03/17/17

Broken Promises with Abilify

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Based upon sales data for the world’s 15 top selling drugs, Abilify was ranked fourth, with $9.3 billion of sales in 2014. Reflect for a moment what this means; an antipsychotic drug had greater worldwide sales than Nexium (for acid reflux) and Crestor (for high cholesterol). While it is an approved medication in the US for bipolar 1 and schizophrenia, it is likely these sales figures reflect it use as an adjunct medication for major depression. Oh, and along with other antipsychotics, it is used off label to treat several other behavioral disorders such as Tourette’s and irritability associated with autism. This popularity is despite the reality that antipsychotics have a high incidence of negative side effects—greater than antidepressants and anti-anxiety medications.

The problems with antipsychotics have been known for a few years. As far back as 2010, Robert Field wrote: “Antipsychotic Medications Are Spelling Legal Trouble for Drugmakers” for the journal Pharmacy and Therapeutics. In 2007, Bristol-Myers Squibb paid $515 million to settle charges of illegally marketing Abilify for children and the elderly, “In contravention of FDA-approved labeling.” But that hasn’t been the end of legal troubles regarding Abilify. On May 3, 2016, the FDA published a safety announcement warning that Abilify (aripiprazole) can trigger impulse-control problems such as “compulsive or uncontrollable urges to gamble, binge eat, shop, and have sex.” These urges reportedly stop when the drug is discontinued or the dose reduced.

These compulsive behaviors can affect anyone who is taking the medicine. As a result, we are adding new warnings about all of these compulsive behaviors to the drug labels and the patient Medication Guides for all aripiprazole products.

The mechanism of action for Abilify is not clearly understood, but researchers think it over-stimulates dopamine 3 (D3) reward receptors, which are mainly located in the limbic system. This in turn triggers the compulsive behaviors. Gaboriau et al. reviewed case reports in Addictive Behaviors and indicated that pathological gambling (PG) appeared as quickly as a few days after Abilify was started; sometimes after an increase in dosage with 7 of the 8 case reports. PG then decreased after Abilify treatment was stopped or decreased; again sometimes as soon as a few days afterwards.

Limitations on the Gaboriau et al. findings included that most of the patients were already gambling before starting with Abilify. Several patients also had a history of substance use disorders. However, the authors noted that the same D3 receptor was implicated in another study by J. E. Ahiskog of the dopamine agonist medications, pramipexole and ropinirole, which are commonly used to treat Parkinson’s disease.

This hyperstimulation would apparently be particularly enhanced in cases of a previous treatment by antipsychotics acting as a dopaminergic receptors antagonist, owing to the up-regulation and the dopaminergic receptor hypersensitivity processes. The partial agonist action of aripiprazole then causes stronger effects. Moreover, the intrinsic dopamine pharmacodynamic activity of aripiprazole imparts it less action agonist than a complete agonist, which could explain why the occurrence of PG is sometimes late or due to dosage increase.

The above concern with Abilify was also supported by the findings of a study by Moore, Glenmullen and Mattison reported in JAMA Internal Medicine. Adverse drug event reports received by the FDA from 2003 to 2012 were reviewed for the six dopamine receptor agonist drugs marketed in the U.S. The review identified 1580 reports of impulse control disorder events, including pathological gambling, hypersexuality, compulsive shopping and others. They also detected weaker signals for antidepressants and antipsychotics.

The Daily Beast reported on a massive tort lawsuit being filed against Otuska and Bristol-Myers Squibb charging that Abilify created a compulsion for sex and gambling. Moreover, the suit claims the drug makers knew of the serious side effects because of required changes in Canadian and European warning labels, but waited for years to warn U.S. consumers. Thomas Moore of the Institute for Safe Medication Practices explained the drug triggers an urge to gamble constantly, sometimes with people with no prior interest. “It might be people starting to spend $300 a week on lottery tickets, and in other cases people will gamble away tens of thousands of dollars.” Moore went on to say:

We live in a society whose rules and laws assume people are responsible for their actions, including running up a large gambling debt. . . But we have scientific evidence that sometimes a drug can trigger a pathological urge to gamble so severe it can ruin someone’s life.

