04/21/20

Pros and Cons of Antipsychotics

Antipsychotic treatment is often associated with weight gain and metabolic syndrome, a cluster of symptoms that increases the risk of heart disease, stroke and diabetes, independent of other adverse effects like sexual dysfunction, drowsiness, dizziness, restlessness, and others. In The Lancet, Pillinger et al compared and ranked 18 antipsychotics on the basis of their metabolic side-effects. They found that antipsychotics varied widely in their effects on body weight, BMI, total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, and glucose concentrations. Olanzapine (Zyprexa) and clozapine (Clozaril) were ranked the worst for metabolic-related adverse effects, while ironically being identified as among the most effective antipsychotic drugs. Aripiprazole (Abilify, Aristada), brexpiprazole (Rexulti), cariprazine (Vraylar), lurasidone (Latuda), and ziprasidone (Geodon) were the most benign profiles.

In the same issue of The Lancet, Yoav Domany and Mark Weiser compared the results of this study with a network meta-analysis on the efficacy and adverse effects of antipsychotics. Clozapine was the most efficacious in reducing overall symptoms and amisulpride (Solian) was the most efficacious in reducing positive symptoms. “One would hope that data on efficacy and adverse events could be taken together with the detailed information on metabolic adverse events from this study to consider a personalized medicine approach in treating patients with schizophrenia.”

This approach could be part of a shared decision-making process, based on a discussion with the patient weighing the benefits and disadvantages of each treatment option. Such an approach is hampered by the fact that clozapine and olanzapine, which consistently come out among the best in terms of efficacy, are also consistently associated with the highest rates of metabolic adverse effects, hindering such a process at this stage.

One limitation of the Pillinger et al study was the studies in its meta-analysis were quite short, in the range of 2-13 weeks. The authors noted how randomized controlled trials are generally short and recommended that future studies should “examine antipsychotic-induced metabolic dysregulation in patients receiving long-term maintenance therapy.” Further, lifestyle and treatment factors (physical comorbidity, alcohol use, smoking, diet, exercise, and co-prescription of psychiatric—eg, mood stabilisers—or physical health medications—eg, statins or anti-glycaemic drugs) may have influenced metabolic outcomes. “Treatment guidelines should be updated to reflect differences in metabolic risk, but the choice of the treatment intervention should be made on an individual patient basis, considering the clinical circumstances and preferences of patients, carers, and clinicians.”

Standard treatment guidelines are that antipsychotic medications should continue indefinitely after someone has experienced more than one psychotic episode. But according to Sandra Steingard, there is less agreement treatment guidelines after a single psychotic episode. “Current guidelines recommend drug treatment for two to five years, the idea being that if a person remains well during that time, it might then be safe to stop the drug.” She said most psychiatrists assumed that by reducing risk of relapse you would improve long-term outcomes. But that assumption may not be correct. Not only are there risks of weight gain and tardive dyskinesia, antipsychotics seem to impair functional outcome. Robert Whitaker reported that Martin Harrow and Thomas Jobe did a long-term study of 200 psychotic patients. Patients who were off medication had better cognitive functioning and lower levels of anxiety than medicated patients. Patients on medication were more likely to be psychotic at follow-up. “Eighty-six percent of the medication-compliant patients were psychotic at the 4.5-year follow-up, compared to 21% of those who had stayed off antipsychotics. This dramatic difference remained throughout the study.” See the following chart.

Harrow also found that once patients who went off medication were stable, they were likely to remain stable for extended time periods. None of the stable, off-med patients stable at the 7.5-year follow-up relapsed in the next 7.5 years. Seventy to 90% of the unmedicated patients were working more than half time, compared to roughly 25% of the medicated patients. Those with milder disorders who continued taking medications had worse outcomes than schizophrenia patients who were off their medications.

Harrow discovered that patients off medication regularly recovered from their psychotic symptoms over time (2-year to 4.5-year outcomes), and that once this happened, they had very low relapse rates. At the same time, a majority of the patients on medication regularly remained psychotic, and even those who did recover often relapsed. Harrow’s results provide a clear picture of how antipsychotics worsen psychotic symptoms over the long term.

