03/17/17

Broken Promises with Abilify

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.

03/8/16

Chemical Straightjackets for Children

In a five-minute video, “Stop the Psych Drugging of Children—Now!, Dr. Peter Breggin made some alarming statements about the consequences of several decades of giving children psychiatric drugs. He said we have parents who believe their children are incorrigible. And we have children who grow up thinking they are defective and need psychiatric drugs. Many of the children who started out with a mere ADHD diagnosis when they were younger are growing up to be “career mental patients, taking multiple psychiatric drugs.” In an article he published in the journal Children & Society, Breggin reviewed in more detail many of the concerns he just touched on in his video. Here, I want to look at the growing problem of using antipsychotics with children.

Mad in America reported that a study published in JAMA Psychiatry indicated that the majority of children, adolescents and young adults who are prescribed antipsychotic medications have not been diagnosed with a mental disorder. “Most of the younger children (60.0%), older children (56.7%), adolescents (62.0%), and young adults (67.1%) treated with antipsychotics had no outpatient or inpatient claim that included a mental disorder diagnosis.” Among the children who do have a diagnosis for a mental disorder, many of them are being prescribed antipsychotics off label.

In other words, while antipsychotics are only approved to treat children diagnosed with schizophrenia and bipolar disorder, children with diagnoses like ADHD are being given these powerful drugs to “treat” their behavior problems. In addition, very few of the children receiving antipsychotics also receive psychotherapeutic care. Mark Olfson, the lead author of the study said:

Relatively few of these young people are receiving psychotherapy. We may need to put greater effort into increasing access to psychosocial interventions that can treat symptoms and behaviors that are currently being addressed with antipsychotic medications.

In the same issue of JAMA Psychiatry in which the Olfson et al. article was published, Drs. Carroll and Blader acknowledged in “Antipsychotic Use in Youth Without Psychosis” that the use of antipsychotic medications has been increasing since the mid-1990s. They added this pattern was most pronounced in the U.S. They affirmed evidence suggests that second-generation antipsychotic use was chiefly with children with aggression and behavioral problems, ADHD, and disruptive behavior disorders. “Although antipsychotics are clearly effective for aggressive behaviors … other interventions with lower adverse effect burdens, when implemented adequately, can avert the need for antipsychotic treatment.”

Reporting for the StarTribune, Gail Rosenblum noted that in 2014 20,000 prescriptions for antipsychotic medications were written for children 2 and younger. According to IMS Health, a healthcare data company, that was a 50% increase over the year before. Turn to the article to see a photo of a child playing with Lego-like blocks branded with “Risperdal” at a pediatrician’s office.

IMS found that at least 10,000 children, ages 2 and 3, were prescribed medications such as Adderall to treat attention deficit hyperactivity disorder (ADHD). The protocol falls outside of American Academy of Pediatrics guidelines. Children younger than age 2 received prescriptions for risperidone (commonly known as Risperdal), quetiapine (Seroquel) and the antidepressant Prozac.

In his Children & Society article, Dr. Breggin noted where the so-called second-generation antipsychotics cause the same adverse effects as the older antipsychotics. These adverse effects include: “lobotomy-like indifference and apathy, Parkinsonian symptoms, akathisia, dystonia, tardive dyskinesia, neuroleptic malignant syndrome, gynecomastia [enlarged breasts in men] and other sexual dysfunctions.” Tardive dyskinesia (TD), a movement disorder caused by antipsychotic drugs, is a major threat to children, according to Breggin. TD can effect any muscle functions that are wholly or partially under voluntary control. That includes the face, eyes, tongue, jaw, neck, back, abdomen, and more. Here are two videos of what TD looks like in a child. The first is a girl after she stopped taking her medications, presumably because of the TD. The second one is of another young girl trying to fall asleep.

Even ‘mild’ cases of eye blinking or grimacing can humiliate, stigmatize and isolate a child. More severe cases disable children with painful spasms in the neck and shoulders, abnormal posture and gait, or constant agitated body movements.

Additional concerns with the newer antipsychotics include a potential predisposition to heart disease and early death; weight gain and obesity; elevated blood sugar and diabetes; elevated blood lipids and atherosclerosis, and high blood pressure.

The New York Times published an article by Alan Schwartz, that looked at the growing practice of giving antipsychotics to children under the age of 2. His introductory case illustration was a boy who was first prescribed the antipsychotic Risperdal when he was 18 months of age. His mother indicated that she was never told of the potential risks to her son with Risperdal. “It was just ‘Take this, no big deal,’ like they were Tic Tacs,” said Genesis Rios. The prescribing doctor declined to be interviewed by the NYT.

Cases like that of Andrew Rios, in which children age 2 or younger are prescribed psychiatric medications to address alarmingly violent or withdrawn behavior, are rising rapidly, data shows. Many doctors worry that these drugs, designed for adults and only warily accepted for certain school-age youngsters, are being used to treat children still in cribs despite no published research into their effectiveness and potential health risks for children so young.

Schwartz reported that almost 20,000 prescriptions for antipsychotics such as risperidone (Risperdal) were written for children 2 years old and younger in 2014. This was a 50% jump from the year before. As a side note, prescriptions for the antidepressant fluoxetine (Prozac) rose 23 percent in one year for the same age group. A dozen experts in child psychiatry had never heard of children younger than 3 getting such medication and had difficulty explaining a reason for it. Dr. Martin Drell, a former president of the American Academy of Child and Adolescent Psychiatry said he was “hard pressed to figure out what the rationale would be.” Dr. Ed Tronick, a professor of developmental and brain sciences at the University of Massachusetts said:

I think you simply cannot make anything close to a diagnosis of these types of disorders in children of that age. . . . There’s this very narrow range of what people think the prototype child should look like. Deviations from that lead them to seek out interventions like these. I think it’s just nuts.

