin FM, Reimherr FW, Rosenbaum JF, Schweizer E, Beasley C.
University of Pennsylvania Medical Center, Philadelphia, USA.
Efficacy and safety of fluoxetine in treating bipolar II major depressive episode.
J Clin Psychopharmacol. 1998 Dec;18(6):435-40.
"As many as 45% of patients with major depressive episode also meet DSM-IV criteria for bipolar II (BP II) disorder. Although some clinicians advocate using a mood stabilizer in treating BP II depression, antidepressant monotherapy has been less well studied in this disorder. As part of a prospective, placebo-controlled, relapse-prevention study in 839 patients, the efficacy and safety of short- and long-term fluoxetine treatment in patients with BP II major depression compared with patients with unipolar (UP) major depression was retrospectively examined. Eighty-nine BP II patients (mean age, 41+/-11 years) were compared with 89 age- and gender-matched UP patients and with 661 unmatched UP patients (mean age, 39+/-11 years). All received short-term fluoxetine therapy at 20 mg daily for up to 12 weeks. Complete remission was defined as a final Hamilton Rating Scale for Depression score < or = 7 by week 9 that was then maintained for 3 additional weeks. Remitted patients were then randomly assigned to receive double-blind treatment with one of the following: (1) fluoxetine 20 mg daily for 52 weeks; (2) fluoxetine for 38 weeks, then placebo for 14 weeks; (3) fluoxetine for 14 weeks, then placebo for 38 weeks; or (4) placebo for 52 weeks. Antidepressant efficacy was similar in BP and UP patients during short-term therapy. Discontinuation for lack of efficacy was lower in BP II (5%) than in UP (12%) patients (p = not significant [NS]), whereas dropouts for adverse events were similar in BP II (11%) and UP (9%) patients. During long-term relapse-prevention therapy, relapse rates were similar in BP II and UP patients (p = NS). During short-term fluoxetine therapy, three BP II (3.8%) versus no matched UP (p = NS) and 0.3% unmatched UP (p = 0.01) patients had a "manic switch." During long-term fluoxetine therapy, one (2%) BP II and three (1%) unmatched UP patients (one taking placebo) had a manic switch (p = NS). In conclusion, fluoxetine may be a safe and effective antidepressant monotherapy for the short-term treatment of BP II depression with a relatively low manic switch rate. Fluoxetine may also be effective in relapse-prevention therapy in patients with BP II disorder." [Abstract]

Shelton RC, Stahl SM
Risperidone and paroxetine given singly and in combination for bipolar depression.
J Clin Psychiatry. 2004 Dec;65(12):1715-9.
BACKGROUND: Bipolar depression is a major clinical problem that remains under-researched. The current study was intended to evaluate the effects of the novel antipsychotic risperidone, the selective serotonin reup-take inhibitor (SSRI) paroxetine, and the combination in patients with bipolar disorder. METHOD: Thirty patients with DSM-IV bipolar (I or II) disorder, depressed phase, who were receiving a stable dose of a mood stabilizer were randomly assigned to 12 weeks of double-blind treatment with risperidone (plus placebo), paroxetine (plus placebo), or the combination of risperidone and paroxetine. Data were gathered from August 1999 to September 2001. RESULTS: All 3 groups experienced significant reductions in depression ratings from baseline to endpoint; there were no significant differences in outcome between groups. There were statistically significant differences in paroxetine dose contrasting paroxetine plus placebo against the combined condition. The switch rate into mania or hypomania was very low, with only 1 patient in the paroxetine plus placebo condition experiencing mild hypomania. CONCLUSION: These results suggest that risperidone, paroxetine, and the combination of risperidone and paroxetine are equally but modestly effective when added to a mood stabilizer in bipolar depression. The paroxetine dose differed between groups, possibly because of drug-drug interactions. Using another SSRI in the combined condition could have produced a more robust effect and should be tested. [Abstract]