A woman who began using Abilify to aid in treating her PTSD developed a compulsive gambling problem. She used up her unemployment checks, pawned her husband’s automotive tools, and lied about needing money for baby formula. “Nothing was off-limits when it came to getting the money I needed to keep up the ruse.” She’d stuff her bed at night in order to fool her husband into thinking she was asleep when she was actually at the casino playing the slot machines.

Another woman developed hypersexuality. She started with online chatting with men. She became obsessed with sexual fantasies and took sexualized pictures of herself and sent them to select ‘friends.’ “I just couldn’t stop with the pictures and fantasies.” She also went on shopping sprees. Then her husband caught her. “The drug has destroyed my life, my reputation, and the lives of those I love.”

The website RxISK has multiple reports on adverse events with Abilify. “Abilify from the Inside Out” described bouts of akathisia (a state of agitation, distress, and restlessness), unusual aggression or anger, first time episodes of psychosis, suicidality, at least three confirmed suicides, movement disorders such as tremors, and (of course) compulsive gambling. The author said the reports were hard for him to read. Since most of the patients were on several meds, some patients couldn’t be sure that Abilify alone caused the problem. Even stopping Abilify was related to adverse drug events.

The above noted 2007 lawsuit, where Bristol-Myers Squibb paid $525 million to settle charges of illegal marketing, unveiled some of the marketing records for Abilify. Remember, one of the concerns was that it was illegally marketed for use with the elderly. The sales reps for Abilify would invite nursing home staff to picture a new resident, hunched in their chair, staring off into space because of ‘depression.’ “’Who wants to see that when they come to visit Mom on a Saturday?’ the reps would ask. ‘Wouldn’t we like to see her up and about, looking lively?’” The sale pitch worked. One woman wrote the following to RxISK:

I have seen many commercials about how drugs like Abilify can perk people right up. . . So I was not only disappointed and frightened by the results, but felt once again tricked and exploited by the big promises that drug companies make but never seem to keep.

I wish the above concerns weren’t true. But I’ve known individuals whose experiences on Abilify are consistent with the above discussion of its adverse effects. Sadly, even when sanctions are in the millions of dollars, the profits are higher. And it seems the cards are stacked against pharmaceutical companies being held accountable financially. So consumers have to fight against this by refusing to use Abilify and telling others what you have read here. If you are interested in other articles on the problems with Abilify and the other antipsychotics, try: “Antipsychotic Big Bang” or “Abilify in Denial” on this website.

11/22/16

Antidepressant Misuse Disorder

54164089 - antidepressant pills 3d rendering isolated on white background

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Chances are you know someone who is using an antidepressant. But that doesn’t necessarily mean the person you know has a problem with depression. In 2015, Takayanagi et al. published a study in The Journal of Clinical Psychiatry found that: “Among antidepressant users, 69% never met criteria for major depressive disorder (MDD); and 38% never met criteria for MDD, obsessive-compulsive disorder, panic disorder, social phobia, or generalized anxiety disorder in their lifetime.” Their data indicate that antidepressants were commonly used in the absence of “clear evidence-based indications.”

Writing for Mad in America, Justin Karter noted that previous studies revealed antidepressants were being over-prescribed and prescribed off-label. But others countered that these studies underestimated the lifetime prevalence of so-called mental disorders. The Takayanagi et al. study sought to address this criticism by conducting in-depth interviews to estimate whether participants met criteria for “mental disorders” over their lifetime. The study also indicated an individual was more likely to be prescribed an antidepressant if they were a woman, white, reported physical pain or discomfort to their doctor, or had recently visited a mental health care facility.

Another 2015 report by Kanton et al. published in JAMA found that the percentage of Americans on antidepressants increased from 6.8% to 14% between 1999 and 2012. The report’s authors speculated that the increase could in part reflect shifting attitudes regarding depression. Commenting on this report, Justin Karter pointed out how the increase likely includes a large proportion of off-label use of antidepressants. As was noted above, 69% of antidepressant users did not meet the criteria for major depression.

