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Treatment of acute bipolar depression Print E-mail
Written by Konstantinos N. Fountoulakis   
Tuesday, 04 May 2010 18:02

Konstantinos N Fountoulakis

Assistant Professor of Psychiatry, School of Medicine Aristotle University of Thessaloniki, Greece

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Acute bipolar depression is not well studied, οnly a limited number of RCTs exist and the common practice to carry the clinical data and wisdom from the treatment of unipolar to bipolar depression is proven to be wrong.


The data are negative for lithium (Young et al., 2010) (although earlier studies were positive (Glen, Johnson, & Shepherd, 1984),


Data on the efficacy of antiepileptics against bipolar depression are poor and inadequate. There are only two a small positive studies on valproate suggesting it is effective in reducing the symptoms of depression and anxiety in bipolar I patients during the acute depressed episode (Davis, Bartolucci, & Petty, 2005; Ghaemi et al., 2007), (two more on the extended release form of valproate; one positive and one negaitive are not published (Bond, Lam, & Yatham, 2009; Smith et al., 2009)) while for carbamazepine there is only one old positive small withdrawal study (Ballenger & Post, 1980). Five trials concerning the acute depression treatment (SCA100223, SCA30924, SCA40910, SCAA2010 and SCAB2001) (Goldsmith, Wagstaff, Ibbotson, & Perry, 2003) were negative for lamotrigine concerning the primary outcomes but showed some benefit on the basis of secondary outcomes (on the basis of these secondary outcomes, response rates were 50% for lamotrigine and double of those for. placebo) (Calabrese et al., 1999). In this frame it is not surprising that the OFC was reported to be slightly superior to lamotrigine (Brown et al., 2006). Lamotrigine but not Gabapentin was reported to be effective in a mixed unipolar-bipolar population of refractory depressives, with respond rates 52% for lamogrigine, 26% for gabapentin and 23% for placebo (Frye et al., 2000).


Inspite of the fact that antidepressants as a class have an established efficacy against unipolar depression, this can not be carried unequivocally in bipolar depression also. All recent treatment guidelines recommend the concomitant use of an antimanic agent when an antidepressant is prescribed in bipolar patients and never antidepressant monotherapy. Older placebo-controlled studies were largely positive but difficult to judge on the basis of modern criteria and needs. They suggested that amitriptiline (Glen et al., 1984) and maybe imipramine could be useful against bipolar depression (Kane et al., 1982; Prien, Klett, & Caffey, 1973; Prien et al., 1984) with data being stronger for fluoxetine (response rate 86% for fluoxetine vs. 57% for imipramine vs. 38% for placebo) (Cohn, Collins, Ashbrook, & Wernicke, 1989). However in this latter study twice patients under fluoxetine (11/30) were receiving also lithium in comparison to those under impipramine (5/30) or placebo (6/29). Half of patients under fluoxetine were receiving 80 mg daily, while 65% under imipramine were receiving 150-300 mg daily. There is a number of more recent studies who however suffer from a number of methodological drawbacks and they suggest that fluoxetine is effective during the acute phase for bipolar II patients (Amsterdam et al., 1998; Amsterdam & Shults, 2005); a small placebo-controlled, cross-over study (on 10 patients) suggested that SSRIs might be better than placebo as monotherapy for depression in bipolar II disorder (Parker, Tully, Olley, & Hadzi-Pavlovic, 2006). RCTs fulfilling the modern quality standards suggest that the Olanzapine-Fluoxetine combination (OFC) is effective against bipolar I depression with remission rates 24.5% for placebo 32.8% for olanzapine  and 48.8% for OFC however, the study sample was small concerning the OFC arm (N=86) (Tohen et al., 2003). Another study suggested that the OFC is somewhat superior to lamotrigine although the response rates did not differ between groups. (OFC: 68.8% vs. lamotrigine 59.7%). Thus one could interpret this study as somewhat negative for the OFC since lamotrigine is proven to be non-effective. Secondary indices showed that the time to response was significantly shorter for the OFC-treated patients (OFC 17 days vs. lamotrigine 23 days) and there were lesser ‘suicidal and self-injurious behavior’ among OFC treated patiens (OFC, 0.5% vs. lamotrigine 3.4%) (Brown et al., 2006)