The American Academy of Pediatrics and the American Academy of Child and Adolescent Psychiatry have not taken a stand for or against the practice. They have no guidelines or position statements on the use of antidepressant or antipsychotics with children younger than 3. One possible factor in their silence is there are no formal trials in infants and toddlers with these medications. Dr. Mary Gleason a pediatrician and child psychiatrist at Tulane University School of Medicine said children with ages measured in months have brains whose neurological development was occurring at too rapid of a rate—and in still unknown ways—to risk using medications that could profoundly influence that growth. “There are no studies … and I’m not pushing for them,” said Dr. Gleason.

In an article for Psychiatric Services, psychiatrists at Dartmouth expressed concern about the increasing numbers of children being prescribed antipsychotic medications. In an article summarizing the concerns of the authors, Mad in America quoted them as saying:

The crux of the issue is this: Children in the United States have increasingly been prescribed antipsychotic medications despite potentially serious short- and long-term side effects. . . . Yet other efficacious and safer interventions are available. . . . We should be concerned about overuse of antipsychotics for many reasons. Children are inherently vulnerable because their brains and bodies are still developing and may be permanently altered by powerful medications. . . . Their disruptive behaviors are often related to disruptive parenting and stressful environments, which deserve primary attention. Adults may be motivated by the desire to achieve short-term control of behavior rather than to enhance children’s long-term growth and development.

Daviss et al. recommended five changes to reduce the use of antipsychotics in children. First, there is a need for preventive care that addresses socioenvironmental problems. Second, mental health professionals need to become more aware of the dangers of using antipsychotics in children as well as the availability of evidence-based therapies and interventions. Third, clinical guidelines need to be developed along with steps to ensure compliance with those guidelines. Fourth, there should be shared decision making when treating children with these medications. “Clinicians, patients, and parents all need better information on antipsychotics and should all be involved in deciding on appropriate treatment methods.” And fifth, education programs regarding these concerns are needed to reach the agencies and counselors who take care of and support vulnerable children.

Dr. Gleason commented that people are trying to do the best they can with the tools available to them. “There’s a sense of desperation with families of children who are suffering, and the tool that most providers have is the prescription pad.” These children and families deserve better than a choice between trying to cope with the behaviors they see their child struggle with, and using a chemical straitjacket with the potential of long-term cognitive and physiological harm.

02/26/16

Hollow Man Syndrome

On her blog Joanna Moncrieff reflected on a memory she has of a young woman she encountered as a medical student in the 1980s who was confused and frightened when first brought to the hospital. She thought she was being watched and manipulated by evil forces. She believed there was something implanted in her body. Put on an antipsychotic, she became increasingly quiet as the dose was increased. But she also became emotionless, expressionless and physically sluggish. To Joanna, the woman seemed “empty and lifeless compared to what she had been before, although she was less distressed.” This was seen as making her ‘better.’

That reminded me of a young man I knew briefly around the same time who had a psychotic episode, triggered by his heavy use of marijuana. At least, that was his theory. My impression of him after his release from the hospital, where he also began using an antipsychotic, was that his personality had withered; he’d become a hollow man. A few years ago, I met briefly with someone trying to reclaim their thinking ability after taking lithium for over fifteen years. They wanted to cut back on the levels of lithium they were taking. We began working on that plan, but they kept getting caught up in a cognitive eddy of fear that they were going to lose their salvation. Was that psychosis or impaired thinking from the medication?

Another time I was concerned that after a first time manic episode an adolescent would remain on a maintenance dose of an antipsychotic for the rest of his/her life. Over time I convinced the family to transfer care to a psychiatrist willing to taper the teen off the antipsychotic. The person’s dose was initially halved and symptoms of mania emerged within ten to fourteen days of the initial taper. Was that a suppressed bipolar disorder emerging or was it a reaction to too steep an initial taper? The reaction was viewed by the family as a manifestation of the bipolar disorder that had been kept at bay by a low maintenance dose of the antipsychotic. They decided to stop counseling with me.

These and other experiences have led to the several articles I’ve written on the complications and dangers of antipsychotic medications. Reading the thoughts of psychiatrists like Joanna Moncrieff, Peter Breggin, and David Healy and others on Mad in America over the years had an effect as well. I appreciate the approach of Dr. Moncrieff, who said: “There are times when the use of antipsychotic drugs seems to produce just enough suppression that people can put aside their psychotic preoccupations, and re-establish a connection with the outside world.” Yet she can still see where “they produce an artificial state of neurological restriction,” like a chemical straightjacket.

In my view antipsychotic drugs can be useful in suppressing psychotic symptoms, and sometimes, when people are beset by these symptoms on a continual basis, life on long-term drug treatment, even with all its drawbacks, might be preferable to life without it. But most people who experience a psychotic breakdown recover. [Emphasis added] In this situation, antipsychotics are recommended not on the basis that they provide relief from severe symptoms, but because they are said to reduce the risk of relapse.

The Cochrane Collaboration published a review of antipsychotic maintenance treatment for schizophrenia in 2012. Their report was the first systematic review comparing the effects of all antipsychotic drugs to placebo for maintenance treatment. This is standard care after an acute phase of schizophrenia to prevent relapse. (And it seems, if a teenage manic episode is suspected of being a latent bipolar disorder) Not surprisingly, they found that antipsychotics were more efficacious than placebo in preventing relapse, especially at seven to 12 months. But they noted it was rare to find a study that did follow up longer than 12 months.