A JAMA study published in May of 2016 by Wong et al. found that 45% of the prescriptions given for antidepressants were to treat anxiety disorders, pain, insomnia and various other conditions. The study, which was done in Quebec Canada, looked at all adult prescriptions written for antidepressants (100,000 patients) between January 1, 2006 and September 30, 2015. Prescriptions for monoamine oxidase inhibitors were excluded. Prescriptions were classified as on or off label depending upon whether the drug was approved by Health Care of Canada or the FDA for the indication noted by September 0f 2015. Physicians prescribed antidepressant off-label for anxiety disorders (18.5%), insomnia (10.2%), pain (6.1%) and panic disorders (4.1%).

An online survey of long-term antidepressant patients by Cartwright et al., published in Patient Preference and Adherence, found that almost 90% reported some degree of improvement, with 30% also saying they had moderate to severe bouts of depression during treatment.  Ten different adverse effects were reported by over 50% of the participants. The five most common were: withdrawal effects (73.5%), sexual dysfunction (71.8%), weight gain (65.3%), feeling emotionally numb (64.5%), and failure to reach orgasm (64.5%). “Between 36% and 57% of respondents experienced these adverse affects at either a moderate or severe level.” Additional adverse effects reported included: agitation (55.1%), feeling not like myself (54.4%), reduced positive feelings (45.6%), caring less about others (36.4%), suicidality (36.0%), and feeling aggressive (31.6%).

Some patients in this study were particularly concerned about severe withdrawal symptoms that undermined their confidence to discontinue should they wish to and therefore limited their choices. In line with this, 45% patients also believed that they had some level of addiction to the antidepressant. Some patients were also critical of the lack of information given by prescribers with regard to adverse effects, including withdrawal symptoms. Some also expressed disappointment or frustration with the perceived lack of support available to them in managing withdrawal.

Limitations of the study include the fact that the data were self-reported and that the study was not a randomized control study—the gold standard methodology for evidence-based medicine. However, there are relatively few long-term outcome studies of antidepressant use.

A 2009 systematic review published in the Journal of Affective Disorders, concluded that long-term outcomes in depression were poor, with no clear relationship between drug treatment and positive outcomes.  The outcomes for non-antidepressant treatment were no worse than those for antidepressant treatment.

Overall 40% to 85% of patients experienced a recurrence during follow-up. Average time to recurrence was around 3.2 years across eight studies that provided data on this outcome. Around 25% of patients achieved a global rating of well or improved at the end of the study and a similar number had a poor outcome marked by multiple recurrences or continuous impairment. Most participants recovered from the index episode, but experienced multiple recurrences.

The August 2016 issue of Psychotherapy and Psychosomatics published a literature review of long-term use of newer generation antidepressants (i.e., SSRIs and SNRIs and others) by Carvalho et al. While many side effects were transient, disappearing after a few weeks, other potentially serious adverse events may persist or occur later. The main adverse events related to using newer antidepressant drugs included the following:

  • Gastrointestinal issues
  • Weight gain and metabolic disturbances
  • Genitourinary issues (issues related to the genital or urinary organs)
  • Sexual dysfunction
  • Hyponatremia (low sodium level in the blood)
  • Osteoporosis and risk of fractures
  • Bleeding
  • Central nervous system issues
  • Sweating
  • Sleep disturbances
  • Affective disturbances
  • Suicidality
  • Discontinuation syndromes

You can read more information on the above adverse effects and others in the Carvalho et al. review. What follows is a brief discussion of their findings for weight gain and diabetes, bleeding, sleep disturbances, affective disturbances, suicidality, and discontinuation syndromes.

Several studies have shown that long-term use of antidepressants (more than 6 months) is associated with weight gain. Paroxetine (Paxil) may be the worst offender. A population-based study indicated the use of antidepressants could be associated with a higher risk of obesity. The association between antidepressants and diabetes mellitus is inconclusive. Some reports indicate a higher risk; others do not. But a recent review and meta-analysis found that SSRIs were associated with an increased risk of diabetes mellitus.

All SSRIs have been associated with an increased risk of bleeding. “The most likely mechanism responsible for these adverse reactions is a reduction of serotonin reuptake by platelets.” Fluoxetine (Prozac), paroxetine (Paxil), and sertraline (Zoloft) have a higher risk of platelet dysfunction than other SSRIs. Veniafaxine (Effexor) and mirtazapine (Remeron) have been associated with an increased risk of bleeding. SSRIs have been associated with a higher risk of bleeding during operations.

