“Bipolar depression” is a commonly used term, but it is not technically correct. It refers to a depressive episode occurring within bipolar disorder, regardless of the degree of expression or severity.
The correct term would simply be “bipolar disorder, depressive episode,” but the expression is widespread for two reasons:
The first is that patients usually seek treatment because of depression and anxiety, or rather because of depressive and anxiety symptoms, whereas excitatory symptoms are not usually the main focus.
The second reason is that the first episode for which a person with bipolar disorder seeks psychiatric outpatient treatment is often a depressive episode, especially in bipolar II disorder. Thus, the patient is initially classified as depressed, and only when other, excitatory phenomena subsequently appear is the diagnosis changed to bipolar disorder, while the term “bipolar depression” is retained because it reflects the sequence in which the manifestations occurred (first depression, then excitation).
This term is incorrect because it suggests that bipolar depression is a subtype of depression, meaning that it is essentially depression that is, secondarily, of the bipolar type.
In reality, depressive illness and bipolar illness are two different entities, and the basis of treatment is therefore different, as are the patient’s subjective experience and the types of complications and problems these two illnesses produce over time.
According to treatment guidelines for “acute bipolar depression” (that is, an acute depressive episode in a patient with a diagnosis of bipolar disorder), the initial therapeutic options never consist of an antidepressant alone. They may instead consist of a so-called mood stabilizer or an antipsychotic combined with an antidepressant.
The following are the possible first-, second-, and third-line options*, listed on the assumption that the patient is being diagnosed either at that moment or has already been diagnosed, and is either not taking treatment or is already taking treatment for a mood disorder.
Depression in Bipolar I Disorder
First-line options
Lithium
Quetiapine
Lamotrigine
Quetiapine (extended release)
Olanzapine + SSRI
Lithium + lamotrigine
Second-line options
Lithium + valproate
Valproate
Lithium + SSRI
Lithium + lamotrigine
Lithium + carbamazepine
Lithium + valproate
Valproate + lamotrigine
Lithium + MAOI
Lithium + TCA
Valproate + TCA
Atypical antipsychotic + TCA
Valproate + lamotrigine + SSRI
Third-line options
Lithium + valproate + SSRI
Lithium + valproate + bupropion
Carbamazepine + lamotrigine + SSRI
Lithium + venlafaxine
Valproate + venlafaxine
Electroconvulsive therapy
*Adapted according to the availability and indications of products for depression and/or bipolar disorder on the Italian market.
Therefore, in a patient with bipolar disorder who is not already receiving treatment, several options are possible, ranging from the simplest approach (a classic anti-bipolar medication, which would also have been appropriate during another phase, such as a manic or excitatory phase, for example lithium), whereas if the patient is already taking an anti-bipolar medication, various changes or additions may be considered.
Probably the best approach is not to change the medication that has worked in resolving or preventing previously observed manic episodes, but rather to supplement the treatment with a second medication during the depressive phase.
In the case of an initial treatment, or treatment started in a patient who is not currently receiving medication, it is also possible to begin with treatment directed toward depressive symptoms and not effective in preventing mania, such as lamotrigine, unless the patient’s history already includes major manic episodes. In that case, even in the presence of depression, treatment for bipolar disorder should nevertheless also cover the possibility of major manic episodes.
If one looks through the table of treatment options from the first column to the third, it becomes apparent that the initial options tend to limit the use of antidepressants, which instead appear with all the main available classes as third-choice options (SSRIs, TCAs, dual-action antidepressants, MAOIs).
These indications for acute bipolar depression probably also have preventive implications, that is, when treating an excitatory phase with the aim of preventing the subsequent depressive phase, which is otherwise frequent and difficult to manage while waiting for it to resolve spontaneously.
Another observation should be made: some of the options reproduce a strategy that many clinicians already use empirically, namely antidepressant + antipsychotic, as in the olanzapine/SSRI combination and in extended-release quetiapine, which produces a secondary metabolite with antidepressant activity. The difference, however, is that in this case the anti-manic or antipsychotic medication is started first or simultaneously, whereas in empirical approaches that follow the symptoms, the antidepressant is usually started first and the antipsychotic is added later when the patient shows agitation or clear signs of mania, often without discontinuing the antidepressant itself.
In practice, the guidelines approach bipolar depression by attempting to treat the depression within the context of bipolar disorder, whose priority is the control and prevention of mania. In symptom-driven management, treatment usually starts with the depression and then adjusts the strategy to address manic symptoms as well, without considering that antidepressants themselves may have induced those symptoms.
Depression in Bipolar II Disorder
Quetiapine
Lithium
Antidepressant*
Lamotrigine
Valproate
Lithium + antidepressants
Valproate + antidepressants
*In cases with rare hypomanic episodes.
Here too, it can be seen that the initial choices, despite bipolar II disorder being a milder and never psychotic form of the disorder, are directed toward anti-manic medications, and only as a third step is an antidepressant alone considered.
In bipolar II depression, antipsychotics are not recommended as they are in bipolar I, partly because bipolar II disorder does not involve psychotic episodes and therefore the patient will almost certainly not present already taking an antipsychotic medication. The exception is quetiapine, which therefore should not be considered only an antipsychotic but also, as is probably true of other antipsychotics, an anti-bipolar medication.
Naturally, in outpatient practice the choice is influenced by other factors, such as the fact that very solid efficacy may nevertheless be associated with a higher incidence of certain adverse effects, such as weight gain, or the fact that SSRI antidepressant treatment, although beneficial, may be associated with sexual side effects, to mention two commonly observed problems.
The use of antidepressants in bipolar disorder should therefore not be understood as the primary tool for treating depressive or anxiety symptoms. It must be remembered that antidepressants may facilitate excitatory episodes, and that this can happen partly because excitatory symptoms are not always observable (they may be intermittent), are often not reported by the patient as such (but, for example, as “anxiety” or as well-being in the case of euphoria), and past manic episodes are often omitted or minimized in the patient’s spontaneous account.
What appears to happen instead is that exposure of bipolar disorder to antidepressants, although it may have resolved the first depressive episode, often fails to do so in subsequent episodes and does not prevent depressive relapses in the long term. In addition, there is a risk of chronic mood instability and treatment-induced episodes. In this respect too, patients who have already experienced excitation while taking antidepressants are predisposed to experiencing it again.
Ultimately, treatment of bipolar disorder should be defined as early as possible once the diagnosis has been established or suspected, bearing in mind that a substantial proportion of depressive disorders already fall, or will eventually fall, within the bipolar category rather than within the generic category of “depressive syndrome,” and that in every case of recurrent depression, its possible belonging to the bipolar spectrum should be assessed.
What is at stake during treatment of the very first episodes is not only the preservation of the patient’s adaptation and potential, but also the response to subsequent episodes and the prevention of progressive worsening over time.
Essential bibliography
Yatham LN et al. Bipolar Disord 2009;11:225–255.
CANMAT/ISBD: recommendations for the pharmacological treatment of acute bipolar depression.