Randomised controlled trials (RCTs) since the 1950s have consistently shown that antipsychotic drugs effectively reduce relapses and need for hospitalisation. Conversely, they are, as a group, associated with a number of side effects such as movement disorders, weight gain and sedation.

Moncrieff pointed out two additional problems with these kinds of comparisons. First is the fact that they don’t compare people started on long-term medication treatment and people who were drug free in the placebo groups. Rather, the latter group consists of people who are withdrawn from long-term antipsychotics. Usually the taper or withdrawal occurs too quickly, precipitating discontinuation symptoms, like with the teen I described above. “The difference in relapse rates is almost certainly exaggerated in these studies, therefore, especially since relapse is often defined only in terms of a modest deterioration in general condition or symptoms.”

Another problem is there is typically little data in the studies on anything other than the so-called “relapse,” which is too loosely defined in most studies. So global functioning could be worse for people on continuous drug treatment than they would have been without it, even if they did experience a relapse. “Since the data has not been collected, we just don’t know.”

The first problem perpetuates a distorted message of how antipsychotic medications prevent relapse. The second problem means there is no information on whether someone might be better off if they didn’t use medication.

Moncrieff recently published an article in PLOS Medicine that called for a rethinking of antipsychotic maintenance: “Antipsychotic Maintenance Treatment: Time to Rethink?” Her summary points in the article were:

Existing studies of long-term antipsychotic treatment for people with schizophrenia and related conditions are too short and have ignored the impact of discontinuation-related adverse effects.
Recent evidence confirms that antipsychotics have a range of serious adverse effects, including reduction of brain volume.
The first really long-term follow-up of a randomised trial found that patients with first-episode psychosis who had been allocated to a gradual antipsychotic reduction and discontinuation programme had better functioning at seven-year follow-up than those allocated to maintenance treatment, with no increase in relapse.
Further studies with long-term follow-up and a range of outcomes should be conducted on alternatives to antipsychotic maintenance treatment for people with recurrent psychotic conditions.

She described a long-term randomized controlled trial (RCT) by Wunderlink et al. in the Netherlands (in this article as well as in her blog) that confirms how long-term antipsychotic use will impair a person’s ability to function. The study also showed that when you gradually reduce people’s antipsychotics in a supportive manner, they are better off in the long-term.

This study should fundamentally change the way antipsychotics are used. These are not innocuous drugs, and people should be given the opportunity to see if they can manage without them, both during an acute psychotic episode and after recovery from one. If psychiatrists had not forgotten the lessons of the past, and if they had been prepared to acknowledge what they saw the drugs doing with their own eyes, this would have come about long ago.

The studies used to justify current clinical practice don’t provide reliable data on the pros and cons of long-term antipsychotic therapy. More research is needed to evaluate the efficacy of a gradual and individualized approach to antipsychotic discontinuation. Assessment of outcomes in addition to relapse is needed. Moncrieff recommended that while we await the results of further long-term discontinuation studies, that we reconsider antipsychotic maintenance treatment as the default strategy for people with recurrent psychotic disorders.

In “Psychiatric Drug-Induced Chronic Brain Impairment,” Peter Breggin described how chronic brain impairment (CBI) from chronic exposure to psychiatric drugs produces effects similar to those from a traumatic brain injury. He drew a parallel of effects between electroshock treatment, closed head injuries from repeated concussions (like what was portrayed in the movie, Concussion), and long exposure to psychiatric drugs:

The brain and its associated mental processes respond in a very similar fashion to injuries from causes as diverse as electroshock treatment closed head injury from repeated sports-induced concussions or TBI in wartime, chronic abuse of alcohol and street drugs, long-term exposure to psychiatric polydrug treatment, and long-term exposure to particular classes of psychiatric drugs including stimulants, benzodiazepines, lithium and antipsychotic drugs.

He said that by recognizing CBI, clinicians can enhance their ability to identify individuals who need to be withdrawn from long-term psychiatric drug treatment. Most patients show signs of recovery from CBI early in the withdrawal process. “Many patients, especially children and teenagers, will experience complete recovery.” With others, recovery could take place gradually; sometimes over years. Even when recovery is incomplete, Breggin said most patients wish to remain on reduced medication or none at all.

The symptoms of this syndrome include (1) Cognitive deficits, often first noticed as short-term memory dysfunction and impaired new learning, and difficulty with attention and concentration; (2) Apathy, indifference or an overall loss of enjoyment and interest in life activities; (3) Affective dysregulation, including emotional lability, loss of empathy and increased irritability; (4) Anosognosia or a lack of self-awareness about these changes in mental function and behavior.

02/5/16

Wolves in Sheep’s Clothing

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.

11/11/15

Trick or Trick

A grocery store pharmacy in Quebec Canada was giving out psychiatric drugs for Halloween treats this year. A mother accidentally dropped divalproex (Depakote) and quetiapine (Seroquel) pills that she had picked up for her son. Other customers picked up the pills, which were wrapped in a blister packet, and placed them on the counter next to a candy basket. Somehow the pills were mixed in with the candy. “Seven of the pills ended up in the hands and bags of trick-or-treating children.”