Sleep disturbances are one of the hallmark symptoms of depression. However,  studies have shown that SSRIs and Effexor are associated with increased REM sleep latency and an overall reduction in the time spent in REM sleep. These effects are usually associated with the initial period of treatment and may return to baseline after 8 weeks. Remeron and trazodone have been associated with improving sleep. In my clinical experience, trazadone is regularly used off-label to help promote sleep.

Many individuals taking SSRIs report they experience emotional blunting. They say their emotions have been “toned down.” Others say they just don’t care about issues that were significant to them before. “Evidence indicates that these adverse affective manifestations may persist even after the symptoms of depression have improved and can occur in patients of all ages.” Mania or agitation can occur. These response have been said to unveil unrecognized bipolar disorder. But since this can also occur in previously unipolar patients, the mania could be drug-induced. An activation syndrome, where patients experience anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness and impulsivity can occur.

Carvalho et al. limited the occurrence of these adverse effects to the first three months of treatment. However, psychiatrist Peter Breggin has documented the emergence of agitation and activation with antidepressants in Medication Madness and other writings. Carvalho et al. said using antidepressants could also be associated with the return of depressive symptoms during baseline treatment, and the appearance of new symptoms or paradoxically, exacerbate the baseline clinical picture. The occurrence of paradoxical effects was reported in random control trials with Prozac and Zoloft.

The emergence of suicidality and self-injurious behavior with antidepressant treatment is one of the most debated and controversial risks. Nevertheless, the FDA has required a black box warning regarding the risk of suicidality for children and adolescents using antidepressants since 2014. The incidence of successful and attempted suicide has been frequently underreported in antidepressant RCTs. Carvalho et al. said:

Two recent meta-analyses have not identified a clear increased risk of treatment-emergent suicidality in adult individuals treated with antidepressants in RCTs. Notwithstanding that the use of antidepressants is efficacious for the treatment of MDD in adults, there is no clear evidence for either specific protective effects or increased risk related to suicidality.

Often underappreciated, is the emergence of withdrawal symptoms of varying degrees with treatment discontinuation and/or interruption with almost all SSRIs and SNRIs. These reactions have been described as “discontinuation syndromes” in an attempt to avoid the suggestion of dependence that could effect marketing. A review suggested the dependence and withdrawal with newer antidepressants was comparable to those experienced with benzodiazepines. “Due to the severity and unpredictability of these manifestations, it has been recently suggested that the term ‘discontinuation syndrome’ should be replaced by ‘withdrawal syndrome.’” These symptoms can include:

flu-like symptoms, tremors, tachycardia, shock-like sensations, paresthesia, myalgia, tinnitus, neuralgia, ataxia, vertigo, sexual dysfunction, sleep disturbances, vivid dreams, nausea vomiting, diarrhea, worsening anxiety and mood instability.

In their conclusion, Carvalho et al. said the common belief of fewer side effects with the newer generation antidepressants (especially the SSRIs) only pertains to their safety in overdose. “On the contrary, the long-term use of SSRIs and SNRIs is likely to yield important side effects.” The likelihood of treatment-emergent adverse effects is related to the duration of antidepressant treatment—particularly with weight gain, diabetes, and osteoporsis. Some adverse side effects may persist long after discontinuation of the drug. Particularly following long-term use, antidepressants,

 … may increase the risk of experiencing additional psychopathological (e.g. treatment emergent affective switches and paradoxical symptoms), or medical (e.g. obesity and bleeding) problems that do not necessarily subside after discontinuation of the drug.

This leads to their conclusion that: “The findings of this review suggest that long-term treatment with new generation ADs should be avoided if alternative treatments are available.”

01/22/16

Discovering Adverse Drug Events

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© Sherry Yates Young | 123f.com

Okay, you probably don’t wonder about things like how many people to visit the emergency department (ED) of a hospital when they experience serious side effects or have an adverse drug reaction (ADE) from psychiatric medications. But when 26.8 million US adults, approximately 11.5% of the adult population, are using psychiatric medications, it’s a good thing that some people do wonder—and then set out to find an answer to their question. A study published in 2014 estimated that there were over 89,000 ED visits due to ADEs from the use of psychiatric medications from 2009 through 2011. That accounted for 9.6% of all adult ADE ED visits during the same time period. Almost half (49.4%) of the visits involved adult patients aged 19 to 44 years old; 33.3% were between 45 and 64; 17.3% of the ED visits were with adults 65 and older.