Nemeroff CB, Evans DL, Gyulai L, Sachs GS, Bowden CL, Gergel IP, Oakes R, Pitts CD.
Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, 1639 Pierce Dr., Suite 4000, Atlanta, GA 30322, USA.
Double-blind, placebo-controlled comparison of imipramine and paroxetine in the treatment of bipolar depression.
Am J Psychiatry. 2001 Jun;158(6):906-12.
"OBJECTIVE: This study compared the efficacy and safety of paroxetine and imipramine with that of placebo in the treatment of bipolar depression in adult outpatients stabilized on a regimen of lithium. METHOD: In a double-blind, placebo-controlled study, 117 outpatients with DSM-III-R bipolar disorder, depressive phase, were randomly assigned to treatment with paroxetine (N=35), imipramine (N=39), or placebo (N=43) for 10 weeks. In addition to lithium monotherapy, patients may have received either carbamazepine or valproate in combination with lithium for control of manic symptoms. Patients were stratified on the basis of trough serum lithium levels determined at the screening visit (high: >0.8 meq/liter; low: </=0.8 meq/liter). Primary efficacy was assessed by change from baseline in scores on the Hamilton Rating Scale for Depression and the Clinical Global Impression illness severity scale. RESULTS: Differences in overall efficacy among the three groups were not statistically significant. For patients with high serum lithium levels, antidepressant response at endpoint also did not significantly differ from placebo. However, both paroxetine and imipramine were superior to placebo for patients with low serum lithium levels. Compared to imipramine, paroxetine resulted in a lower incidence of adverse events, most notably emergence of manic symptoms. CONCLUSIONS: Antidepressants may not be useful adjunctive therapy for bipolar depressed patients with high serum lithium levels. However, antidepressant therapy may be beneficial for patients who cannot tolerate high serum lithium levels or who have symptoms that are refractory to the antidepressant effects of lithium." [Abstract]

Costa e Silva JA, Ruschel SI, Caetano D, Rocha FL, da Silva Lippi JR, Arruda S, Ozun M.
Jardim Botanico, Rio de Janeiro, Brazil.
Placebo-controlled study of tianeptine in major depressive episodes.
Neuropsychobiology. 1997;35(1):24-9.
"The efficacy and safety of tianeptine were compared, in the course of a multicentre randomised, double-blind, parallel group study, to those of placebo in the treatment of Major Depressions and Bipolar Disorder, Depressed with or without melancholia, without psychotic features. After a 1-week run-in placebo period, 126 depressed out-patients presenting DSM-III-R Major Depression or Bipolar Disorder, Depressed, with a total MADRS score of at least 25, were treated for 42 days with either tianeptine (25-50 mg/day) or placebo. Efficacy assessments were MADRS, CGI, HARS, Zung Depression Self Rating Scale and a VAS. Better efficacy of tianeptine was shown, and confirmed by covariance analyses, in final MADRS scores of the intention-to-treat population, of patients treated for at least 14 days and of completers; also in CGI items 1 and 2, MADRS item 10, and VAS. The results confirmed the efficacy of tianeptine (mean dosage: 37.5 mg/day) in the treatment of Major Depression and Bipolar Disorder, Depressed, with or without melancholia, compared to placebo. Tianeptine's acceptability did not differ from that of placebo. For adverse events, a higher incidence of headaches was found with tianeptine." [Abstract]

Prien RF, Kupfer DJ, Mansky PA, Small JG, Tuason VB, Voss CB, Johnson WE.
Drug therapy in the prevention of recurrences in unipolar and bipolar affective disorders. Report of the NIMH Collaborative Study Group comparing lithium carbonate, imipramine, and a lithium carbonate-imipramine combination.
Arch Gen Psychiatry. 1984 Nov;41(11):1096-104.
"In a double-blind, long-term follow-up study, 117 bipolar patients received lithium carbonate, imipramine hydrochloride, or both and 150 unipolar patients received lithium carbonate, imipramine, both lithium carbonate and imipramine, or placebo. With bipolar patients, lithium carbonate and the combination treatment were superior to imipramine in preventing manic recurrences and were as effective as imipramine in preventing manic recurrences and were as effective as imipramine in preventing depressive episodes. The combination treatment provided no advantage over lithium carbonate alone. With unipolar patients, imipramine and the combination treatment were more effective than lithium carbonate and placebo in preventing depressive recurrences. The combination treatment provided no advantage over imipramine alone. The lithium carbonate-treated group had fewer manic episodes than the other groups. Treatment outcome, which was evaluated primarily in terms of the occurrence of major depression or manic episodes, was significantly related to characteristics of the index episode, ie, the episode that brought the patient into the study." [Abstract]