A Constable said that an employee mixed the medications in with the candy by accident. But one mother said she immediately recognized the pills were drugs and took them away from her daughter who had “chewed and spat out the drugs distributed by mistake.” The “mistake” is puzzling, as the girl’s mother said: “It was a transparent bag, with the name of the person, the drug, the dosage, the pharmacist and the date and time the prescription was filled; October 31 at 8 a.m. in the morning,”

Police told parents that the pills weren’t dangerous, but that is just not true. The medication guide for quetiapine lists potential side effects as: the risk of suicidal thoughts or actions, depression, anxiety, panic attacks, irritability, anger or aggression, unusual changes in mood or behavior. The medication guide for divalproex lists similar potential side effects: the risk of suicidal thoughts or actions, depression, anxiety, agitation or restlessness, anxiety, irritability, anger or aggression, unusual changes in mood or behavior. And it can cause serious liver damage in children younger than 2 years old. Granted, these adverse effects would in all probability not occur if a child had wrongly ingested one pill, but the describing the pills as not dangerous was deceitful. Read more on this incident at The Fix or Vice.

Seroquel is an antipsychotic medication and Depakote is an anti-seizure medication that carries the label of “mood stabilizer” when used as a psychiatric medication. Antipsychotics are frequently combined with mood stabilizers in the treatment of bipolar disorder. A September 2105 study published in JAMA Psychiatry, “Treatment of Young People with Antipsychotic Medications in the United States,” examined at the prescription patterns among young people in the United States. The study looked at four age groups: younger children (1-6 years), older children (7-12 years), adolescents (13-18 years), and young adults (19-24 years).

The researchers found that most of the individuals treated with antipsychotics did not have a medical claim that included a mental disorder diagnosis. The percentages by age group were as follows: younger children (60.0%), older children (56.7%), adolescents (62.0%), and young adults (67.1%). When there was a diagnosis, the most common one was ADHD with younger children (52.5%), older children (60.1%) and adolescents (34.9%). Depression was the most commonly given diagnosis among young adults (34.5%).

Consistent with clinical diagnoses suggesting that antipsychotics are primarily used to manage impulsive or aggressive behaviors in children associated with ADHD, the highest rate of antipsychotic treatment was in adolescent boys, approximately half of whom also filled prescriptions for stimulants. Young adults treated with antipsychotics were more frequently diagnosed as having depression, bipolar disorder, and anxiety disorder than ADHD.

A National Institute of Mental Health (NIMH) press release on the study, quoted a co-author, Michael Schoenbaum, as saying antipsychotics should be prescribed with care. “They can adversely affect both physical and neurological function and some of their adverse effects can persist even after the medication is stopped.” He added what was particularly important about the study’s findings was that 1.5% of boys aged 10-18 are on antipsychotics. This rate was abruptly cut in half as adolescents become young adults.

In the current study, the combination of peak use of antipsychotics in adolescent boys and the diagnoses associated with prescriptions (often ADHD) suggest that these medications are being used to treat developmentally limited impulsivity and aggression rather than psychosis.

Mad in America quoted Dr. Christopher Correll, the medical director of the New York State Office of Mental Health, who noted that the powerful and almost immediate problems with antipsychotics can include weight gain and high glucose levels (a possible precursor of diabetes). “Prescribing antipsychotics seems predominantly aimed at aggressive and impulsive behaviors, especially in males, where the disruption in school and home insists on action and remediating symptoms.”

The study commented how the above noted decrease in prescribed antipsychotics after adolescence may be due to the normal maturation of neurobiological systems in late adolescence and early adulthood. “This normal maturation of neurobiological systems may underlie the decrease in antipsychotic treatment prevalence during late adolescence among youth who do not have enduring cognitive impairments and long-term severe behavioral disorders.” High rates of coprescribing antipsychotics with other classes of drugs were observed across all age groups. Stimulants (probably for ADHD) were the most commonly prescribed psychotropic class during preadolescent years.

A likely outcome in these cases is that agitation from the ADHD stimulants contributes to an increase in aggression among preadolescents, which results in the prescription of an antipsychotic to address the aggression. Dr. Peter Breggin said: “The antipsychotic drugs are often given to children when their behavior and mental state deteriorates as a result of being given stimulants.” Follow the link here to a page on his website where he discusses the potential harm from the psychiatric diagnosing and drugging of children. The page includes links to several videos in his Simple Truth series on YouTube that address topics such as: the harmful effects and action of stimulant drugs; and the negative effects of diagnosing children with ADHD. There is also a link to one of his articles published in Children & Society that “presents a scientific and ethical overview of the harm done to children by stimulants and by antipsychotics.”

The drugging of children in America and increasingly throughout the world is a tragedy. Millions upon millions of children and youth will never know their full potential because they grew up with an intoxicated brain — their neurotransmitters forever deformed by being bathed in these drugs during their formative years. Additional millions will become career consumers of psychiatric drugs with a vastly reduced quality of life and shortened lives.

11/4/15

Abilify in Denial

Modern Healthcare reported that Proteus Digital Health, a California company, is partnering with Otusuka Pharmaceuticals to approve an Abilify “smart pill.” When a medication embedded with a sensor reaches the stomach, it sends a signal to a wearable sensor patch. The patch records and time-stamps the information and other information such as rest and activity patterns. Then the information can be relayed to patients on their phones or other Bluetooth-enabled devices; or it can be forwarded to physicians or caregivers.

It was just in July of 2015 that Proteus announced that the FDA had expanded the Indications for Use statement for its Ingestible Sensor technology to be used as an aid in measuring medication adherence. At this point in time, it seems to be the only device with an FDA-sanctioned claim for measuring medication compliance. Proteus and Modern Healthcare pointed to findings from a 2014 article in Risk Management and Healthcare Policy that estimated avoidable healthcare costs from poor medication adherence as between $100 to $300 billion annually in the U.S. That represents 3% to 10% of total U.S. healthcare costs.

Dr. George Savage, the co-founder and chief medical officer of Proteus, said the company hopes to give patients feedback on their adherence so they can improve their health and avoid adverse medication events. Dr. William Carson, the president and CEO of Otsuka Pharmaceuticals said: “We believe this new digital medicine could revolutionize the way adherence is measured and fulfill a serious unmet medical need in this population.” They expect a response from the FDA by April of 2016.

