When the Alternative Just Looks Better: Bipolar and Medication Non-adherence

When the Alternative Just Looks Better: Bipolar and Medication Non-adherence

Why would anyone choose an injection (getting to the medical office, waiting, waiting, more waiting, and then mild discomfort) over taking a daily pill?

The simple answer: many folks can’t be relied upon to take their daily dose.

That’s true of people with all sorts of illnesses, all kinds of prognoses, and a variety of life circumstances.

But it’s particularly concerning among the mentally ill, where non-adherence is high, and the results can be devastating.

To be perfectly honest, it was as I was thinking how to start this topic of medication adherence that a wonderfully subtle and humble way came to me: Why not refer you to a piece I’ve already published? I’m sure no one else has thought of this technique before, so feel free to use my innovative idea the next time you’re stuck for a beginning.

So I thought we’d best start off by addressing mental illness and adherence by means of a long-acting injectable named Zyprexa relprevv, one of several formulations of long-acting atypical antipsychotics that are put straight into the muscle.  To find out more about Zyprexa relprevv (including two unfortunate deaths that seem to have occurred as a result of the injection–almost two months later the FDA is still “looking into it”–all you need to is click on “ZyprexaRelprevv – Till Death Do Us Part,” which takes you to my alternative universe, where I only blog about drugs (hey–it’s a living).

But to return from the land of pure self-promotion, the injectable, which allows patients to come in either every two weeks or just once a month for medication, didn’t come about (solely) because Eli Lilly, makers of Zyprexa relprevv, needed a few more bucks. In 2011 Lilly’s original drug, Zyprexa, was among the top 25 psychiatric medications prescribed in the U.S., with $2,496,000,000 in 2010 sales.

Atypical antipsychotic makers started creating long-acting injectable formulations because psych patients are notoriously non-compliant with their medication regimes. The idea’s a good one—but we’re going to focus on bipolar disorder in this piece, and, with fewer than 10% of bipolar patients receiving prescriptions for these meds, they really don’t make a dent in this serious problem.

It’s serious enough that a 2007 study addressing mental illness in general found the following, highly distressing information:

“Over the course of a year, about three-quarters of patients prescribed psychotropic medication will discontinue, often coming to the decision themselves and without informing a health professional.”

Well, that’s hardly off to a good start.  Those numbers are hard to beat, and bipolar people—fortunately–don’t beat them.  So the truth is that when you break down the numbers, bipolar non-adherence is not that bad—it’s just plain bad.  And each time a researcher is convinced they’re looking into a new drug, with a better side effect profile, that will increase adherence–they’re unpleasantly surprised.

Most estimates are that around 50% of those with bipolar disorder are not medicine adherent, although according to Miklowitz and Johnson in a 2006 article in the Annual Review of Clinical Psychology, the numbers who are fully or partially non-adherent to their regime a mere year after a mixed or manic episode can run as high as 60%. The two quote two further studies, one which found that patients treated in a local community clinic took their lithium for an average of only 76 days after receiving their prescription, and another study, two years later, found that only about 21% of patients who take lithium are continuously adherent with it.

But of course we’ve come a long way, baby, with enough mood stabilizers to fill a little corner aisle at Target. There’s Depakote, of course, which, apparently, didn’t snow anybody in a research study quoted by Mitchell and Selmes (2007)–they reported “premature discontinuation rates,” as they politely called it, of about 70% of a 1-year trial of lithium, placebo, and Depakote.  They also found that 23.2% of those on lithium as maintenance, and 17.1% on those on Depakote maintenance, stopped their medicine early due to side effects (that’s versus 4.8% taking placebo).

People had originally thought that adherence to other mood stabilizers (Tegretol, Depakote, Topamax, Lamictal–you know, the fun ones) would be higher.  (For those who have been on them–perhaps you can explain their reasoning.)  But when Scott and Pope (2002) lumped all mood stabilizers together, they came up with quite a range, concluding that “[t]he prevalence of nonadherence with mood stabilizers ranges from about 18% to 52%.” Aha.

In general researchers found results similar to lithium among the other anticonvulsants. Sajatovic et al (2007) studied adherence among lithium, Depakote, Tegretol and Lamictal, thereby hitting the “top 4″ of mood stabilizers, if you’re not going to let the antipsychotics play, and although there was a tad bit difference here and a bit of a bump there, they were surprised to find not a lot of “there” there.  Out of a huge database of 44,637, 54.1% won the “fully adherent” reward (this strikes me as a very slight majority, and not much to write home about). 24.5% were partially adherent, with 21.4% belonging in the ‘bad boy’ chair. The scientists, who had been hoping for better compliance than what they’d been getting with lithium, were a little let down.  “Our results emphasize the point,” they clarify, for those who might have missed it, that compliance is not better at all with “newer, theoretically better-tolerated agents and that, in fact, adherence rates are rather similar across mood-stabilizing compounds.”