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Recent Antidepressant RCT Results

1) Dierckx B, Heijnen WT, van den Broek WW, Birkenhäger TK
Efficacy of electroconvulsive therapy in bipolar versus unipolar major depression: a meta-analysis.
Bipolar Disord. 2012 Mar;14(2):146-50.
[PubMed Citation] [Order full text from Infotrieve]

2) Anand A, Gunn AD, Barkay G, Karne HS, Nurnberger JI, Mathew SJ, Ghosh S
Early antidepressant effect of memantine during augmentation of lamotrigine inadequate response in bipolar depression: a double-blind, randomized, placebo-controlled trial.
Bipolar Disord. 2012 Feb;14(1):64-70.
[PubMed Citation] [Order full text from Infotrieve]

3) Berk M, Dean O, Cotton SM, Gama CS, Kapczinski F, Fernandes BS, Kohlmann K, Jeavons S, Hewitt K, Allwang C, Cobb H, Bush AI, Schapkaitz I, Dodd S, Malhi GS
The efficacy of N-acetylcysteine as an adjunctive treatment in bipolar depression: an open label trial.
J Affect Disord. 2011 Dec;135(1-3):389-94.
[PubMed Citation] [Order full text from Infotrieve]

4) Biernacka JM, McElroy SL, Crow S, Sharp A, Benitez J, Veldic M, Kung S, Cunningham JM, Post RM, Mrazek D, Frye MA
Pharmacogenomics of antidepressant induced mania: a review and meta-analysis of the serotonin transporter gene (5HTTLPR) association.
J Affect Disord. 2012 Jan;136(1-2):e21-9.
[PubMed Citation] [Order full text from Infotrieve]

5) Prisciandaro JJ, Brown DG, Brady KT, Tolliver BK
Comorbid anxiety disorders and baseline medication regimens predict clinical outcomes in individuals with co-occurring bipolar disorder and alcohol dependence: Results of a randomized controlled trial.
Psychiatry Res. 2011 Aug 15;188(3):361-5.
Despite the high prevalence and detrimental impact of alcoholism on bipolar patients, the diagnostic and treatment factors associated with better or worse clinical outcomes in alcohol-dependent patients with bipolar disorder are not well understood. The present study investigated the prospective impact of baseline psychiatric comorbidities and treatment regimens on clinical outcomes in bipolar alcoholics. Data were drawn from an 8-week randomized controlled clinical trial of acamprosate for individuals (n=30) with co-occurring bipolar disorder and alcohol dependence. Depressive and manic symptoms, and alcohol craving and consumption were monitored longitudinally using standardized instruments. Path analysis was used to estimate the prospective associations between patient characteristics and outcomes. More than 50% of patients were diagnosed with at least one anxiety (76.7%) or drug dependence disorder (60.0%). Comorbid anxiety disorders were prospectively associated with increased depressive symptoms and alcohol use. Participants were prescribed an average of 2.6 psychotropic medications at baseline. Antipsychotics and anticonvulsants were prospectively associated with increased alcohol use; anticonvulsants and benzodiazepines were associated with increased alcohol craving. Antidepressants were associated with increased depressive symptoms. Conversely, lithium was associated with decreased alcohol craving and depressive symptoms. The findings from the present study suggest areas for future research in this population. [PubMed Citation] [Order full text from Infotrieve]

6) Perlis RH, Uher R, Ostacher M, Goldberg JF, Trivedi MH, Rush AJ, Fava M
Association between bipolar spectrum features and treatment outcomes in outpatients with major depressive disorder.
Arch Gen Psychiatry. 2011 Apr;68(4):351-60.
[PubMed Citation] [Order full text from Infotrieve]

7) Daray FM, Thommi SB, Ghaemi SN
The pharmacogenetics of antidepressant-induced mania: a systematic review and meta-analysis.
Bipolar Disord. 2010 Nov;12(7):702-6.
[PubMed Citation] [Order full text from Infotrieve]

8) Sidor MM, Macqueen GM
Antidepressants for the acute treatment of bipolar depression: a systematic review and meta-analysis.
J Clin Psychiatry. 2011 Feb;72(2):156-67.
[PubMed Citation] [Order full text from Infotrieve]