Hampton et al. used nationally representative public health data to estimate the numbers and rates of ED visits and hospitalizations for ADEs from psychiatric medications among adults between January 1, 2009 and December 31, 2011. To estimate the use of specific medications, they used publically available data from the National Ambulatory Medical Care Survey. To determine the number of US adults, men and women, between 2009 and 2011, they used National Center for Health statistics estimates, which are based on US census data. They excluded all ED visits resulting from intentional self-harm, documents drug abuse, therapeutic failures, nonadherence or drug withdrawal. They looked at the following classes of drugs: antidepressants, antipsychotics, lithium salts, anxiolytics (anti-anxiety drugs) and stimulants.

The researchers found that 52.8% of the adverse events were negative reactions to the drug. Unintentional therapeutic overdoses accounted for 33.8% of the adverse events and 12.9% were due to allergic reactions. Most of the cases were treated and released or left against medical advice (80.7%). But 19.3% were admitted, observed or transferred to another facility. Around 73 percent of the ADEs involved one implicated medication.

But the percentage of individuals seeking treatment for ADEs who were using multiple concurrent medications was high. Only 34.4% were only using one medication. 34.5% were using 1 to 3 medications. 17.7% were using 4 to 5 medications and 13.4% were using six or more concurrent medications. Polypharmacy of four or more concurrent medications involved 31.1% of the ED visits.

Ten specific medications, either alone or in combination with other medications were involved in 57.5% of the adverse drug—related ED visits. The brand names of the medication are in parenthesis. Surprisingly, Ambien or its generic version, was the number one medication implicated in adverse drug—related ED visits. Among adults 65 and over, Ambien alone was responsible for 21% of ED visits.  See the table below.

Data from the Drug Abuse Warning Network have shown that ED visits for zolpidem ADEs increased 220% from 2005 to 2010, and previous studieshave indicated that zolpidem use is associated with a substantial risk of falls. While the FDA’s recent efforts to modify recommended dosing regimens hold promise for reducing zolpidem ADEs, clinicians can also reduce zolpidem ADEs by prescribing zolpidem for insomnia, its sole FDA-approved indication, only after considering other treatments such as sleep hygiene education, stimulus control, sleep restriction, relaxation training, and cognitive behavior therapy.

Medications

No of Cases

Estimated # of visits

% of visits 

Zolpidem (Ambien)

445

10,212

11.5

Quetiapine (Seroquel)

320

6900

7.7

Alprazolam (Xanax)

241

5616

6.3

Lorazepam (Ativan)

233

5517

6.2

Haloperidol (Haldol)

250

4879

5.5

Clonazepam (Klonopin)

215

4571

5.1

Trazodone (Oleptro)

182

4249

4.8

Citalopram (Celexa)

175

4143

4.6

Lithium

217

4034

4.5

Risperidone (Risperdal)

166

3662

4.1

Antipsychotic medications, such as Seroquel, and lithium salts were implicated in significantly more ED visits relative to the number of outpatient visits at which they were prescribed than other psychiatric medications.” Since over 60% of antipsychotic prescribing has been found to be for off-label uses, it is probable that many of these ED visits were from off-label use. Disturbingly, “well over half of the off-label use of antipsychotics may be based on inadequate evidence.

Concerns about antipsychotics’ risks and their possible overuse have prompted the leaders of the American Psychiatric Association to urge providers to prescribe antipsychotics cautiously and only after exploring the feasibility of using alternate treatments.Avoiding antipsychotics in favor of other options less likely to cause ADEs could be particularly appropriate when considering treatment of major depressive disorder, insomnia, or anxiety disorders because the FDA has not approved the use of any antipsychotic for the first-line treatment of major depressive disorder, the use of any antipsychotic for the treatment of insomnia, or the use of any atypical antipsychotic for the treatment of anxiety disorders.

So adverse drug events with psychiatric medications contribute to a significant amount of the ED traffic in US hospitals. And the majority of them were from the misuse of ten specific medications. But it also seems that these adverse events are under reported—perhaps intentionally.

