The Unfolding Story of Poor Response to Antidepressants in Bipolar Depression

October 17, 2012 · Posted in Current Treatments, Risk Factors 


The role of the traditional antidepressants in the treatment of depression in bipolar illness remains controversial. Despite mounting evidence that they are not efficacious in the treatment of bipolar depression, they are still among the most widely used treatments for that condition.  At the first biennial conference of the International Society for Bipolar Disorders held in Istanbul this past March, Mark A. Frye and Shigenobu Kanba chaired a symposium on antidepressant-induced mania and individualized treatment for bipolar depression.

This editor (Robert M. Post) discussed factors influencing antidepressants’ effects on patients with bipolar depression. In a recent meta-analysis, researchers Sidor and MacQueen reviewed data from studies encompassing 2373 patients with bipolar depression and found that antidepressants had no significant benefits over placebo on measures of response or remission. Pooled estimates for a thousand patients showed no increase in patients’ risk of switching into mania after treating with antidepressants. However, in a smaller sub-analysis, the risks of switching into mania following treatment with the older tricyclic antidepressants (43%) and venlafaxine (15%) was greater than the risk of switching after being treated with SSRIs (7%) or bupropion (5%).

There is a conundrum in the literature. While antidepressants don’t work very well in bipolar depression, there is a small subgroup of patients who, having responded well to antidepressants for two months, benefit more from continuing the antidepressant treatment than from discontinuing the drug. Continued treatment with adjunctive antidepressants (added to regular treatment with a mood stabilizer or an atypical antipsychotic) was associated with fewer relapses into depression over the next year when the antidepressants were continued compared to when they were discontinued.  Lori Altshuler et al. have published two uncontrolled studies to this effect, Russell Joffe et al. have published one, and a more recent randomized study of this by Nassir Ghaemi replicated some of the results in patients who had non-rapid-cycling bipolar disorder. At the same time, the literature shows that there are number of risk factors for switching into hypomania during antidepressant treatment in bipolar depression.

Risk factors for switching into mania upon treatment with an antidepressant include: younger age, bipolar I compared to bipolar II, rapid cycling in the past year, mixed depression, use of older tricyclic antidepressants compared to newer second-generation antidepressants, use of noradrenergic active antidepressants compared to those that act on serotonin or dopamine, and a history of substance abuse. Another potentially confounding set of studies comes from J. Amsterdam at the University of Pennsylvania. Amsterdam found that in non-rapid-cycling patients with bipolar II disorder, long-term treatment with the antidepressant fluoxetine as monotherapy was more effective than either lithium or placebo in the treatment of bipolar depression and in preventing relapse.

One way of making sense of all the data is to consider that antidepressant response may be related to where a patient with depression falls on the spectrum of unipolar to bipolar disorder and what their rate of episode recurrence is. That is, in unipolar major depression, the antidepressants work well acutely and prophylactically with minimal risk of switching into mania. In non-rapid cycling bipolar II disorder, antidepressants may still be effective. However in rapid cycling and bipolar I disorder, antidepressants may not only be ineffective but may increase the risk of switching into mania.

Two studies (one by Mark Frye and one by Joe Goldberg) indicate that classically depressed patients with bipolar disorder who have even one or two symptoms typical of hypomania, such as racing thoughts or increased energy, are more likely to switch on antidepressants compared to those without this symptomatology. In addition, depressed patients with more typical mixed episodes, i.e. episodes that would meet the criteria for both a mania and depression, are also much more likely to experience switching on antidepressants.

Studies by Vieta et al. and this editor Post and colleagues have shown that venlafaxine (which is active in blocking both serotonin and norepinephrine reuptake sites) is more likely to switch patients into mania then serotonin selective antidepressants (SSRIs) such as paroxetine (Paxil) or sertraline (Zoloft) as well as the dopamine active antidepressant bupropion (Wellbutrin). Rapid cycling patients were particularly likely to switch on venlafaxine (43% of rapid cyclers compared to 28% of non-rapid cyclers), and these rates of switching were much higher than those seen on bupropion or sertraline, which ranged from 8% to 17% in both rapid and non-rapid cycling patients.

A study called Emboldened II by Sue McElroy and colleagues compared acute response in bipolar depression among patients who were given monotherapy with either of two doses of the atypical antipsychotic quetiapine, the antidepressant paroxetine, or placebo. In this study both 300mg/day and 600mg/day doses of quetiapine were more effective than placebo, while paroxetine was not better than placebo. These data are consistent with those of Gary Sachs and colleagues in the treatment network STEP-BD. Sachs’ data indicated that adding the antidepressants bupropion or paroxetine to mood stabilizers in patients with bipolar depression was no more effective than adding placebo.