9) Vázquez G, Tondo L, Baldessarini RJ
Comparison of antidepressant responses in patients with bipolar vs. unipolar depression: a meta-analytic review.
Pharmacopsychiatry. 2011 Jan;44(1):21-6.
[PubMed Citation] [Order full text from Infotrieve]

10) Mah L, Zarate CA, Nugent AC, Singh JB, Manji HK, Drevets WC
Neural mechanisms of antidepressant efficacy of the dopamine receptor agonist pramipexole in treatment of bipolar depression.
Int J Neuropsychopharmacol. 2011 May;14(4):545-51.
The D?/D? receptor agonist pramipexole has clinical efficacy as an antidepressant, but its neural mechanisms are unknown. We used ¹?FDG-PET to investigate the cerebral metabolic effects of pramipexole augmentation of mood stabilizers in bipolar II depression. Fifteen bipolar II depressed patients on mood stabilizers were imaged at baseline and following 6 wk of pramipexole (n=7) or placebo (n=8) augmentation. Relative to placebo, pramipexole treatment was associated with reductions in normalized metabolism in bilateral orbitofrontal cortex, left ventrolateral prefrontal cortex (PFC), and right anteromedial PFC. Voxel-wise analyses additionally showed decreased normalized metabolism in the left inferior parietal cortex and medial frontopolar cortical (BA 10P) area of the anteromedial PFC following pramipexole treatment. These pramipexole-induced effects on regional metabolism suggest a mechanism of antidepressant action distinct from that previously reported under serotonin reuptake inhibitor treatment and appear compatible with evidence that the central dopaminergic system plays a role in the pathophysiology of bipolar depression. [PubMed Citation] [Order full text from Infotrieve]

11) Miskowiak KW, Vinberg M, Harmer CJ, Ehrenreich H, Knudsen GM, Macoveanu J, Hansen AR, Paulson OB, Siebner HR, Kessing LV
Effects of erythropoietin on depressive symptoms and neurocognitive deficits in depression and bipolar disorder.
Trials. 2010;11:97.
BACKGROUND: Depression and bipolar disorder are associated with reduced neural plasticity and deficits in memory, attention and executive function. Drug treatments for these affective disorders have insufficient clinical effects in a large group and fail to reverse cognitive deficits. There is thus a need for more effective treatments which aid cognitive function. Erythropoietin (Epo) is involved in neuroplasticity and is a candidate for future treatment of affective disorders. The investigators have demonstrated that a single dose of Epo improves cognitive function and reduces neurocognitive processing of negative emotional information in healthy and depressed individuals similar to effects seen with conventional antidepressants. The current study adds to the previous findings by investigating whether repeated Epo administration has antidepressant effects in patients with treatment resistant depression and reverses cognitive impairments in these patients and in patients with bipolar disorder in remission. METHODS/DESIGN: The trial has a double-blind, placebo-controlled, parallel-group design. 40 patients with treatment-resistant major depression and 40 patients with bipolar disorder in remission are recruited and randomised to receive weekly infusions of Epo (Eprex; 40,000 IU) or saline (NaCl 0.9%) for 8 weeks. Randomisation is stratified for age and gender. The primary outcome parameters for the two studies are: depression severity measured with the Hamilton Depression Rating Scale 17 items (HDRS-17) 1 in study 1 and, in study 2, verbal memory measured with the Rey Auditory Verbal Learning Test (RAVLT) 23. With inclusion of 40 patients in each study we obtain 86% power to detect clinically relevant differences between intervention and placebo groups on these primary outcomes. TRIAL REGISTRATION: The trial is approved by the Local Ethics Committee: H-C-2008-092, Danish Medicines Agency: 2612-4020, EudraCT: 2008-04857-14, Danish Data Agency: 2008-41-2711 and ClinicalTrials.gov: NCT 00916552. [PubMed Citation] [Order full text from Infotrieve]

