10/17/17

Tell It Like It Is

© Iculig | 123rf.com

Recently I saw one of the ubiquitous “ask your doctor if … is right for you” commercials for Rexulti. The slick 90-second ad tells you that when Rexulti is added to your antidepressant, it has been shown to reduce symptoms of depression. The smiley faces used by the actors illustrate how: “Even when you’re taking an antidepressant, you may still be struggling with depression.” You learn that 2 out of 3 people taking an antidepressant may experience unresolved symptoms of depression; and that antidepressants can cause unusual changes in behavior, worsening depression and thought of suicide, especially in those 24 and younger. But you never learn that Rexulti is not an antidepressant.

The commercial never claims Rexulti is an antidepressant, but it clearly leads its viewers in that direction. Counter intuitively, in order to make the case for using Rexulti, it not-so-subtly tells you that antidepressants alone aren’t always effective, since 67% of people taking them have “unresolved symptoms” of depression. But then you learn Rexulti has been shown to reduce symptoms of depression when it is added to an antidepressant. The message is that Rexulti is effective relieving symptoms of depression. But let’s deconstruct what the commercial is telling you even further.

In the mix of the marketing rhetoric, you hear a litany of possible adverse medication side effects. The initial side effects are found with antidepressants: there could be unusual changes in behavior, worsening depression, even thoughts of suicide. “Antidepressants can increase these in those 24 and younger.” This information is legitimately about the side effects from antidepressant medications. See “Antidepressant Misuse Disorder” and “Antidepressants: Their Ineffectiveness and Risks” on this website.

Actually, Rexulti is an atypical antipsychotic or neuroleptic; in the same drug class as Abilify, Zyprexa, Seroquel and Risperdal. The other described side effects and warnings in the commercial are commonly found with atypical antipsychotics. See “Adverse Effects of Antipsychotic Medications” by Muench and Hamer for further information.

Looking further, the commercial said: “Elderly dementia patients taking Rexulti have an increased risk of death or stroke.” Antipsychotics were being used to control behavior problems in elderly patients with dementia. Then research demonstrated there was an increased risk of death in the elderly patients given antipsychotics. So the FDA issued a black box warning to that effect. There was also evidence that antidepressants increased the risk of stroke with elderly patients, thus the Rexulti warning. See “Seniors and Antipsychotics” and “Stroke Risk in Elderly Treated with Antipsychotics” for more information on this.

“Uncontrollable muscle movements” in the commercial is likely referring to tardive dyskinesia, a serious and potentially permanent neurological side effect from antipsychotics. The risks for developing metabolic syndrome (high blood pressure, high blood sugar, excess body fat at the waist, and abnormal cholesterol levels) are mentioned as well. Tardive dyskinesia and metabolic syndrome are widely acknowledged as potential adverse effects from antipsychotics, but not antidepressants. Try “Blind Spots with Antipsychotics,” Part 1 and Part 2 for a discussion on metabolic syndrome and other side effects from antipsychotics. Stiff muscles, confusion, and high fever are symptoms of “a possible life threatening condition” known as Neuroleptic Malignant Syndrome (See “Neuroleptic Malignant Syndrome”).

So you wouldn’t know Rexulti was an atypical antipsychotic or neuroleptic drug from listening to the commercial unless you knew the above were typical side effects with that class of drug. And you may not even discover this from reading the required Medication Guide, unless you knew what to look for. The FDA’s highlights of prescribing information for Rexulti, all 38 pages worth, does have a more complete discussion of the warnings and precautions as well as the adverse reactions. And Rexulti is referred to there as an atypical antipsychotic. However, in the shorter, two page medication guide, that is made available to individuals filling a prescription for Rexulti, there is no explicit reference to it being an atypical antipsychotic or neuroleptic.

The Rexulti Medication Guide does describe tardive dyskinesia, “problems with your metabolism” and Neuroleptic Malignant Syndrome as possible side effects, which are all potential side effects from antipsychotic or neuroleptic medications. But the only place in the medication guide that the word “antipsychotics” is used is in the section “What should I tell my healthcare provider before taking Rexulti?” There, the medication guide advised that if you become pregnant while taking Rexulti, you should “talk to your healthcare provider” about registering with the National Pregnancy Registry for Atypical Antipsychotics. The only place in the Rexulti medication guide the word “neuroleptic” in mentioned is when it notes how Neuroleptic Malignant Syndrome is a possible side effect.