There is reportedly a widespread problem of with non-adherence to taking medications as prescribed, especially with individuals with mental illness. So the FDA suggested to Proteus that the need for an ingestible sensor was most needed by mental health patients. It seems to have been rushed through the approval process, with about nine months from the FDA approved expansion of the Indications for Use statement for Proteus’s Ingestible Sensor to the expected response by the FDA approving the Abiliy “smart pill.” So there are two questions to ask about this. Why the rush? Why is the greatest need for a smart pill with antipsychotics like Abilify?

Abilify went off of patent in October of 2014 and was made available as a generic in April of 2015. The Abilify smart pill would probably be a new molecular entity (NME) and thus eligible for a new patent. While aripiprazole (Abilify) will be available as a generic, only Otsuka and Proteus will be able to sell the smart pill version. Otsuka and its former distribution partner, Bristol-Myers Squibb, grossed $5.5 billion in Abilify sales for 2014.

The pressing need for a smart pill with psychiatric medications to help counter non-adherence issues is because there are serious, and sometimes debilitating side effects from taking them. Here is a link to an advertisement for Abilify as an add-on medication with antidepressants to treat depression. Most of the audio in the 90-second commercial is describing the potential side effects.

The side effects from antipsychotics can include: weight gain, diabetes, pancreatitis, gynecomastia (abnormal breast tissue growth), hypotension, akathesia (a feeling of inner restlessness), cardiac arrhythmias, seizures, sexual dysfuntion, tardive dyskinesia, anticholinergic effects (constipation, dry mouth, blurred vision, urinary retention and at times cognitive impairment). Read more about these and other side effects at: “Side Effect of Atypical Antipsychotics: A Brief Overview”; “Antipsychotic Drugs, Their Adverse Effects”; “Adverse Effects of Antipsychotic Medications”; and “An Overview of Side Effects Caused by Typical Antipsychotics.”

The website RxISK described some of the reports and first-hand accounts about individuals who had used Abilify in: “Abilify From the Inside Out.” Out of 34 who had used Abilify, only five had taken it for a “psychotic” diagnosis. Fourteen were taking it for depression. Six used it for bipolar disorder; three for other diagnoses; two for “stress”; and three for unknown reasons. Fifteen individuals were taking Abilify in conjunction with antidepressants.

Most patients were on more than one medication, so they could not be sure that if Abilify alone caused these adverse effects. Nevertheless, there were three confirmed suicides and several episodes of severe emotional stress or physical misery. Eight people reported akathisia and six reported unusual anger or aggression. Two of the aggression episodes were violent physical attacks on family members. One woman assaulted her husband when she had “bizarre and frightening thoughts.”

At the other extreme, 14 people reported over-sedation and cognitive slowing, with memory, concentration and word-finding problems. About half felt a profound emotional numbing, an inability to feel pleasure or care about anything. One man regretted this state, but felt it was better than his prior severe depression. For the rest, however, it brought new or worse depression. Three felt trapped at home by “total lack of interest in life” along with anxious depression; loss of the ability to pursue, or even care about, formerly cherished goals was painful for others. Most reported suicidal thoughts of varying intensity.

Three people had tremors, but of these cases cleared up when they stopped the drug. Four others had tardive dyskinesia. Their symptoms started after using Abilify for at least a year; and they continued despite stopping the drug. “They found their condition painful, debilitating, disfiguring and socially isolating.” Four men reported sexual dysfunction. One man had a gambling problem that began two months after starting Abilify. “Eight people had their worst problems on stopping Abilify.”

Johanna Ryan, who wrote the article on RxISK, said that most antidepressants are metabolized in the liver by the same enzymes that process Abilify. So the resulting “traffic jam” will effectively raise the level of Abilify in your blood. Some SSRIs have also a stronger effect than others on this issue. “Your actual Abilify levels might be 150% to 300% of your official dose.” Side effects such as agitation, anxiety, insomnia and nervousness commonly occur with antidepressants and can increase your chances of akathisia with Abilify.

In other words, the “little baby dose” was an illusion. Even 2 mg was bigger than it seemed – and doses over 5 mg could put you on a par with patients taking Abilify for psychosis. (Those patients may be taking excessive doses as well: Two patients with psychotic symptoms in the RxISK group found they did better on half the dose their doctor initially prescribed.)

In “Dodging Abilify” on RxISK, Johanna Ryan related how a psychiatrist had tried to convince her once to try Abilify for her depression. He told her “these drugs” (referring to Abilify) weren’t really antipsychotics since they were used to treat several kinds of things. “’Oh, come on,’ he coaxed. ‘We’re talking about little baby doses here, just a fraction what they give people for schizophrenia.’” Like other antipsychotics, it blocks certain dopamine receptors. Unlike them, it is a “partial agonist,” meaning it activates others.

Now let’s go back to the cute Abilify commercials. This one includes a woman and her umbrella. Listen to see if Abilify is ever referred to as an antipsychotic or neuroleptic. As a matter of fact, it wasn’t. The same is true for the link to the commercial above. Admittedly, these commercials were pushing Abilify as an add-on to antidepressants. But now download the FDA Medication Guide for Abilify, and search through it. You won’t find the word “antipsychotic.” The word “neuroleptic” appears once within the listing of a side effect: neuroleptic malignant syndrome. Abilify is described and presented as an “antidepressant medicine” throughout the medication guide. There were other antipsychotics that seemed to also minimize using these two words (neuroleptic and antipsychotic) in referring to their drug, but not to the same extent as noted for Abilify. My thought is Otusuka decided that referring to Abilify as an antipsychotic or neuroleptic was bad for business.