The same time the data are negative for paroxetine monotherapy (McElroy et al., 2010). Further analysis suggested that the OFC also improved many secondary idices (Shi et al., 2004) and could produce the beneficial effect already from day 7 (Dube et al., 2007)

Studies without a placebo arm suggested both paroxetine and venlafaxine are effective (Vieta et al., 2002), but placebo-controlled studies have not confirmed these findings for paroxetine. Studies comparing the response rates of bipolar vs. unipolar depression report the rates to be similar (Amsterdam et al., 1998; Amsterdam & Garcia-Espana, 2000) but since there does not seem to be a class effect for antidepressants in bipolar depression, these studies should be read with great caution.

Atypical antipsychotics

As mentioned above, one RCT in Bipolar I depression reported that the remission criteria were met by 24.5% of the placebo group vs. 32.8% of the olanzapine group (Tohen et al., 2003) however there is concern on the effect olanzapine monotherapy had on the ‘depressive core’ of symptoms, while it is certain that the patients manifested a significant improvement in symptoms ‘peripheral’ to the definition of depression like insomnia, anxiety, loss of appetite etc. (Bech, 2001; Lecrubier & Bech, 2007). Quetiapine is reported to be effective at dosages of 600 and 300 mg/day and produced response rates of 58.2% and 57.6%, respectively, vs. 36.1% for placebo, with remission rates being 52.9% in the groups taking quetiapine 600 and 300 mg/day vs. 28.4% for placebo. It is important that quetiapine significantly improved all the MADRS items corresponding to the core symptoms of depression. Post hoc analysis suggests 300 mg and 600 mg are equally effective although there seems to be small difference in the effect size (Cookson, Keck, Ketter, & Macfadden, 2007; Weisler et al., 2008), they both improved secondary measures including quality of life indices (Endicott, Rajagopalan, Minkwitz, & Macfadden, 2007) and they are also effective against depression in bipolar II depression (Suppes, Hirschfeld, Vieta, Raines, & Paulsson, 2008). Similar results were obtained from two more recent RCTs (McElroy et al., 2010; Young et al., 2010). Quetiapine extended release at 300 mg daily was significantly more effective than placebo in bipolar I depression, throughout an 8-week study, with significance observed as early as Day 7 (Suppes et al., 2010). Two 8-week placebo controlled RCTs were both negative for aripiprazole (Thase et al., 2008) as well as one (unpublished) for ziprasidone (NCT00141271)

other agents and therapeutic modalities

A prospective, randomised controlled, multi-centre 6-week trial involving 132 bipolar depressive patients resistant to treatment compared ECT vs algorithm-based pharmacological treatment as usual. Trial registration: NCT00664976 (Kessler et al., 2010).

Meta analytic studies suggest that in the case of bipolar depression only quetiapine and to a lesser extent, olanzapine showed efficacy as monotherapy (Tamayo, Zarate, Vieta, Vazquez, & Tohen, 2010). However two meta-analysis of four randomized placebo-controlled trials (6 and 8 weeks duration) with a total sample size of 142 patients, suggested that divalproex could also be efficaceous in acute bipolar depression with response rates 39.3% for divalproex vs. 17.5% for placebo, and remission rates were 40.6% vs. 24.3%, respectively (Bond et al., 2009) with effect size d equal to 0.35 (Smith et al., 2009). The meta-analyisis of the 5 negative trials with lamotrigine monotherapy (1072 patients) reported that lamotrigine was superior to placebo in people with HRSD score >24 but not in people with HRSD score < or =24 (Geddes, Calabrese, & Goodwin, 2009)

A review on the effect of atypical antipsychotics which included 4 monotherapy and one with both monotherapy and combination with an antidepressant reported that the quetiapine and olanzapine trials demonstrated superiority over placebo but both aripiprazole trials failed (Cruz et al., 2010). The narrative review on the quetiapine data confirms the above (McIntyre et al., 2009)

The meta analysis of data on paroxetine or MAOIs (52 patients) confirmed that the paroxetine effectiveness was unacceptably low, but rates of recovery with MAOIs were significantly higher.(Mallinger et al., 2009)




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Last Updated on Wednesday, 05 May 2010 12:48