This rhetorical sleight-of-hand is also present in the medication guides for three other antipsychotics approved by the FDA as adjunct medications for depression. Aripiprazole (Abilify), Olanzapine (Zyprexa) and Quetispine (Seroquel) all use the same descriptive technique of avoiding reference to the drugs as antipsychotics or neuroleptics in their medication guides. And several have an extended discussion of information on antidepressants. Again, someone not familiar with the medications might think they are taking an antidepressant rather than an antipsychotic medication.

The rational for this would appear to be because the initial market for antipsychotics, treating schizophrenia, is limited. Atypical antipsychotics are now the largest-selling class of drugs in the U.S. with more than $14.6 billion in annual sales for 2014. They also are the class of psychiatric drugs with the most side effects. See “Wolves in Sheep’s Clothing” and “Abilify in Denial” for more on these observations.

Another piece of information about Rexulti in contrast to the other antipsychotics approved as adjunct medications for depression is that it is the only one still on patent. Rexulti patents don’t expire until February of 2027 Abilify, Zyprexa, and Seroquel have all been approved as generics.  So Otsuka Pharmaceutical Company Ltd. has the potential for much greater profits from Resulti over the next ten years than the generic pharmaceutical companies have for the off-patent atypical antipsychotics.

There seems to be a general trend when discussing psychiatric medications to avoid any reference to them as atypical antipsychotics or neuroleptics. You can even see this in the FDA press release for the approval of Rexulti in July of 2015. This means a consumer looking for information on the potential adverse effects from an atypical antipsychotic may have some difficulty finding and then understanding what the risk is for them to take the drug.

For clarity’s sake, I think the FDA should require all consumer medication guides to clearly identify the drug class for approved psychiatric medications. They should also direct a patient to where they can find a more complete discussion of the potential adverse effects of the medication than what is contained within the brief summary of the medication guide. Confusing discussions of depression, its symptoms and the side effects from antidepressants included in antipsychotic medication guides should be clarified or removed entirely by the FDA. Additionally, there should be a truth in advertising requirement that tells it like it is for all psychiatric drug advertisements. An antipsychotic by any other name is still an antipsychotic and the commercials should say so.

02/5/16

Wolves in Sheep’s Clothing

© Eros Erika | 123rf.com

© Eros Erika | 123rf.com

Atypical antipsychotics are now the largest-selling class of drugs in the U.S., accounting for more than $14.6 billion in annual sales by 2010. They are also the class of psychiatric drugs with the most negative side effects—and that’s saying something when you consider the others, namely antidepressants and anti-anxiety meds. Because schizophrenia effects such a small percentage of the population, the initial market for atypical antipsychotics was limited. The path to increased sales led through finding a wider market than just individuals with schizophrenia. So the pharmaceutical companies began to look at the behavioral disorders.

For the most part, these disorders are less serious than schizophrenia, but many are severe nonetheless, including hyper-activity in children and agitation in elderly patients. Marketing atypical anti-psychotic agents to patients with this broader category of disorders held the promise of sales reaching blockbuster levels.

There were two obstacles to this broader promotion. First, the FDA had only approved atypicals for the treatment of severe psychosis—schizophrenia—in adults. Their use for other disorders was then off-label. FDA regulations prohibit pharmaceutical companies from promoting drugs for such additional uses.

The second obstacle was that they didn’t have a very good safety profile. Used for a serious disorder like schizophrenia, the adverse effects of atypicals were understood to be a trade off. “But the risk–benefit calculus is much less favorable when milder conditions are involved.” Despite these impediments, the temptation was too much for the manufacturers to resist and a number of lawsuits over the past few years attest to this. Read “Antipsychotic Medications Are Spelling Legal Trouble for Drugmakers” for more information on this. Robert Field concluded his article with this observation:

 In light of the large number of successful enforcement actions and the continued potential for abuses, prosecutors are likely to remain vigilant concerning the marketing of atypical antipsychotic agents. Repeated violations could generate even larger penalties. Publicity over the large settlements has put physicians and the public on notice about the hazards of indiscriminate use of this class of drugs. In the future, regulators, clinicians and patients should view atypical antipsychotics and marketing claims concerning them with caution.