12) Furey ML, Khanna A, Hoffman EM, Drevets WC
Scopolamine produces larger antidepressant and antianxiety effects in women than in men.
Neuropsychopharmacology. 2010 Nov;35(12):2479-88.
Some antidepressant agents generate differential benefit based on gender. Blocking cholinergic muscarinic receptors using scopolamine produces robust and rapid antidepressant effects in males and females combined. This study evaluated if males and females differ in the antidepressant response magnitude following scopolamine administration. A total of 52 male and female outpatients meeting criteria for recurrent major depressive or bipolar disorder participated in a double-blind, randomized, placebo-controlled, crossover clinical trial involving seven i.v. infusions of placebo or scopolamine (4??g/kg). Following a single-blind placebo lead-in, participants entered either a placebo-block/scopolamine-block or a scopolamine-block/placebo-block sequence. Each block included three sessions. Clinical ratings were acquired before each infusion and included the Montgomery-Asberg Depression Rating Scale (MADRS) and the Hamilton Anxiety Rating Scale (HAM-A). A treatment group × block interaction (F=21.0, p<0.001) was observed in MADRS scores across gender, and the reduction was significant by the evaluation following the first scopolamine administration (F=8.4, p=0.006). The treatment group × block interaction was also significant in males (F=3.8, p=0.043) and females (F=35.6, p<0.001) separately. A block × gender interaction (F=7.4, p=0.009) indicated that the response magnitude was larger in women. The treatment × block interaction was significant for the HAM-A across gender (F=12.0, p<0.001), and was significant for females (F=24.9, p<0.001) but not for males (F=1.3, p=0.30). When comparing the baseline block to study end, the block × gender interaction (F=12.6, p=0.001) showed that the antianxiety response was greater in women. Men and women show a rapid antidepressant response following scopolamine, but the magnitude of response is larger in women than in men. [PubMed Citation] [Order full text from Infotrieve]

13) Licht RW, Nielsen JN, Gram LF, Vestergaard P, Bendz H
Lamotrigine versus lithium as maintenance treatment in bipolar I disorder: an open, randomized effectiveness study mimicking clinical practice. The 6th trial of the Danish University Antidepressant Group (DUAG-6).
Bipolar Disord. 2010 Aug;12(5):483-93.
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14) Diazgranados N, Ibrahim L, Brutsche NE, Newberg A, Kronstein P, Khalife S, Kammerer WA, Quezado Z, Luckenbaugh DA, Salvadore G, Machado-Vieira R, Manji HK, Zarate CA
A randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression.
Arch Gen Psychiatry. 2010 Aug;67(8):793-802.
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15) Lobello KW, Preskorn SH, Guico-Pabia CJ, Jiang Q, Paul J, Nichols AI, Patroneva A, Ninan PT
Cytochrome P450 2D6 phenotype predicts antidepressant efficacy of venlafaxine: a secondary analysis of 4 studies in major depressive disorder.
J Clin Psychiatry. 2010 Nov;71(11):1482-7.
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16) Ghaemi SN, Ostacher MM, El-Mallakh RS, Borrelli D, Baldassano CF, Kelley ME, Filkowski MM, Hennen J, Sachs GS, Goodwin FK, Baldessarini RJ
Antidepressant discontinuation in bipolar depression: a Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) randomized clinical trial of long-term effectiveness and safety.
J Clin Psychiatry. 2010 Apr;71(4):372-80.
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17) Van Lieshout RJ, MacQueen GM
Efficacy and acceptability of mood stabilisers in the treatment of acute bipolar depression: systematic review.
Br J Psychiatry. 2010 Apr;196(4):266-73.
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18) Kessler U, Vaaler AE, Schøyen H, Oedegaard KJ, Bergsholm P, Andreassen OA, Malt UF, Morken G
The study protocol of the Norwegian randomized controlled trial of electroconvulsive therapy in treatment resistant depression in bipolar disorder.
BMC Psychiatry. 2010;10:16.
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19) Perlis RH, Adams DH, Fijal B, Sutton VK, Farmen M, Breier A, Houston JP
Genetic association study of treatment response with olanzapine/fluoxetine combination or lamotrigine in bipolar I depression.
J Clin Psychiatry. 2010 May;71(5):599-605.
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20) Tondo L, Vázquez G, Baldessarini RJ
Mania associated with antidepressant treatment: comprehensive meta-analytic review.
Acta Psychiatr Scand. 2010 Jun;121(6):404-14.
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