Schizophrenia monotherapy treatment is not always effective, and some individuals receive additional interventions, such as electroconvulsive therapy (ECT), transcranial magnetic stimulation (TMS) and psychological therapies. Ortiz-Orendain and others conducted a Cochrane review that compared antipsychotic monotherapy and combined treatment. The authors found low-quality evidence that combined antipsychotics improved the clinical response. The study indicated that more people who received combination therapy showed an improvement in symptoms. But there were no clear differences with other outcomes, such as relapse, hospitalization, adverse events, discontinuing treatment or leaving the study early. In her review of the Ortiz-Orendain et al study for The Mental Elf, Elena Marcus said it was a well conducted systematic review. However,

One of the main limitations of this review lies in the quality of included studies, with outcomes rated as low or very low quality which really questions our confidence in the reported estimates. There was a particularly high or unclear risk of reporting bias and attrition bias across studies and as authors included quasi-randomised trials there was a risk of selection bias in ~70% of studies. Whilst five studies were clearly quasi-randomised, for 39 studies there was not enough information to judge whether sequence generation was truly random, so the risk of bias here was unclear rather than high.

Users of antipsychotic medications also describe a distinctive experience, characterized by sedation, cognitive impairment, emotional blunting and reduced motivation. These are in addition to the various physical effects, including weight gain, sexual dysfunction and neurological consequences. Thompson et al described a synthesis of qualitative data about mental and behavioral changes associated with taking antipsychotics, and how these interact with symptoms of psychosis and people’s sense of self and agency. They found that neuroleptics interfered with people’s ability to carry out basic activities. But they also reduced the intensity of intrusive psychotic experiences and other symptoms, such as anxiety and insomnia.

Anything that changes our mental faculties is likely to impact on our sense of ourselves, and this is a common experience in relation to mood or experience-modifying agents. In the studies we reviewed, some participants felt neuroleptic-induced effects deprived them of important aspects of their personality; their drives, imagination or humour, for example. Others felt that by reducing the symptoms of psychosis, the drugs were able to restore them to a state in which they felt ‘themselves’ again. Similarly, some people were content to view themselves as having a disease requiring ongoing treatment, while others felt that taking neuroleptic medication symbolised a tainted identity. Schizophrenia or psychosis can disrupt people’s sense of self, and studies of personal recovery have described the importance of reconstructing a sense of self in a way that is distinct from symptom improvement. Therefore, although neuroleptics may effectively suppress symptoms, their effects can nevertheless be experienced as detrimental to sense of self and identity, with important implications for social functioning and achievement of life goals.

John Read and Ann Sacia of the University of East London surveyed 650 individual’s experiences with antipsychotics. Two-thirds (66.9%) of the participants said their experiences with antipsychotic drugs was more negative than positive, with 34.9% stating their experiences were extremely negative. Nearly a quarter (22.1%) of the participants said their experiences were more positive than negative, with 5.7% saying their experiences were extremely positive. The authors said at the point of prescription clinicians should provide a full range of information about antipsychotics, including potential benefits and harms, difficulties withdrawing, and information on alternative treatments, such as psychological therapies.

Implied in the above critique of antipsychotics is the view that psychiatric drugs are psychoactive substances in the same way alcohol or heroin are psychoactive substances. This is what Joanna Moncrieff refers to as the ‘drug-centered’ model of drug action. Conversely, the opening study by Pillinger et al seems to view antipsychotics according to a ‘disease-centered’ model of drug action. Moncreiff said the disease-centered model is borrowed from medicine and presents drugs through the prism of disease, disorder or the symptoms the drugs are thought to treat. The significant effects (or efficacy) are the ones the drugs exert on the diseased or abnormal nervous system. Any others are of secondary interest and referred to as above as side effects or adverse effects.

In contrast, the ‘drug-centred’ model suggests that far from correcting an abnormal state, as the disease model suggests, psychiatric drugs induce an abnormal or altered state. Psychiatric drugs are psychoactive substances, like alcohol and heroin. Psychoactive substances modify the way the brain functions and by doing so produce alterations in thinking, feeling and behaviour. Psychoactive drugs exert their effects in anyone who takes them regardless of whether or not they have a mental condition. Different psychoactive substances produce different effects, however. The drug-centred model suggests that the psychoactive effects produced by some drugs can be useful therapeutically in some situations. They don’t do this in the way the disease-centred model suggests by normalising brain function. They do it by creating an abnormal or altered brain state that suppresses or replaces the manifestations of mental and behavioural problems.

