Kostas N. Fountoulakis, MD, PhD

Treatment guidelines constitute an important element of present day medicine and psychiatry. The first guidelines published concerning the treatment of bipolar disorder were from the American Psychiatric Association in 1994. A significant number of guidelines and algorithms have been published since that time, reflecting the advancement in knowledge as well as changing opinions and concepts. Some of the guidelines try to keep up with the evidence; others rely more on expert opinion.

This article reviews the most recent (after 2010) published guidelines concerning bipolar depression: the WFSBP (World Federation of Societies of Biological Psychiatry), the CANMAT/ISBD (Canadian Network for Mood and Anxiety Treatments/International Society for Bipolar Disorders), and the draft NICE (National Institute for Health and Care Excellence) guidelines.

The WFSBP guidelines for the treatment of bipolar depression were updated in 2010 and use a detailed classification of agents on the basis of their evidence (quantity and quality) as well as their risk to benefit ratio.

 This results in ranking only quetiapine as A-1 (that is A for top efficacy and 1 for excellent safety and tolerability) and olanzapine, lamotrigine, fluoxetine, and valproate monotherapy together with the olanzapine/fluoxetine combination (OFC) as B-3. The guidelines are not detailed and stick to the ranking of available evidence; however, they provide a balanced analysis and recommendation of how to treat bipolar depression, and at the same time leave sufficient informed freedom to the clinician. It may be that these guidelines are the most balanced and clinically useful to date.

The CANMAT/ISBD guidelines for bipolar disorder were updated in 2013.

 The recommended first-line monotherapy options for bipolar depression are lithium, lamotrigine, and quetiapine (immediate release or extended release); first-line combination therapy options are lithium or divalproex plus an SSRI, olanzapine plus an SSRI, lithium plus divalproex, and lithium or divalproex plus bupropion.

There are a number of important considerations concerning these recommendations because the data on the efficacy of lithium in bipolar depression are clearly negative: only 1 of 7 placebo-controlled studies showed positive results for lithium.

 Results were also negative in a study of patients with lithium levels higher than 0.8 mEq/L.

Similarly, the recommendation of lamotrigine monotherapy is problematic because the results from 5 trials have been negative. Data on lamotrigine are weaker than data on aripiprazole, which is “not recommended.” Thus, the recommendation of lamotrigine as first-line treatment on the basis of the results of one meta-analysis is probably not justified.

 These meta-analytical results indicated that lamotrigine might be effective in more severely depressed patients.

 On the other hand, the results for aripiprazole suggest that it could be effective in all patients.

 It may have been better to include the two agents as options in the later stages of the algorithm (second- and third-line).

Although there are limited data to suggest that adding specific antidepressants to lithium or valproate could be beneficial, it is clear that no class effect exists for antidepressants or SSRIs concerning the treatment of bipolar depression.

 There are no data that show that the combination of olanzapine with any SSRI (except fluoxetine) would be beneficial; neither are there data that show that the combination of lithium plus valproate is effective.

Lurasidone is not included as a first-line recommendation, but at the time of the publication of the guidelines, lurasidone had no proven efficacy. Lurasidone has now been shown to have efficacy in bipolar depression as monotherapy and as add-on therapy.

 Thus, it deserves to be included as a first-line agent.

Although valproate monotherapy has been found to be beneficial, it has not been included as a first-line option

; it is only recommended as a second-line option.

The guidelines recommend divalproex and lurasidone as second-line monotherapy options. Quetiapine plus an SSRI; adjunctive modafinil, lithium, or divalproex plus lamotrigine; and lithium or divalproex plus lurasidone are recommended as second-line combination therapy. Only the lithium plus lamotrigine combination has supportive data for use as second-line therapy.

Third-line monotherapy recommendations are primarily opinion-based and are reserved for treatment-refractory patients. The recommendations include monotherapy with carbamazepine, olanzapine, or ECT. Combination therapy includes lithium plus carbamazepine; lithium plus pramipexole; lithium or divalproex plus venlafaxine; lithium plus an MAOI; lithium, divalproex, or an atypical antipsychotic plus a TCA; lithium, divalproex, or carbamazepine plus an SSRI and lamotrigine; and quetiapine plus lamotrigine. Monotherapy with gabapentin, aripiprazole, or ziprasidone is not recommended, nor is combination therapy with ziprasidone and levetira-cetam recommeded.

Olanzapine monotherapy is not an option for patients in whom a trial of the OFC failed, thus the inclusion of olanzapine as a third-line option is useless. The non-recommendation of aripiprazole takes into consideration the data from 2 trials with negative results, although not the results of a positive meta-analysis.

The authors of these guidelines (still in draft form) conducted a network meta-analysis that included studies of different design (eg, both with and without placebo). This is common practice; however, questions remain about the impact this might have on the data analysis, since different approaches may produce different results.

In general, at this point, the guidelines try to balance clinical practice and hard data. Thus, although quetiapine monotherapy or the OFC is recommended as the backbone of treatment, olanzapine or lamotrigine monotherapy is also recommended.

If a patient is receiving lithium or valproate and experiences a breakthrough episode of depression, the suggestion of first optimizing existing therapy and then adding quetiapine or the OFC is problematic. Use of valproate is supported by data but use of lithium is not.

 Another suggestion is to add quetiapine or the OFC, but it is unclear why this combination treatment would be superior to quetiapine or OFC alone. The guidelines do not take into consideration the lithium plus lamotrigine combination, which is the only one with supportive data.

These recent guidelines make use of the data but fail to develop guidance in an evidence-based manner. This is to be expected because of a lack of data as well as the fact that the developers of guidelines err on the side of caution. The tendency is not to be radical, but to take into consideration expert opinion as well as the expected reaction and acceptance from clinicians. One important benefit from the efforts to develop guidelines is the charting of the dark areas of our knowledge.

According to the evidence available, only quetiapine; the OFC, lurasidone; and the combination of lithium plus lamotrigine have proven treatment efficacy for bipolar depression. Valproate, aripiprazole, lamotrigine, and olanzapine monotherapy also constitute reasonable treatment options. Antidepressants should be reserved for later stages of treatment and always in combination with an antimanic agent.

 This information has yet to be used in everyday clinical practice. Clinicians still seem to adhere to the concept of “mood stabilizers,” for which there is still no supportive data. Often the evidence demands a radical change rather than a conservative add-on to existing treatment.

Dr Fountoulakis is Associate Professor of Psychiatry at the School of Medicine of Aristotle University of Thessaloniki in Greece. He has received support for conference attendance and honoraria from AtraZeneca, BMS, Elpen, Janssen, Lilly, Lundbeck, Pfizer, and others. He has been on advisory panels for BMS, Janssen, and Lundbeck, and he has received 3 major research grants from the Pfizer foundation and several small research grants from the companies mentioned above.

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