So Abilify is a neuroleptic that apparently wants to be known as an antidepressant and absolutely HATES to be referred to as an antipsychotic. Yet it has the same kinds of adverse side effects as other neuroleptics. (If it walks like a duck and talks like a duck …) And of all the current antipsychotics on the market, Proteus partnered with Otsuka first to create an Abilify smart pill to facilitate medication compliance with its drug. To borrow a phrase from addiction recovery, it sounds like Abilify is in denial about being an antipsychotic.

10/14/15

Antipsychotic Big Bang

Duff Wilson wrote in “Side Effects May Include Lawsuits” that antipsychotics were a niche product for decades. Yet they have recently generated sales that have surpassed that of “blockbusters like heart-protective statins.” In the 1990s, pharmaceutical companies began marketing them for much broader uses than the original FDA approved uses for more serious mental illnesses, like schizophrenia and bipolar disorder. A Scientific American article reported that pediatric prescriptions for atypical antipsychotics rose 65%—from 2.9 million to 4.8 million—between 2002 and 2009. And a New York Times article noted that federal investigators have found widespread overuse of psychiatric drugs by older Americans with Alzheimer’s disease.

There are two more facts to introduce you to about neuroleptics or atypical antipsychotics. First, in 2008, antipsychotics sales reached $14.6 billion, making them the biggest selling therapeutic class of drugs in the U.S. Second, each of the following pharmaceutical companies that marketed antipsychotics has been investigated for misleading marketing under the False claims Act. All their neuroleptics—Risperdal (risperidone; Johnson & Johnson), Zyprexa (olanzapine; Eli Lilly), Seroquel (quetiapine; AstraZeneca), Geodon (ziprasidone; Pfizer), and Abilify (aripiprazole; Bristol-Myers Squibb and Otsuka)—are now off patent.

The primary use off-label use of neuroleptics for the elderly and with children has been for behavioral control. A recent study commissioned by the Pennsylvania Department of Human Services found that children between the ages of 6 and 18 who were in foster care was four times higher than other youth in Medicaid. More than half of these youth had a diagnosis of ADHD. “This is concerning, as the majority of these youth did not have another diagnosis that clinically indicated the use of antipsychotics.” Risperidone was the most frequently prescribed antipsychotic medication among the youth. However, Abilify and Seroquel grew to exceed risperodone over the course of the study. Zyprexa was the least commonly used antipsychotic among all youth.

A trade group for nursing homes, The American Health Care Association, indicated that while antipsychotics helped some dementia patients who have hallucinations or delusions, “They also increase the risk of death, falls with fractures, hospitalizations and other complications.” The American Psychiatric Association, among others pointed to a JAMA Psychiatry study that showed mortality risks increased in patients given antipsychotics to reduce their symptoms of dementia. Another study published in Health Policy said the benefits and harms of using antipsychotic medications in nursing homes should be reviewed.

Antipsychotic medication use in nursing home residents was found to have variable efficacy when used off-label with an increased risk of many adverse events, including mortality, hip fractures, thrombotic events, cardiovascular events and hospitalizations.

Another “add on” area for neuroleptic use is when it is used with an antidepressant for “treatment resistant” depression. On BuzzFeed, Cat Ferguson reported how the sale of antipsychotics such as Abilify, and Zyprexa “skyrocketed” as they were approved to treat depression as an add-on medication. Seroquel is not FDA approved to treat major depression, but along with Abilify and Zyprexa is approved to treat bipolar depression in adults. Zyprexa and Seroquel are approved for some indications of bipolar disorder in adolsecents, but Abilify is only used off label with bipolar children, having “low or very low evidence of efficacy.” See the Psychopharmacology Institute for more information on these drugs and their approved and off-label uses.

Ferguson quoted a few psychiatrists expressing concern about the antipsychotic boom, and there are some surprises given other stands they’ve taken. Allen Frances, the former chair for the DSM-IV, agreed there has been heavy marketing of antipsychotics. He thought they are prescribed too quickly for depression and without clear indication of their efficacy. He added there seemed to be pressure from the pharmaceutical companies. He said: “These drugs should have a narrow indication, and instead they’ve become the highest revenue-producing drugs in America.”

Over the past few years Allen Frances has become an outspoken critic of some psychiatric practices, including the overuse of antipsychotics and antidepressants. He’s also been critical of the DSM-5. He’s even written Saving Normal to address his concerns with psychiatry and psychiatric practice. Search for his name here to find several articles where he is mentioned.

I was surprised and encouraged to see Jeffrey Lieberman, the chair of psychiatry at the Columbia University College of Physicians and Surgeons express concern with the over prescribing of antipsychotics. Lieberman has positioned himself as defender of psychiatry and psychiatric practice, recently publishing Shrinks. You can also search his name here to see other articles interacting with his book and position on psychiatry. Lieberman said that antipsychotic medication should be used sparingly in treating nonpsychotic disorder, including depression. He said: “I think there’s the possibility that antipsychotics are overprescribed, not just for depression, but in other areas.”

My point is that when two prominent psychiatrists with opposing views on many areas of psychiatry and psychiatric practice agree that antipsychotics are overused, pay attention. Both Frances and Lieberman have pointed out elsewhere how pharmaceutical marketing strategies contribute to this problem, but some pharma companies and representatives put the blame back on doctors. An Eli Lilly spokesperson said pharmaceutical companies aren’t responsible for how their drugs are used by doctors. “Physicians make prescribing decisions, not pharmaceutical companies. . . . While certainly we inform doctors of the benefits and risks of our medicine, it’s really up to physicians to prescribe the right medicine.”