Over time, antipsychotics have “evolved.” Some are now approved as adjunct medication for treating major depression. Many are now are also prescribed for the treatment of bipolar disorder. And then there is off-label market for several behavioral disorders. No longer are they relegated to just the niche market of people diagnosed with schizophrenia.

The FDA-approved uses for antipsychotics now include the treatment of bipolar I disorder, schizophrenia, schizoaffective disorder and as an adjunct treatment for major depression. In addition to their FDA approved uses, several atypicals are used off-label to treat various psychiatric conditions. They have been studied as off-label treatment for the following conditions: ADHD, anxiety, dementia in elderly patients, depression, eating disorders, insomnia, OCD, personality disorder, PTSD, substance use disorders, and Tourette’s syndrome.

Clozapine (Clozaril) was the first atypical developed. Introduced in Europe in 1971, it was voluntarily pulled by its manufacturer when it was shown to cause a condition called agranulocytosis, a dangerous decrease in the number of white blood cells. It was then approved by the FDA in 1989 for the treatment of treatment-resistant schizophrenia. In 2002 the FDA also approved clozapine for reducing the risk of suicidal behavior. However, the FDA also requires it to carry five black box warnings for a series of adverse health effects including cardiovascular and respiratory problems and increased mortality in elderly patients with dementia-related psychosis.

The five main atypical antipsychotics currently used in the US are: Aripiprazole (Abilify), Olanzapine (Zyprexa), Quetiapine (Seroquel), Risperidone (Risperdal) and Ziprasidone (Geodon).  There are six newer ones whose off-label use have not been documented or researched as extensively as the preceding five have been. These newer ones are: Asenapine (Saphris), Iloperidone (Fanapt), Lurasidone (Latuda) and Paliperidone (Invega). Two brand new antipsychotics, Rexulti (brexpiprazole) and Vraylar (cariprazine), will be discussed below.

There are also six other atypicals that have not been approved for use in the US. They are: Amisulpride, Blonanserin, Melperone, Sertindole, Sulpride and Zotepine.  The following chart lists the FDA-approved indications for atypical antipsychotics.

Atypicals

Bipolar 1

schizophrenia

schizoaffective

Major depression

Aripiprazole

yes

yes

yes

Olanzapine

yes

yes

yes

Quetiapine

yes

yes

yes

Risperidone

yes

yes

Ziprasidone

yes

yes

Asenapine

yes

yes

Iloperidone

yes

Lurasidone

yes

yes

Paliperidone

yes

yes

Clozapine

yes

yes

Brexpiprazole

yes

yes

Cariprazine

yes

yes

Schizophrenia is the primary disorder for which antipsychotics are targeted and bipolar 1 disorder is second. Three of the main antipsychotics have been approved as augmentations for antidepressants, Aripiprazole, Olanzapine and Quetiapine. Interestingly, the medication guides for most of the antipsychotics seem to downplay the drug class they are in. They only refer to themselves as “antipsychotic” within the warning of a potential side effect called neuroleptic malignant syndrome. Coincidentally, that is the only place the other common term for antipsychotic, neuroleptic, is found.

Here is an example of how the warning for the potential side effect of neuroleptic malignant syndrome: was worded for Seroquel (quetiapine): “neuroleptic malignant syndrome (NMS). NMS is a rare but very serious condition that can happen in people who take antipsychotic medicines, including SEROQUEL.” Many of the other antipsychotics have similar wording for the discussion of this side effect. Abilify never refers to itself as an antipsychotic or neuroleptic in its medication guide. Under the discussion of possible side effects with Abilify is the following:

 Neuroleptic malignant syndrome (NMS): Tell your healthcare provider right away if you have some or all of the following symptoms: high fever, stiff muscles, confusion, sweating, changes in pulse, heart rate, and blood pressure. These maybe symptoms of a rare and serious condition that can lead to death. Call your healthcare provider right away if you have any of these symptoms.

But you will find a lot of discussion about antidepressants in some of these medication guides. Many of the antipsychotics use language that gives the impression that the drug is an “antidepressant,” not an “antipsychotic.” The medication guides for Abilify (aripiprazole), Seroquel (quetiapine) and Latuda (lurasidone) have an entire section that discusses what someone needs to know about antidepressant medications. Someone not familiar with the various classes of medications who are taking these drugs might think they are taking antidepressant and not an antipsychotic.