The above discussion suggests individuals being treated with antipsychotics should weigh the risks and benefits of the medication prescribed to them. They need to gather information on their medication, its potential side effects and then monitor how they respond to the drug. This is consistent with what Joanna Moncrieff called the drug-centered model of drug action. The Harrow study also indicated that the use of antipsychotics may not be the best long-term treatment protocol for schizophrenia. If you are using or considering the use of antipsychotics, weigh the pros and cons.

11/3/17

Downward Spiral of Antipsychotics

Antipsychotic or neuroleptic drugs became big business for pharmaceutical companies about nine years ago, reaching sales of $14.6 billion in 2008. This made them the best selling therapeutic class of medications in the U.S. that year. Not only are they used to treat psychosis and bipolar disorder, several have been approved as an add-on medication to treat depression. Additionally they are used off-label with children and the elderly for behavioral control. And they are the primary cause for a serious neurological disorder called tardive dyskinesia.

Tardive dyskinesia (TD) is a group of involuntary movement disorders caused by drug-induced (iatrogenic) neurological damage, primarily from antipsychotic drugs and a few others that block the function of dopamine in the brain. “TD can vary from a disfiguring grimace to a totally disabling array of spasms and often bizarre movements of any part of the body.” If TD is not identified early on and the drugs stopped, “these disorders nearly always become permanent.” Both patients and their doctors often fail to recognize or diagnose its symptoms.

The above short introduction was gleaned from Dr. Peter Breggin’s “Antipsychotic Drugs and Tardive Dyskinesia (TD) Resources Center.” If you can spare a few minutes, watch a ten-minute TD video edited by Dr. Breggin from existing videos available on the Internet. The video contains a series of individuals with the three general types of tardive dyskinesia whose ages range from pre-adolescence to seniors. These types are: tardive dystonia, a series of involuntary movements that include painful muscle contractions or spasms; tardive akathisia, psychomotor agitation; and classic tardive dyskinesia, the rapid, jerky movements or uncontrollable head bobbing or movements of the arms, hands, feet fingers or toes. The following is a reproduction of a table from Psychiatric Drug Withdrawal by Peter Breggin more fully describing the symptoms of tardive dyskinesia.

Symptoms of Tardive Dyskinesia

Tardive Dyskinesia (Classic)

Rapid, irregular (choreiform), or slow and serpentine (athetoid) movements; often bizarre looking; involving any voluntary muscle, including:

Face, eyelids and eye muscles, jaw (chewing movements, tongue biting), mouth lips, or tongue (protruding, trembling curling, cupping)

Head (nodding), neck (twisting, turning), shoulders (shrugging), back, torso (rocking movements), or abdomen

Arms and legs (may move slowly or jerk out of control)

Ankles, feet and toes; wrists, hands, and fingers (sometimes producing flexion, extension or rotation)

Breathing (diaphragm and ribs; grunting), swallowing (choking), and speaking (dysphonis)

Balance, posture, and gait (sometimes worse when slow, often spastic)

Tardive Dystonia

Often painful sustained contractions (spasms) of any voluntary muscle group; potentially causing muscular hypertrophy, arthritis, and fixed joints; frequently involving the following:

Neck (torticolis, retrocollis) and shoulders

Face (sustained grimacing and tongue protrusion)

Mouth and jaw (sustained opening or clamping shut)

Arms and hands; legs and feet (spastic flexion or extension)

Torso (twisting and thrusting movements; flexion of spine)

Eye lids (blepharospasm)

Gait (spastic; mincing)

Tardive Akathisia

Potential agonizing inner agitation or tension, usually (but not always) compelling the patient to move, commonly manifested as the following:

Restless leg movements (when awake)

Foot stamping

Marching in place, pacing

Jitteriness

Clasping hands or arms

Inability to sit still

TD can impair any muscle functions that are partially or wholly under voluntary control such as the face, eye muscles, tongue, neck, back, abdomen, extremities, diaphragm and respiration, swallowing, and vocal cords. Coordination and posture can be afflicted. TD can cause tremors, tics, and paresthesias (e.g., burning sensations, numbness). TD can also afflict the autonomic nervous system, especially impairing gastrointestinal functioning.

TD sufferers are often exhausted by these unrelenting body movements; even when they are limited to one area of the body, such as the jaw, neck or feet. They become socially withdrawn and isolated—humiliated by the stigma of their uncontrollable movement disorder. One muscle group, such as the tongue or fingers, or various muscle groups can be afflicted. TD symptoms can also change over time from one muscle group to another. This can occur over a period of minutes, days, weeks or years. “Especially in the dystonic forms, the pain can be very severe, and the physical stress can cause serious orthopedic problems.” Antipsychotic drugs are the primary cause of this neurological disorder.

