Greetings.

I am a psychiatrist from Portugal.
When recently discussing with a colleague about a bipolar patient who presents psychotic symptoms in the context of (depressive) mixed states (and no psychotic symptoms between her acute episodes) we agreed Valproate would be the more apropriate mood stabilizer. When discussing about what other medication should be indicated for maintenance treatment (1) I sugested Lamotrigine (so that relapse of depressive symptoms would be addressed more effectivelly) and (2) my colleague suggested Quetiapine (so that the patient would be protected for the psychotic symptoms and also depressive symptoms). (3) I argued there isn't enough evidence so we should prescribe quetiapine for maintenance treatment on bipolar disorder, (4) he said if it is a fact there was yet no evidence Quetiapine is effective in maintenance treatment there was also no evidence Quetiapine was ineffective.

About this discussion:
(1) Is my suggestion a valid one as my thought is that Valproate isn't as effective as Lamotringe to prevent depressive relapses. If you find it valid, should one always try this association when treating a bipolar patient with a story of predominantly depressive mixed episodes? Or should we start with Valproate and wait to see the clinical response and adding Lamotrigine latter if Valproate alone doesn'r prove effective enough?
(2) What do you think about this association (Valproate and Quetiapine) for maintenance treatment of bipolar depressive mixed states?
(3) According to bmj evidence center Quetiapine is not yet considered useful for maintenance treatment in this kind of patients? Do you know any evidence in favour of its use in the maintenance treatment?
(4) Was my colleague's argument a valid one?

Please leave your opinion.
Sorry for my long message and my bad english.
Thank you.

Joao Parente

1. Lamotrigine is an effective maintenance medication from the perspective of preventing depressive episodes in bipolar disorder. Its usefulness has been demonstrated in two randomized controlled trials and it could be a useful medication as an adjunctive treatment with valproate, if this patient is clinically experiencing predominantly depressive episodes. As an acute treatment the data is more equivocal, although it still appears to have some significant antidepressant effect, its long titration period can limit its effectiveness. It is important to note that while it is a reasonable choice as a combination treatment with valproate, there are important drug-drug interactions with these two medications that must be considered. Valproate levels are lowered when combined with lamotrigine, and lamotrigine levels can be increased resulting in an increase risk of Stevens-Johnson syndrome. This interaction necessitates that the lamotrigine titration schedule be adjusted and the overall titration occurs at a slower rate.

2. The combination of quetiapine and valproate is approved as a maintenance treatment for bipolar disorder and is the only combination treatment approved for maintenance treatment. Two randomized controlled studies lasting 24 months found significantly lower overall, depressive, and manic relapse rates. A study assessing the combination of quetiapine with valproate (or lithium) demonstrated that it was more cost-effective than placebo with valproate or lithium based on fewer acute mood episodes (depressive and manic) and hospitalizations. Further, quetiapine is an effective treatment for bipolar depressed and bipolar mixed states. Therefore, adding quetiapine to valproate would be a reasonable and possibly effective treatment strategy in this patient.

3. As noted above, quetiapine was approved recently as a maintenance treatment in combination with valproate or lithium. Adding quetiapine to valproate as a management strategy for this patient would be a reasonable choice. It is not currently been approved as monotherapy treatment for bipolar disorder, although olanzapine and aripiprazole have been and are supported by clinical trial evidence. There are currently studies examining the effectiveness of quetiapine as monotherapy for bipolar disorder, however we are not aware of any that have been published to date.

As always, medication choices must be adjusted according to a patient’s clinical history and preferences. There are significantly different side effect profiles for lamotrigine and quetiapine, and a given patient may prefer one over the other. For many patients, the side effect profile of lamotrigine may be preferable, although the need for slow titration of dose and reliable treatment adherence may be difficult for some. The atypical antipsychotics, including quetiapine, have a variety of side effects including sedation, anticholnergic effects, weight gain, and other metabolic effects that may be detrimental, particularly considering that there is overlap with the side effects of valproate. These issues do not preclude using these medications, but does necessitate careful discussion with patients and appropriate monitoring after making a decision.

References:
Ketter, TA: Monotherapy Versus Combined Treatment With Second-Generation Antipsychotics in Bipolar disorder. J Clin Psychiatry 2008;69 suppl 5, 9-15.

Woodward TC, Tafesse E, Quon P, Kim J, Lazarus A.: Cost-effectiveness of quetiapine with lithium or divalproex for maintenance treatment of bipolar I disorder. J Med Econ. 2009;12(4):259-68.

Malhi GS, Adams D, Berk M. Medicating mood with maintenance in mind: bipolar depression pharmacotherapy. Bipolar Disord 2009: 11 (Suppl. 2): 55–76.