Even though the antipsychotic drug Zyprexa was approved by the FDA in 2000 to treat bipolar mania, Sajatovic et al write in their 2006 article in Bipolar Disorders of the “relatively new, increasingly prominent component of the treatment armamentarium for bipolar disorder,” meaning using the atypical antipsychotics to treat the illness. And, indeed, this new set of drugs requires a whole new set of data on adherence, given its issues with side effects. With access to the VA National Psychosis Registry and 73,964 bipolar patients, they determined that slightly over half (51.9%) of those taking antipsychotics were fully adherent, while 48.1% (carry the 1 and. . .yup, that’s right) get partial credit as “partially adherent”–or no credit at all, since they’re just just flat-out non-adherent.

The funny thing about all this—how can I put it?–lack of cooperation on the part of the bipolar person?  Nothing good seems to come of going off those meds–as convinced as the person may be at the time that it will. Non-adherent patients are at a greater risk of suicide and are more likely to relapse. Keller et al (2004), noting that adherence “increases the duration of remission,” makes the point that non-adherence decreases the duration between episodes.  Montes (2013) adds the upbeat observation that non-adherence has been correlated with “poorer clinical and functional outcomes, increased use of emergency psychiatric services, and an increased number of hospital admissions.”

But of course what remains is the obvious question: Why? If you’re faced with illness, suicidal thoughts—or suicide itself–an ER visit, and possible hospitalization–why not just keep taking those meds?

The research community fails to present a united front on this one—and that’s putting it lightly.  In fact, I really appreciated that  Leo et al (2005), in an article in Primary Psychiatry, didn’t run any research study to get their answers, didn’t give any statistics about whether Native Americans or African Americans were more non-adherent, didn’t argue with previous researchers about whether marriage reached significance –nothing like that.  They just made what they called a “table” (to the uninitiated it certainly looked just like a list), and threw in all the reasons for non-adherence, without bothering to argue whether “denial of illness,” “adverse side effects,” or “poor therapeutic alliance” was more relevant. So I’ll give you a list, too, and let you pick and choose–but I can’t help but give you my top three.

My all-time favorite comes to us courtesy of Johnson et al 2007.  I truly wonder if they understood the profundity–and the hilarity–of what they were saying.  In their article, “Factors that affect adherence to bipolar disorder treatments: a stated-preference approach,” they come up with this priceless gem:

“[T]his study suggests patients are likely to be more adherent to medications that reduce the severity of depressive episodes.”

So, if I’ve got this straight–and I really do think I have–Johnson and his colleagues surveyed 469 patients, read all the Web surveys, ran their statistics, worked with their p is greater or less than 0.05 factor–in order to conclude that people are more likely to take medication if it works. Who would have thunk?

A close second was: Side effects.  Would you believe that people will stop taking their medications due only to sexual side effects, irregular heart beat, constant thirst, muscle weakness, fatigue, or a kind of deadened feeling?  Sajatovic et al’s 2011 study interviewed 20 “poorly adherent” bipolar patients in a local community mental health clinic. And simply forgetting blew all other reasons for non-adherence out of the water, clocking in at 55%.  But the silver medal winner was side effects. And the biggest one? Weight gain.

In a cross-sectional survey run by Fakhoury et al in 2001 of over 220 people taking atypical antipsychotics, nearly one-half pronounced themselves dissatisfied with their medication.  Among the most distressing side effect was the amount of weight gain caused by the meds.  A survey done by Fakhoury just two years earlier revealed that over 70% of those surveyed claimed the weight gain from these meds was “extremely distressing,” a percentage that was higher than for any other side effect.  Viva Zyprexa.

My choice for third is one I find terribly poignant.  A number of those who suffer from bipolar–and even more who suffer from other serious major illnesses–simply don’t believe they’re ill.   Suffering from what is called anosognosia, these are patients who give up on their medicine regimes because–well, what in heaven’s name do they need medicines for? They suffer from a lack of awareness of their disability.

I tried hard to imagine–having been through the bipolar ringer, up, and down, and mixed, and not in my right mind–I’m trying to imagine what it is, what glimmer of hope, or what tendency towards psychosis, or what belief that started the illness with you and you won’t give up, or–and maybe this is it–long durations between episodes, years where you don’t cycle at all–what could convince a person with bipolar that they don’t have it? Whatever it is, the results, if you convince yourself so well that you stop your meds, aren’t all that great.