Antipsychotic drugs are also called neuroleptics. Prescribers often promote them in a misleading fashion as antidepressants, mood stabilizers, bipolar drugs, sleeping pills, and behavior control drugs in children. Recent ones include Risperdal (risperidone), Abilify (aripiprazole), Geodon (ziprasidone), Invega (paliperidone), Latuda (lurasidone), Rexulti (brexpiprazole), Risperdal (risperidone), Saphris (asenapine), Seroquel (quetiapine), and Zyprexa (olanzapine). Older antipsychotics include Haldol (haloperidol) and Thorazine (chlorpromazine). [See a more complete listing of antipsychotics here]

Drug companies have made claims that the newer, so-called atypical antipsychotic drugs are less likely to cause TD, but those claims are false or misleading. A 2008 study by Chouinard found a high prevalence of DIMD (drug-induced movement disorders). Nearly 50% of patients had a definite DIMD. The authors also said that DIMD persisted with atypical antipsychotics. “It is crucial to acknowledge that there is a persistence of DIMD with atypical antipsychotics, which are not recognized and confounded with psychiatric symptoms.” Caroff, Miller and Rosenheck reported in “Extrapyramidal Side Effects” that there were no significant differences in measuring the incident rates of TD and other DIMDs between atypical antipsychotics and an older antipsychotic, perphenazine (Trilafon).

According to Dr. Breggin, TD occurs around a rate of 5 to 8 percent per year in adults up to the age of 40, with an accumulating risk of 20% to 24% after four years. The rates increase rapidly over forty. “For a 40-year-old patient, the risk is 18% at 2 years [9% per year] and 30% at 4 years.” In patients over 45, “the cumulative incident of TD after neuroleptic exposure is 26%, 52%, and 60% after 1, 2, and 3 years, respectively.”

Recently the FDA approved two medications to treat TD. Let this sink in. A serious neurological disease, which is primarily caused by a class of psychiatric medications, is being treated with another medication. Neurology Advisor interviewed two experts medical experts on the current state of treatment for TD. One of the experts interviewed said:

The main issue in the “treatment” of TD is prevention. It is important to use offending agents only when the potential benefit is higher than this risk. Once it appears, the first step is to determine whether symptoms are bothersome or disabling to warrant treatment. If possible, either discontinue the offending agent, although this might not improve symptoms permanently, and they will probably worsen initially, or change to a similar agent less likely to cause TD. In terms of prescription medications for TD, I have observed significant variability in treatment approaches depending on physician choice. Over the last few years, I personally found tetrabenazine to be the most efficient agent.

Tetrabenazine (Xenazine) was approved to treat the movement disorder associated with Huntington’s chorea, but has been used off-label to treat TD. It is now off patent and available as a generic. On patent, it sold for $152,000 per year. The generic version is $96,000 per year. However, there have been two new drugs approved specifically to treat TD: Austedo (deutetrabenazine) and Ingrezza (vabenazine). Both are being priced at around $60,000 per year. All three medications carry “black box” warnings from the FDA because of their risk for depression and suicide. You can read more about these medications here, here, here and here.

In addition to TD, antipsychotics have been linked to adverse cardio vascular events, brain shrinkage, dopamine supersensitivity, weight gain, diabetes, a shortened life span and more. The risk-benefit ratio may see a need for short-term use of antipsychotics, but the long-term benefits of their use are questioned by many credible sources. There have been follow up studies that support that concern. See this blog post by Thomas Insel, the former director of the NIMH, the National Institute of Mental Health.

It seems to be stepping onto a downward spiral to use medications with serious side effects to treat TD, a serious side effect from antipsychotics. As the above quoted expert, suggested, the best treatment for tardive dyskinesia is prevention—avoid antipsychotics if at all possible. For more information on concerns and adverse effects with antipsychotics, see: “Blind Spots with Antipsychotics” Part 1 and Part 2, “Antipsychotic Big Bang”, “Wolves in Sheep’s Clothing” and “Hollow Man Syndrome.”

10/17/17

Tell It Like It Is

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

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

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

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

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

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

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

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

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

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

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

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

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

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.

Faith Seeking Understanding

Charles Sigler, D.Phil.

Tag: neuroleptics

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Antipsychotic Big Bang