But this attempt to deflect responsibility onto physicians is a cop out when you consider the marketing done by pharmaceutical companies for their products. In this YouTube advertisement for Abilify as an antidepressant add-on, you see how Bristol-Myers Squibb actively encouraged individuals to “ask your doctor if Abilify is right for you.” Pay attention to the fact that the first thirty seconds verbally describes how Abilify can help, while the rest of the 90-second commercial has the woman and her family going on a picnic while the adverse side effects are described.

Another problem is that all clinical trials for drug approval are done over short periods of time—six or eight weeks—antipsychotics included. But what are the long-term consequences of antipsychotics? As Dan Iosifescu, the director of the Mood and Anxiety Disorders Program at Ichan School of Medicine at Mount Sinai Hospital said, “It’s just a fallacy to take short-term data and extrapolate it for long term.” His bottom line is that antipsychotics tend to be helpful in the short term, but can have major consequences in the long term.

Thomas Glasen, writing in Schizophrenic Bulletin, weighed the pros and cons of medication treatment for psychosis. In the case for medication, he noted that the benefits of medication were profound. The therapeutic power of antipsychotic medication had been validated in countless studies and was now the primary treatment of schizophrenia. “In today’s climate, treating schizophrenia without medication mobilizes high anxiety among treaters for the safety of their patients from irrationality and for the safety of themselves from litigation.” However, in the case against medication, Glasen said:

Antipsychotics obscure the pathophysiology of psychosis by altering the neurobiology of the brain and the natural history of [the] disorder. . . . Medication can be lifesaving in a crisis, but it may render the patient more psychosis-prone should it be stopped and more deficit-ridden should it be maintained.

So how do individuals on long-term antipsychotics do? In Anatomy of an Epidemic, Robert Whitaker described Martin Harrow’s presentation of a long-term study funded by NIMH on sixty-four individuals diagnosed as schizophrenic between 1975 and 1983. Whitaker had just reviewed a series of studies questioning whether there was a long-term benefit to the use of antidepressants before discussing the Harrow study. He then said: “If the conventional wisdom is to be believed, then those who stayed on antipsychotics should have had better outcomes.” Harrow found that after two years, there was evidence that the off-med group was doing slightly better than the group on drugs.

Then, over the next thirty months, the collective fates of the two groups began to dramatically diverge. The off-med group began to improve significantly, and by the end of 4.5 years, 39 percent were “in recovery” and more than 60 percent working.

The outcomes for the medication group worsened and this divergence continued. At the fifteen-year follow up, 40 percent of those off drugs were in recovery and more than half were working; only 28 percent suffered from psychotic symptoms. “In contrast, only 5 percent of those taking antipsychotics were in recovery, and 64 percent were actively psychotic.” The 2007 Harrow study can be found here. Harrow said that not only was there a significant difference in global functioning between the two groups, 19 of the 23 (83%) schizophrenic patients with uniformly poor outcome after fifteen years were on antipsychotics.

Harrow et al. (2014) continued his study and reported data in Psychological Medicine at the twenty-year stage of his follow-up schedule. Here he investigated whether multi-year treatment with antipsychotics reduced or eliminated psychosis; and whether the results were superior to individuals in the non-medicated group. The data showed that the pattern noted above by Whitaker in Harrow’s 2007 report continued: “A surprisingly high percentage of SZ prescribed antipsychotic medications experienced either mild or more severe psychotic activity.” The figure to the left, originally from the 2014 Harrow et al. report, shows that 68% of the medication group experienced psychotic activity, while only 8% of the off-med group experienced any psychotic activity. The source of the figure was a slide reproducing the Harrow data in a presentation by Robert Whitaker at the “More Harm than Good” conference sponsored by the Council for Evidence-Based Psychiatry (CEP). The slides and videos of the presentation can be found here.

Harrow et al. thought the high percentage of the medication group experiencing psychotic activity was influenced by two factors. One was the high vulnerability to psychosis of many schizophrenic patients, leading to a high risk of psychosis. But that begs the question of how the medication group in the study had such a high number of patients “at risk of psychosis.” Given the above data, their second factor seems to have been the more important factor: prolonged use of antipsychotics (or partial dopamine blockers) may produce a medication-generated build-up of supersensitive dopamine receptors or excess dopamine receptors.

The production of excess or supersensitive dopamine receptors would then be an iatrogenic, drug induced effect from the long-term use of antipsychotics. The brain increases or sensitizes the receptors, thus compensating for the blockade of original receptors in the postsynaptic neuron. Again, drawing from Whitaker’s presentation slides at the CEP conference, it would look like this:

The above presentation of Harrow’s data and the discussion from Whitaker’s CEP presentation seem to affirm Glasen’s thesis that antipsychotics could alter the neurobiology of the brain. Antipsychotics reduce the activity of dopamine systems, stimulating the increase of receptors. When the antipsychotic is tapered or withdrawn, this would not immediately diminish the number of additional dopamine receptors produced by the brain to compensate for the dopamine blocking action of the antidepressant. With decreased antipsychotic levels, the result would be increased activation of the postsynaptic neurons because of the greater number receptors to absorb dopamine.