The FDA has an Adverse Event Reporting System (FAERS) that is the government’s primary safety surveillance system for harm resulting from therapeutic drugs. The Institute for Safe Medicine Practices published a Quarter Watch Report that concluded FAERS suffered from “a flood of low quality reports from drug manufacturers and it has not yet been updated for the changing environment in which drugs are marketed to health professionals and consumers.”

The FAERS system is critically important for two reasons. First, a majority of new FDA safety warnings on FDA approved drugs are generated from these ADE reports. “Despite its limitations, FAERS is the most reliable system for discovering new drug risks that had not been identified in pre-market drug testing.” Second, no other system has comparable international scope. It is sensitive enough to detect rare but catastrophic adverse side effects and the capacity to identify unexpected potential injuries.

The total number of adverse events reported to the FDA over a calendar year ending at the first quarter of 2014 (847,039) was more than double that of 2009 (336,753). Additionally, 96.6% of the case reports were collected and written by drug manufacturers. “Thus, the performance of the drug manufacturers, combined with FDA regulations and compliance activity, determines the quality, coverage and completeness of this safety surveillance system.” While the increased numbers of submitted reports indicate the drug manufacturers are now reporting radically more ADEs than in the past, the overall completeness of the reports was poor.

While drug manufacturers are now reporting adverse drug events in unprecedented numbers from around the world, we judged that the overall completeness of adverse event report was poor. For example, in 36% of cases the age of the patient was not determined; in 44% of cases no event date was indicated. A report was classified as reasonably complete if it contained age, gender, and an event date. While 85% of serious reports sent directly to the FDA were reasonably complete, only 49.4% of the manufacturer serious reports met this basic standard. We also identified thousands of case reports where the adverse event was classified as non-serious and indicated only common health problem such as a cold (n = 1,889), the sniffles (n = 906), or an injection that had been painful (n = 4,331). Manufacturer report quality for serious adverse events varied widely. The weakest performance was seen in four companies that submitted reasonably complete reports in only 15% or fewer cases; not one manufacturer equaled the FDA’s 85% record for complete reports; and only 5/74 (7%) manufacturers reported at least age and gender in 90% or more serious reports.

Some of the problems in the reporting system are that it does a poor job with ADEs from older generic drugs and for events involving newborns and children. For birth defects, the reporting is even more limited. Given the drastic increase in the use of psychiatric medications with children over the past twenty years, this seems to be a serious and dangerous flaw. “Even though 86% of outpatient prescriptions are for generic drugs, according to IMS Health Inc., the major brand name manufacturers provide the overwhelming majority of adverse event reports, even when sales of the brand name drug are extremely small.” And despite major global changes with medications and technology in the past fifteen years, the legally binding FDA guidance document specifying how drug manufacturers are to collect and report ADEs since 2001.

The Institute for Safe Medicine Practices concluded that improving FAERS should be a top priority of the FDA. Modernizing the ADE reporting requirements would provide a low-cost opportunity to improve safety surveillance as well as reduce some of the burden on drug manufacturers and focus resources in a more productive direction.  Some changes are straightforward: “We can’t think of a good reason why the quality and completeness of serious adverse event reports collected by drug manufacturers is so much worse than those collected online at the FDA.” The failure to get basic information like the patient’s age in 36% of the cases of adverse events suggests poor quality control and weak collection systems. “And does the system really need thousands of non-serious reports of the sniffles or that an injection was painful?”

Other changes may require substantial discussion and debate. Developing clear and usable protocols for manufacturer-initiated contacts with patients or health professionals may require new report data elements, and specific lists of questions to ask. Improving the quality of patient death reports is non-trivial because patient deaths typically involve multiple contributing factors, and assigning cause may be a subjective medical judgment. But there is no point in manufacturers submitting thousands of reports of deaths in which a possible drug role was never alleged, ascertained, or investigated. In all of these situations, much could be gained from requiring a simple critical question in company-initiated contacts that asked: “Was the drug suspected of contributing to the event?”

But can these simple and reasonable changes ever make it past the vast lobbying efforts of the pharmaceutical industry? Links to other reporting on this FDA study can be found here on Mad in America: “FDA System for Recording Adverse Drug Effects Perilously Deficient.”