The following table summarizes the evidence for off-label use of the five primary atypical antipsychotics currently used in the US are: Aripiprazole, Olanzapine, Quetiapine, Risperidone and Ziprasidone. The strongest evidence of efficacy is noted as “++”, then “+”.  “0” means there have been no clinical trials attempted; “-“ represents no efficacy and “+-“ is for mixed results. “FDA” represents FDA approval for the condition. Keep in mind these ratings are based upon the data from the drug companies in their quest to expand the antipsychotic market.

Disorder

Aripiprazole

Olanzapine

Quetiapine

Risperidone

Ziprasidone

Anxiety

0

++

ADHD

0

0

0

+

0

Dementia

++

+

+

++

0

Depression

FDA

FDA

FDA

++

+

OCD

0

+

++

PTSD

0

+-

+-

++

0

Tourette’s

0

0

0

+

Risperidone was the first of the main five antipsychotics brought to market in 1990 by Janssen. In 1996 Eli Lilly brought olanzapine to market in September of 1996 and AstraZeneca brought quetiapine to market in September of 1997. Pfizer brought ziprasidone to market in June of 2002 and Bristol-Myers Squibb had aripiprazole approved in November of 2002.  All five are currently off patent. The patent expiration dates for the newer antipsychotics are as follows: Asenapine (Saphris) in 2020, Iloperidone (Fanapt) 2027, Lurasidone (Latuda) 2018. Paliperidone (Invega) lost its exclusivity on October 6, 2014.

Two brand new antipsychotics, Rexulti (brexpiprazole) and Vraylar (cariprazine) were just approved by the FDA in the summer of 2015.  Vraylar was approved for the treatment of schizophrenia and bipolar disorder in adults. Rexulti was approved as a treatment for schizophrenia and as an add-on treatment for adults with major depression.

The Rexulti medication guide also has a section describing what you need to know about antidepressants. It has the same warning for the potential side effect of neuroleptic malignant syndrome (NMS) found with Abilify. It also lists major depression as the first disorder it is used to treat; schizophrenia is listed second. So it seems that it is positioning itself to be seen more a treatment for depression than schizophrenia.

To its credit, Vraylar’s medication guide regularly refers to antipsychotics and the side effects of antipsychotics. And I did not find even ONE reference to “antidepressant.” However, its discussion of NMS is subtle, never explicitly saying it could occur from Vraylar. Under warnings and precautions it says:

Neuroleptic Malignant Syndrome (NMS), a potentially fatal symptom complex, has been reported in association with administration of antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, delirium, and autonomic instability. Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.

However, truth in advertising isn’t the only concern, at least with Vraylar. Johanna Ryan described a detailed investigation she did of the Vraylar studies registered with ClinicalTrials.gov. Out of the twenty registered studies, seventeen were completed, but still had not shared their results on the government website, a mandatory step in the process. I reviewed all the registered studies for Vraylar on December 4, 2015 and there were still no posted results from the completed clinical trials for Vraylar almost two months after Ryan’s article was posted on davidhealy.org.

She found at least six published papers directly based on these studies; only two were posted on CT.gov. The average number of listed authors was six to eight, with an academic noted as the “lead” author. The rest were drug company employees. Some papers only had employee-authors.

Overwhelmingly they were contract researchers. Some were freestanding clinical trial businesses. Others were busy medical practices with a thriving research business “on the side.” The first recruited subjects largely by TV, newspaper and online advertising which emphasized free treatment. The second combined some advertising with recruitment among their own patients.

The adverse side effects with antidepressants are increasingly evident, as is their well-documented ineffectiveness. But they are more acceptable by our cultural psyche than antipsychotics. Remember Listening to Prozac? Antipsychotics (neuroleptics) are now the “it” class of psychiatric medications. As they expand their market reach to beyond schizophrenia, the term “antipsychotics” has become a liability for sales. “Anti “depression” medication is an easier sell than anti “psychotic.” So it seems there has been an intentional effort by some pharmaceutical companies to blur the lines between the drug classes of antidepressants and antipsychotics.

I think a fitting metaphor for what’s happening is to think of this marketing strategy as an attempt to pass off wolves in sheep’s clothing. But you have to wonder just how bad the adverse effects of antipsychotics  (the wolves) are when the less harmful half of the metaphor—the “sheep”—is antidepressants.