Most of the research about anosognosia and non-adherence addresses schizophrenics, but apparently there were enough researchers and enough bipolar people willing to proudly announce they were done with meds because they were done with their illness that I got a few studies out of the old lit search.  As early as 1971, Polatin and Fieve wrote about lithium non-adherence (Tegretol, Risperdal, and Latuda were just gleams in drug-makers’ eyes):  patients felt it decreased their creativity and productivity–and denial of illness played a major role in noncompliance (see the tome by Goodwin &  Jamison, Manic Depressive Illness: Bipolar Disorders and Recurrent Depression, published in 2007).

Or as Keck et al wrote, back in 1997, after following 140 patients for a year after hospitalization for bipolar, and finding 51% partially or totally noncompliant,  “[d]enial of need was the most common reason cited [63%] for noncompliance.” Greenhouse et al (2000) again found that–his words–“low levels of acceptance and high levels of denial undermine medication adherence.” And Scott and Pope wrote in 2002 that, in a group where just under 50% acknowledged some degree of medication non-adherence in the past two years, and 32% reported only partial adherence in the last month, some tricky statistical maneuver led them to conclude that those who were noncompliant had (this is a shocker) a history of being noncompliant–but so did those with greater “denial of severity of illness.”

Look–to go through each reason would keep us here forever, so I’ll just give you a list* of other reasons for non-adherence , and I’ll try to keep quiet while doing it–except when I just can’t help myself:

  • younger age
  • male gender
  • forgetting (and the fun really starts here.  Sajatovic et al (2011) write that “[f]orgetting to take medications was the top reason for nonadherence (55%).” Makes sense.  But Magura et al write, in the self-same year, “relatively few patients attributed low adherence to forgetting to take medication.” The key difference between the two groups studied is that Magura’s also had substance abuse issues.  However, it should be noted that chronic forgetting of one’s medications, if they are atypical antipsychotics, could call for a prescription for long-acting injections–you known, the kind that killed the two people in June.)
  • low educational level
  • complexity of medication regime (ok, here I am again.  I can’t help but think that, when it comes to meds, a ‘keep it simple, stupid,” philosophy should reign.  So along came these researchers, led by Claxton, in 2001, and did a lit search comparing those who had once-daily, twice-daily, 3-times-daily, and 4-times-daily dosing regimens. [I, frankly, fail to be impressed by these 4-times-a-day-ers.  I believe I’m up to 6.  I’m going for “doser of the year.”] Anyway, I have a feeling this isn’t going to shock anybody, but compliance was “significantly higher” for once-daily versus 3-times daily and 4-times-daily, and twice-daily versus 4-times-daily [by 3-times-daily, I guess, adding on a 4th time made little significant difference].  Conclude the authors, “A review of studies that measured compliance . . . confirmed that the prescribed number of doses per day is inversely related to compliance. Simpler, less frequent dosing regimens resulted in better compliance across a variety of therapeutic classes.”)
  • Back to scheduled programming:  psychosis
  • comorbid disorders, like personality disorders
  • substance abuse
  • poor social supports/lack of a supportive network
  • medication costs and accessibility
  • hopelessness in depression
  • preferring the “high” of one’s mania
  • poor therapeutic alliance. (“With regard to side effects, one-third of the patients also said their psychiatrists did not spend enough time with them to explain side effects or were “rushed.” Strengthening adherence should include better education about side effects and the importance of adherence to sustain the benefits of medication. This education, which might also involve assertiveness training, should encourage patients to discuss their symptoms and side effects with their psychiatrists ” [2011 article in The Open Addiction Journal, authors Magura, Rosenblum and Fong].)
  • limited financial resources
  • non-Caucasion ethnicity
  • lower cognitive functioning
  • concern about stigma
  • single status. (This is a fascinating one. Perlick et al (2010) found that marital status/living situation was the most important sociodemographic variable correlated with adherence, which really begs for a blog on its own. Connelly et al (1982) had found the same thing when it came to  lithium adherence–the married ones beat out the single ones with their hands behind their backs. And Sajatovic et al (2007) found marriage was among their “big 3,” as they wrote, “[o]ur study found that nonadherent individuals were younger, unmarried, and of minority ethnicity.”)

Such a long list is distressing (and not just for bored readers).  How will the health care community–doctors, nurses, patients, and care-takers)–address so many problems? Where to even begin?

I know: When all else fails, it’s time to blog.

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