Third Time’s a Charm: Latuda Approved for Bipolar Depression

Having bipolar disorder isn’t exactly a kick. Now that it’s all the trend for famous people to have it, perhaps sufferers feel a bit better–but so often the names call up a manic hilarity. Think Jim Carey or Rowan Atkinson or Hugh Laurie or Robin Williams.  Seems time spent in the disorder is time spent flying high.

That couldn’t be further from the truth.

Offering the type of title that I love, since it really saves me from having to do much work, the August 2007 issue of Bipolar Disorder published the article, “Three times more days depressed than manic or hypomanic in both bipolar I and bipolar II disorder.” I’m assuming you don’t need my help with this. However, other research, for example by Kemp et al in the June 2008 issue of Dialogues in Clinical Neuroscience, claims that those with bipolar II (in which a person has less severe hypomanic–as opposed to full-blown manic–episodes) spend nearly 40 times more days depressed than in any other state.

Those days are hellish.

Feeling hopeless, people long for death. Psychologist and bipolar sufferer Kay Redfield Jamison found that at least 25% to 50% of patients with bipolar disorder attempt suicide at least once. Mitchell and Malhi found that suicidal ideation is reported significantly much more by those with bipolar depression than those in any other state, and many of these suffers go in to, in fact, kill themselves. Of all the disorder’s phases, depression has the highest suicide risk, according to the Center for Quality Assessment and Improvement in Mental Health, and completed suicides occur most frequently during the depressed state.

For those who soldier on, other difficulties await, including functional and cognitive impairment. The World Health Organization estimates that bipolar disorder is the sixth leading cause of disability. And researchers have determined that the vast majority of this disability time is due to the depressed state of the illness (Mitchell and Malhi 2001).

DataMonitor (Healthcare) noted that more doctors recognize the importance of addressing cognitive symptoms in bipolar patients, a problem that affects somewhere between 26-64% of those with the illness.  Zarate et al (2000) specifically noted that those with bipolar depression showed “significant impairments” in both verbal memory and executive function in comparison with controls.

So, with an illness this bad–which has been know for so long–you’d think we’d have some good treatments.

You’d think wrong.

The first thing that probably comes to mind for a depressed person is. . . .(3 guesses here. . ..)

Well, if you said an antidepressant. . .  you’d have made the wrong choice.

It has been known for years that antidepressants are at best useless in treating bipolar depression (let me offer you another title I love, from the British Medical Journal (BMJ), May 5, 2007, “Antidepressants ineffective in bipolar depression“), and, at worst, can cause ‘switching,’ or a rapid trip right out of depression and into mania or hypomania  You can start with, if you want an example of the literature behind that assertion, a June 2002 article from Acta Psychiatrica Scandinavica entitled, “Induction of mania and cycle acceleration in bipolar disorder: effect of different classes of antidepressant.”

Well, you probably think, I’m sure there are many other choices of treatment that I’m just not aware of.

Yet again. . .wrong.

There are precisely two (I mean it–two) FDA-approved treatments for bipolar depression:

  • Symbyax, a combination of Prozac, an antidepressant, and Zyprexa, an atypical antipsychotic, was approved in 2004, and
  • Seroquel, an atypical antipsychotic, was approved in 2007.

[In shameless self-promotion–but with the best of intentions–I let you know that I’ve written two posts on the topic of what’s coming down the pipeline [we hope] for treatment-resistant bipolar depression. If you’d like to check it out, click here for the pharmaceuticals headed our way, and here for the more ‘natural’ approaches to treatment.]

Thus there is room for some more options.  Apparently the FDA thought so, too, since on Friday, June 28, the two treatments welcomed a third, Latuda, also an atypical antipsychotic  The FDA went all out in its approval of this one.

Not only is Latuda (generic lurasidone) approved to individually treat  depression for those with bipolar I , but then it got approval (and to tell you the truth, it seems like if you got the first you’d automatically have the second, but I guess some people like to spell out everything) to treat bipolar depression in conjunction with lithium or a mood stabilizer called Depakote.

Latuda’s arrival in the world of bipolar depression is being heralded like the second–or, in this case, third–coming.

Now the truth is that the drug starts at a bit of a disadvantage in being a Johny-Come-Lately.  Although each one has some unique component, all of the atypical antipsychotics–and for that matter most of the rather ‘typical’ ones– share a general mechanism of action  You really don’t want me to go into this here–so hopefully  you can live with the following: All antipsychotics block dopamine receptors and generally lower dopamine levels.  Schizophrenics demonstrate increased dopamine levels. The theory is that high levels of dopamine in the brain cause mania while low levels cause depression. Some of the newer, fancier atypicals also work to block serotonin receptors in addition,  to hopefully increase a person’s feeling of well-being.

