Vladimir Maletic, MD, MS: You mentioned a couple of important scenarios, one is nonadherence. We know that depending on the study, anywhere between 40% and 60% of individuals with bipolar disorder do not adhere to the treatment plans and recommendations. Another scenario you mentioned is a very important one, patient preference. Some patients may prefer taking oral medications. There’s also some indication that using long-acting injectables [LAIs] may cut down on the rate of hospitalization, which would also be an important consideration. Now, I have a very tough question for you. You mentioned 2 options, aripiprazole and risperidone long-acting injectables, and the evidence suggests that these medicines are quite effective in preventing recurrence of future manic episodes. But what about depression?

Andrew Cutler, MD: That’s less clear because these trials tended to be in patients who had recent manic episodes. But in my experience risperidone is not as good an antidepressant as aripiprazole, but I believe that they both have some evidence of also preventing depressive episodes, particularly the aripiprazole studies. They are certainly very good options for that. The indication is for maintenance, which means to prevent the recurrence of either a manic or a depressive episode. If I were to use one of those two long-acting injectables, it’s very possible I might add something else such as lamotrigine to help stabilize from below. They’re both especially good at preventing manias, and they may also help prevent depressions.

Vladimir Maletic, MD, MS: What I hear you say is that they do not exclude using some other agents to minimize the risk of recurrence of bipolar depression. How about the safety records of these medicines? I know you have done research with these compounds as well as use them in your own practice. What is your impression of the safety records?

Andrew Cutler, MD: My opinion is that long-acting injectables are better tolerated than orals. If you simply think about the pharmacokinetics of an oral, the medicine has a lot of peak-to-trough variability, whereas the LAIs tend to have a much smoother blood level with less peak-to-trough variability. It’s not only about the peaks, at peak levels you can have more adverse effects, but sometimes it’s also about the variability in the peak-to-trough ratio. The brain doesn’t like things going up and down as much as it does more smoothness. There is some evidence that there may be less risk of movement disorders with LAIs, and the tolerability in my experience has been very good. One of the things I always wondered about was, we used to use haloperidol decanoate, and I found I didn’t see as much acute dystonia and movement disorders as I did with the oral version. I wonder if it isn’t this pharmacokinetic thing. In general, the tolerability has been quite good, particularly these two, which are not terribly sedating and don’t have significant amounts of weight gain. Patients with bipolar disorders don’t like weight gain and sedation. In the case of aripiprazole, you’re not elevating prolactin, so you don’t expect much sexual dysfunction. Patients with bipolar disorder also don’t like sexual dysfunction.

Vladimir Maletic, MD, MS: Andy, as you know, there is much skepticism and reluctance among our colleagues, and long-acting injectables may be underutilized. You’ve mentioned some really good reasons why they should be considered: a favorable balance between efficacy and safety, cutting down on nonadherence, the diminishing hospitalization rates.

Andrew Cutler, MD: There’s another thing we haven’t mentioned. There is evidence, certainly in the schizophrenia literature, that long-acting injectables may be better at preserving the brain and preventing deterioration. Now I tend to think of bipolar as potentially a neurodegenerative or neuroprogressive disorder. I had a professor once years ago who said to me, “Never let anybody stay manic or psychotic because they’re bad for the brain.” There is now evidence that may be true. As we know with subsequent manic or depressive episodes, you can see a decrease not only in brain tissue but also in cognitive performance. Use of a long-acting injectable may not only prevent clinical relapse, but it may also be disease-modifying.

Vladimir Maletic, MD, MS: Potentially neuroprotective. As you mentioned there are studies looking at both number of episodes and duration of episodes. It appears that manic episodes are particularly toxic to brain tissue, but there’s also clear evidence of thinning of gray matter volume, and there’s a lot of prefrontal cortex involvement related to repeated manic episodes. Indeed, we do have imaging evidence supporting your claims.

Transcript edited for clarity