The person’s symptoms could intensify through the increased absorption of dopamine because of this disregulation of the dopamine system. In other words, tapering off of antipsychotics could activate symptoms like mania, paranoia and hallucinations because of the chemical imbalance produced by the medication. The experience of mania from a too sudden withdrawal of an antipsychotic is in this view, likely a withdrawal or discontinuation symptom instead of proof that the person needs to remain on an antipsychotic because they have a chemical imbalance. Robert Whitaker’s conclusion in Anatomy of an Epidemic was:

What the scientific literature reveals is that once a person is on an antipsychotic, it can be very difficult and risky to withdraw from the medication, and that many people suffer severe relapses. But the literature also reveals that there are people who can successfully withdraw from the medications and that it is this group that fares best in the long term.

06/10/15

Seniors and Antipsychotics

Healthcare Finance News reported that a long-time Chicago psychiatrist faces over 18 months in prison after he pled guilty to receiving $600,000 in kickbacks from pharmaceutical companies. Dr. Michael Reinstein also agreed to pay $3.79 million in a parallel civil lawsuit settlement for prescribing clozapine in exchange for kickbacks. His medical license has also been suspended.

In 2009, ProPublica and the Chicago Tribune reported that in one year, Reinstein prescribed more clozapine to patients in Medicaid’s Illinois program than all doctors in the Medicaid programs of Texas, Florida and North Carolina combined.

The Chicago Tribune reported that autopsy and court records show that at least three patients under Reinstein’s care died of clozapine intoxication. Medical records for a fifty-year-old man showed that he had more than five times the toxic level of clozapine in his blood when he died. A 27 year-old woman died after her dose of cloazpine was increased twice as fast as recommended. Reinstein served as the psychiatric medical director for 13 different nursing homes.

Up until 2003, the manufacturer of Clozaril (Novartis) paid Reinstein thousands of dollars for speaking engagements to promote the drug, according to Healthcare Finance News. IVAX Pharmaceuticals then began paying him $50,000 per year as a consultant, so he switched his patients to generic clozapine. That arrangement continued when Teva Pharmaceuticals acquired IVAX in 2006. In 2009, as the Tribune began to examine his prescribing habits, Reinstein asked Teva to terminate the consulting agreements. Incidentally, in March of 2014 Teva agreed to pay $27.6 million to settle federal and state claims that the company paid Reinstein to prescribe clozapine.

The actions of Dr. Reinstein were extreme, but not really those of a lone rogue psychiatrist. On March 1, 2015, Robert Pear with The New York Times wrote that federal investigators with the Government Accountability Office (GAO) would announce the next day that they had found evidence of widespread overuse of psychiatric drugs by older adults with Alzheimer’s. Not only was this a concern in nursing homes, but investigators also said officials needed to focus on the overuse of these drugs by individuals with dementia who live at home or in assisted living facilities.

The GAO found that approximately one-third of older adults with dementia who spent more than 100 days in a nursing home in 2012 were prescribed an antipsychotic (neuroleptic). Among older adults with dementia living outside of a nursing home, about 14 percent were prescribed an antipsychotic. While the Department of Health and Human Services (HHS) has taken several steps to address antipsychotic use in nursing homes, nothing has been directed to settings outside of nursing homes. Therefore, the GAO recommended that HHS expand its outreach and educational efforts to include those living outside of nursing homes.

Neuroleptic (antipsychotic) drugs are classified into two sub-groups. The older, “typical” ones were developed in the 1950s. Examples include haloperidol (Haldol) and chlorpromazine (Throazine). The second generation, “atypical” antipsychotics were developed in the 1980s and initially thought to cause fewer side effects than the older, typical antipsychotics. Examples of atypical antipsychotics include aripiprazole (Abilify) and risperidone (Risperdal). Abilify was the number 13 best selling drug for 2014, according to Genetic Engineering & Biotechnology News. Clozapine (Clozaril) is an atypical.

In 2005, the FDA required that atypical antipsychotics carry a boxed warning that they had a higher risk of death related to use among individuals with dementia. In 2008, the FDA required the same warning with typical antipsychotics.

A literature review in Health Policy looked at the extensive off-label use of antipsychotics in nursing homes for residents with dementia and behavioral problems. They were found to have mixed efficacy “with an increased risk of many adverse events, including mortality, hip fractures, thrombotic events, cardiovascular events and hospitalizations.” Non-pharmacological options were recommended as first-line treatment options. The authors also noted when studies were subsidized by the pharmaceutical industry, the studies showed more favorable outcomes with antipsychotics.

Researchers from the University of Michigan Medical School and John Hopkins University reviewed two decades worth of research and concluded: “The evidence for non-pharmaceutical approaches to the behavioral problems often seen in dementia is better than the evidence for antipsychotics.” They noted there still was a place for using antipsychotics when patients have psychosis or aggression that could lead to harming themselves or others. “But these uses should be closely monitored and ended as soon as possible.”

Another study from the University of Michigan (abstract here) examined the records of 91,000 elderly veterans with dementia and found that mortality risks increased in patients taking antipsychotics to reduce symptoms of dementia, when compared to patients not being treated. A MinnPost report of the study said the mortality risks were two to four times higher than previously cited in the medical literature. “The new analysis also revealed that the higher the dose of an antipsychotic medication, the greater the risk of premature death.” Dr. Helen Kales, one of the study’s researchers, said:

Our research indicates that antipsychotics may increase mortality more than previously realized. . . . We hope this creates a dialogue about the advantages and disadvantages of antipsychotic and other psychotropic use as first-line treatment strategies for behavioral symptoms, which are universal and require effective treatments to address serious suffering among patients, families, and caregivers.

I hope it creates a dialogue as well. Thankfully we do not have the older state hospital system where the elderly with dementia and Alzheimer’s were often warehoused. But shackling them mentally with neuroleptics so they can be managed with minimal behavior problems seems to be just about the same thing.

Faith Seeking Understanding

Charles Sigler, D.Phil.

Tag: antipsychotics