Given that Latuda also functions in the above two ways, it’s really a “me-too” drug. It will have to complete with the highly successful  Seroquel franchise (”franchise’ just means AstraZeneca got Seroquel XR thrown in, too, to the tune of a new patent and new FDA approval in 2008–I just can’t bring myself to count it as separate). Seroquel, approved for both bipolar I and bipolar II depression (the only–and I mean the only–drug that is), was found both to ease high levels of anxiety and be associated with “significant improvements in health-related quality of life” (Thase 2008).  Seroquel demonstrated improvement, too, in suicidal and pessimistic thoughts–and, as  everyone in the field knows–it is a good sleep drug.

Yet Latuda has not let itself be scared away by the competition. It has put itself forward and made itself sound so great, that–well, you just want to believe all its claims are true.

What fancy things can it do that the other two can’t, you wonder? Well, Sunovion Pharmaceuticals, Latuda’s maker, is just so glad you asked.

Most of this is based on the original research done on schizophrenics, but it could surely be applicable to those with bipolar, as well.  First, Latuda has shown the potential to improve some of the cognitive impairment that goes with these mental illnesses. Yuen et al in Molecular Biology (2012) point out that the drug has already been shown to improve cognition in animal models of schizophrenia and has the right molecular and cellular mechanisms to make a difference in humans. Cruz in PT (2011) notes that “experimental data support the theory that [the mechanism of Latuda] can improve cognition, memory and mood symptoms.”

Sign me up, right?

And even better is what it doesn’t have.

Zyprexa, one-half of Symbyax, the first FDA-approved treatment for bipolar depression, is a pretty effective drug. But it comes with a fairly staggering side effect: subjects on it gained, on average, 5.07 pounds per month (numbers from Nihalani 2011, in, appropriate, the Journal of Obesity).

Needless to say, lawsuits heaven.

Seroquel, considered not as bad on that front, brings with it about 4 pounds a month.

None of that is pretty.  But Sunovion presented their results (again, these are from the schizophrenic studies) at the Annual Meeting of the American Psychiatric Association in Honolulu, Hawaii:

Short-term (6-week) data from seven double-blind, placebo-controlled studies showed an average of  0.95 lbs. weight gain, with 4.8% clinically significant weight gain. (I’m glad they shared how many had ” significant weight gain”–but remain slightly curious how many pounds make up “significant”.)

Sunovion was quick to tell us how monumental this was. “These two approvals represent a significant milestone not only for Sunovion and DSP, but for the millions of Americans who are living with bipolar disorder and struggling to manage the symptoms of bipolar depression,” said Masayo Tada, Representative Director, President and Chief Executive Officer of Dainippon Sumitomo Pharma Co., Ltd.

Although I own no stock in either Sunovion or DSP–I hope Latuda’s a huge hit in easing the suffering of everyone with bipolar depression. Just a few quick “wonderings” before I go, because, frankly, I’ve found that each new wonder drug has come with some price to pay. Please write in and tell me I’m wrong–and that your experience with the drug is all good.

1. Despite having a lower rate of weight gain, which I’m all for, there are obviously still side effects from Latuda– no point ignoring them. There was a pretty high percentage of nausea reported in PREVAIL 1 (17.5%), with headache at 10.4% (actually lower than placebo), and somnolence at 8.7% (this time double placebo), A really miserable side effect was akathisia ( motor restlessness with internal internally agitation leading to the inability to sit still) coming in It’s worrisome from the rate of akathesia exceeds 5% ;  7.7%) in the Latuda studied suffered this discomfort. In fact, Kane (2011), writes in The Psychiatrist that longer (6-month) trials yielded a 15% rate of akathisia (vs. 3% placebo).

2. Even if Latuda does look like the second coming for bipolar I depression, sometimes it takes time for a drug’s ‘alter ego’ to appear. Take Zyprexa. Released by Eli Lilly in 1996, over the next years, even as other atypicals came out, it was considered one of the best drugs to treat schizophrenia and also bipolar mania.

Now, early in the game, before its reps even began promoting the drug, Lilly knew Zyprexa caused tremendous weight gain. But, according to the Times, it wasn’t until 2001 that (according to Lilly’s marketing research) psychiatrists were publically saying that their patients were putting on weight and developing diabetes.

By my computation, that’s a good 5 years between its arrival on the scene and the awareness of storm clouds.

 Latuda hasn’t been on the market for 3 full years yet.  Who knows what we might still find?

Then again, maybe I’m wrong. Maybe the drug fixes depression, improves cognition, eases anxiety–hey! maybe it even helps you take off weight.  Maybe all these things are true, because, you know, in the world of psych meds, third time is a charm.

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