Antidepressant controversy 3: Antidepressants as Mood Destabilizers?

Table of Contents

(continued from the main Antidepressant Controversies page):

Dr. Ghaemi refers to two randomized trials regarding this question. Here they are, in perhaps excruciating detail (because I think they’re so important! not sure you will find it worth the slogging, though).

Study One

From back in 1988Wehr. In this study, patients with bipolar disorder so an increase in the frequency of their cycles after an antidepressant (a tricyclic) was added to their ongoing lithium. Think about it: an increase in frequency of episodes. We’re not talking about switching here, we’re talking about changing the course of bipolar disorder, at least while they’re on an antidepressant. Not just one switch, but more switches than they would have had were they not on the antidepressant.

Study Two

This one is less obvious. But because antidepressants are so widely used in bipolar disorder, the idea that they can actually make people worse, or at least keep them from getting better, has tremendous implications. In that spirit then, I would like to show you these data (presented in this format before they were later published using different graphsGhaemi; used by permission, Dr. Ghaemi).

Seventy patients with bipolar disorder who had been on an antidepressant for at least two months were randomly assigned to either continue their antidepressant, or stop it. Here’s what happened in the following year (solid line, antidepressants stopped; dotted line, antidepressants continued:


This graph shows the patient’s scores on their “Clinical Monitoring Form” (CMF). This form is used by the doctor to rate the patient’s symptoms, either manic or depressed. A zero would mean complete mood stability. Higher scores, like the 3-6 range you see here, mean the patients are having symptoms. You cannot tell whether those symptoms are mania or depression from this graph; it contains both such mood changes. What you can see is that patients in both groups wobble up and down, but their average scores over the year are in the same range – except for the big initial spike in the patients taken off antidepressants. You might guess that this was an increase in depression scores, and you would be right, as you can see in the next graph.

(I am not certain how quickly these antidepressants were tapered, but I believe one of the authors told me it was over one month or less. A much slower taper rate, closer to four months, might have eliminated that spike entirely. I have used that rate for years now after hearing it recommended by Harvard’s Dr. Sachs, and I think it has allowed me to taper patients off antidepressants without seeing an increase in depression very often). UPDATE 2008: I finally found a reference supporting this practice, sort of anyway. If you want it, read this page on Antidepressant Withdrawal.

In the following graph, you see the CMF scores for depression only. Now that early black spike is even more obvious. However, note that both groups show roughly the same results thereafter, over the year. If antidepressants really kept patients from being depressed, you’d expect that the group which stayed on them would look better in this graph: the dotted line would be significantly lower than the solid line, right?


As you can see, the two lines are roughly similar. This is the first of two very important results from this study. Here we see data suggesting that continuing an antidepressant does not make patients experience less depression. In other words, if you pull an antidepressant out fairly quickly, many patients may have an initial increase in their depression scores, but this worsening does not persist. Over the course of a year, that group will be indistinguishable from a group of patients who continued their antidepressant. At minimum, this suggests that long-term antidepressants provide no sustained benefit. But might they present sustained risk?

In this same study, we see results that suggest patients actually do worse if they stay on their antidepressant. I will show you those in a moment. However, caution is needed here: these are preliminary results from a rather small study. Before we draw any firm conclusions, it would be great to have a larger study showing the same results. Unfortunately, we are likely to be waiting a long time. Replicating this study is likely to be very difficult, because it took a huge sample of research patients to set the stage for this small group to be studied like this.

That’s a problem, because even though this is the best study we have, it has some serious drawbacks. For example: patients were selected to enter this study knowing that they might be taken off their antidepressant. Those who were completely convinced the antidepressant was helping them were probably reluctant to participate. Their physicians were probably reluctant to refer them to this study. Thus we have a selection bias: patients who entered this study may have been much more likely to be able to do well without an antidepressant than the general group of patients with bipolar disorder. This is a serious problem with this study.

Worse yet, this was not a “blinded” study. Both the investigators and the patients knew who was in which group. They may have had expectations of what would happen. Those expectations could easily have influenced the numbers which were recorded on the Clinical Monitoring Form (CMF).

Finally, although the results you’re about to see look impressive, suggesting that antidepressants make outcomes worse, they are not statistically significant. They illustrate a trend. The trend is in exactly the direction one would predict if antidepressants really do cause mood instability. With a larger sample size, if the same results were obtained, they would be statistically significant. Thus the small size of this study is very limiting.

Therefore, the following graph must be interpreted with great caution. I present it because it supports my point of view! To my knowledge there are no data to the contrary from any study of similar design. Again, this is the best we have right now, and as such it is relevant for patients who need a decision right now. Okay, enough warnings. Here are the results, this time looking just at CMF manic symptoms (solid line, antidepressants stopped; dotted line, antidepressants continued):


Although blurry (I scanned this from a poster handout), you can see now that the dotted line is mapping out a different course than the solid line. (This is not as big a difference as it looks, because the scale has changed: the difference between these two groups is really quite tiny, only one unit on the CMF; in the previous graph, the scale was about three times as big).

These data suggest that patients on antidepressants seemed to have more manic symptoms in the following year than those whose antidepressant was discontinued. But this is a weak result, not to be relied upon as the basis for an opinion — by itself, anyway. Remember, the earlier finding: patients who were maintained on antidepressants didn’t do better than those whose antidepressant was discontinued. Actually, even that is overstated: in a separate analysis, the authors found a slight advantage for those patients who stayed on their antidepressants. But the difference was very small, and if the patient had rapid cycling, they were clearly better off to have stopped their antidepressant. A more skeptical reader might find that the two results presented here cancel one another: some very slight evidence of increased risk of mania amongst patients who stayed on their antidepressant, versus a benefit of slightly less depression. Clearly what is needed is another study, a bigger one. But my patients need to know what to do now.

Next… Tolerance and Kindling. Can Antidepressants Stop Working?

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