In an article published in the Journal of Clinical Psychiatry in 2012, this editor Post and associates from the Bipolar Collaborative Network assessed the number and duration of prior antidepressant trials in patients who were to enter treatment and follow-up studies in the network. (The average age at entry in these studies was 41.) These patients then received naturalistic treatment in the network, and many of them eventually experienced a good or excellent response for a period of at least 6 months. However, a substantial subgroup failed to respond when treated with the same number and intensity of medications. Analysis showed that those patients who had previously had more antidepressant trials were less likely to achieve good long-term response to this prospective naturalistic treatment. Patients’ number of prior antidepressant trials remained an independent predictor of nonresponse whether or not the antidepressant had been used with a mood stabilizer, and even when other course-of-illness characteristics were considered. Other correlates of poor prospective long-term response were having had more than 20 prior episodes and having had a comorbid anxiety disorder.

Thus, the bulk of the data suggest that antidepressants may be no more acutely effective than placebo on average and may induce switching into mania in certain subgroups of patients even when used as adjuncts to mood stabilizers or antipsychotic drugs.

A new randomized study by Nassir Ghaemi may help explain why antidepressants remain a common treatment for bipolar depression among clinicians despite the poor results seen in published studies in the literature. Ghaemi found that in patients with bipolar disorder who had been stable for 2 months after the addition of antidepressants to their treatment regimen, continuing those antidepressants was associated with a delay in the duration of time until the next depressive episode compared to discontinuing the antidepressant. These results are similar to the non-randomized, observational findings of Altshuler et al. and Joffe et al. However, in the subgroup of patients who were rapid cyclers, i.e. those who had had 4 or more episodes in the prior year, those patients randomized to antidepressant continuation experienced an exacerbation of their illness and an increased number of depressive recurrences compared to those who discontinued antidepressants.

Thus the take-home message would be to use mood stabilizers and atypical antipsychotics before anti-depressants for the treatment of bipolar depression. If patients continue to be nonresponsive to these mood stabilizers or atypical antipsychotics alone and in combination and after trying different options within these drug categories, then it would seem reasonable to add an antidepressant to a mood stabilizer. For patients with non-rapid cycling illness, a physician might consider earlier use of antidepressants as adjuncts to mood stabilizers, but for those with rapid cycling bipolar disorder presenting in the depressed phase, antidepressants should clearly be deferred to later in the sequence or avoided altogether.

Meta-Analysis: Antidepressants For Bipolar Depression Not More Effective Than Placebo

In the next formal presentation of the symposium, Glenda MacQueen of the Department of Psychiatry at the University of Calgary also discussed her meta-analysis and the efficacy of antidepressants in patients with bipolar depression and the risk of switching into mania following treatment. Her conclusion was that the overall benefit-risk ratio for antidepressants in the treatment of bipolar depression is too low.

MacQueen listed other agents that do show statistical superiority over placebo in the treatment of bipolar depression. The list included the only monotherapy approved by the Federal Drug Administration (FDA) for bipolar depression, quetiapine (Seroquel). The combination of olanzapine and fluoxetine is also FDA-approved for bipolar depression. Lamotrigine is approved for prevention of depressive episodes in bipolar disorder, but not for their acute treatment. However, some data support the efficacy of lamotrigine in acute depression. One study was positive, then a series of four additional industry-sponsored studies each found that lamotrigine was not significantly superior to placebo, but the meta-analysis of all the studies did show a significant improvement on the drug over placebo. A study undertaken at the National Institute of Mental Health by Mark Frye et al. also indicated that lamotrigine was superior to both gabapentin and placebo in treatment-resistant depressed patients.

Pharmacogenetics of Antidepressant Response and Switch

In the third presentation of the symposium, Mark Frye, Chairman of the Department of Psychiatry at the Mayo Clinic, discussed antidepressant-induced mania and the future possibilities of pharmacogenetics (using a profile of gene markers to predict the effectiveness and side effects of a drug for a given individual).

Serotonin is a neurotransmitter thought to be deficient in depression. After serotonin is released from a presynaptic neuron, it is taken back up by a transporter for storage and re-release the next time the neuron fires. Serotonin-selective antidepressants block the transporter, increasing levels of serotonin in the synapse. The serotonin reuptake transporter comes in 2 common forms—a short form, which is less effective as a transporter, and a long form that is more effective. In patients with unipolar depression, those who have the short form of the serotonin transporter are at greater risk of becoming depressed after stresses in childhood and adulthood. Some data suggest that those with the short form are also less likely to respond to antidepressants.

Frye and colleagues reviewed a series of studies that considered whether the short form of the serotonin transporter would similarly be associated with antidepressant nonresponse and/or switching into mania in patients with bipolar depression, but the literature is not yet sufficiently robust to come to strong conclusions. Nonetheless it is hoped that this kind of pharmacogenetic marker, along with the examination of clinical factors, neurobiological factors, and other common variations in genes, may ultimately be able to usher in an era of personalized medicine where predictions about the best medicine for a given individual can be made with greater confidence than is now currently possible.


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