Diseases of the central nervous system (CNS) have been a treatment target of the biopharma industry for decades, with waves of new products or treatment pathways appearing each decade or so. The urgency comes from the dire situation that patients and their families find themselves in, with debilitating illness and suicide being the endpoints of two of the most common mental illnesses: depression and psychosis (primarily schizophrenia or bipolar disorder).
The successful development of medication for these diseases (other CNS conditions, including memory, sleep and pain management, won’t be treated here) have created business opportunity for biopharma, such that today, anitpsychotics are the highest-value therapeutic class (see table), and antidepressants one of the fastest-growing. But with the opportunity comes risk: Penalties for improper, off-label promotion have been in the hundreds of millions of dollars (with Lilly and its antipsychotic, Zyprexa, receiving the highest DoJ penalty ever—for $1.42 billion—at the beginning of this year). Thousands of lawsuits have been filed by plantiffs claiming damages for many CNS drugs over their side effects. And the relationship between the biopharma industry and mental health professionals is a charged one: the American Psychiatry Assn. is one of the first medical societies to ban nearly all types of sponsored interaction between the industry and the profession (which is all the more ironic in that more education for healthcare providers is a nearly constant refrain for improved care).
Part 1 of this report will look at the current industry product offerings and prospects, and the evolving treatment paradigms. Part II, to be published in the next issue, will look at regulatory challenges in marketing and distribution, and the impact of comparative effectiveness studies.
Cure in search of a disease
Antipsychotic and antidepressant drugs—like the conditions they treat—live under a cloud. Because schizophrenia, bipolar disorder and depression are often underdiagnosed, mental health professionals constantly fight to get society to acknowledge the real harm or debilitation that the conditions cause. For the medications themselves, there is widespread debate over the risks and benefits of the drugs. Off-label use is high (and highly controversial), with some patients and their families desperate for relief, and others accusing the industry of over-promoting the drugs’ value. The fact that considerable consumption occurs among the elderly (including those with various forms of dementia) and the young adds intensity to the debate.
Perhaps the most indicative sign of what’s at stake is that, sadly, one of the measures of antipsychotic and antidepressant drug efficacy is preventing suicide or suicidal ideation.
The notion that individuals afflicted with various forms of debilitating psychiatric illnesses can “pop a pill” provides a desperately needed lifeline for patients and their families, but this mindset tends to downplay the risk of serious side effects and potential health consequences that all antipsychotics and antidepressants carry. As a result, it’s been anything but smooth sailing for brand managers and marketing teams in charge of these drug franchises, and in recent years wave after wave of market-shaping events have rocked the industry.
These include unfavorable results emerging from several head-to-head comparisons of the leading antipsychotics (findings that have challenged many of the widespread assumptions about these drugs), the increasing prevalence of Black Box warnings required for drugs in both groups (sidebar), regulatory litigation and heavy penalties, and heated competition among manufacturers, along with the familiar impact of patent expiry.
Off-label use brings its own controversy Antidepressants and antipsychotics are being dispensed to treat children with behavioral problems and attention deficit disorders, and older adults with dementia related psychoses. But patient advocates and mental health professionals question the practice. For instance, while many physicians argue that suitable alternatives are simply not available to treat the symptoms of mental illness and depression in children and seniors, a growing body of research has brought into question the safety, cost and effectiveness of many of today’s leading antipsychotics and antidepressants in these vulnerable patient sub-populations.
Among these two drug classes, the list of life-threatening side effects includes increased risk of suicide and premature death, weight gain so significant that it statistically increases the risk of heart disease, diabetes, lipid abnormalities and other metabolic disorders, and more. These potential side effects are compounded by the fact that individuals with schizophrenia and other forms of mental illness tend to have a higher risk of diabetes than the general public (due, primarily to lifestyle issues such as a sedentary lifestyle, poor diet, lack of proper medical care, and a high rate of obesity), and those with with moderate to severe depression, if left untreated, already face a higher risk of suicide, as well.
All of these events provide a tense backdrop for brand managers, who are seeking to position their psychoactive drugs as safer and more efficacious than those of their rivals.
Within the realm of antipsychotics, the medications available for use today are classified as typical (first generation) or atypical (second generation) antipsychotics. The older typical antipsychotics include Compazine (prochloroperazine), Haldol (haloperidol), Loxitane (loxapine) Thorazine (chloropromazine) and others, most of which are now available in generic form.
The newer atypical antipsychotics include Abilify (ariprazole), Clozaril (clozapine), Geodon (ziprasidone), Invega (paliperidone), Risperal (risperidone), Seroquel (quetiapine), Zyprexa (olanzapine) and Symbyax (olanzapine and fluoxetine), some of which are available as generics.
Both classes are composed primarily of dopamine receptor antagonists, which work by blocking the action of naturally occurring dopamine in the brain. They differ primarily in their side effects, with the newer atypicals tending to have a lower incidence of neurological side effects such as involuntary movements, tics and Parkinson-like shakes, as well as undesirable cognitive effects that plague many of the older conventional antipsychotics.
In 2008, the therapeutic class of antipsychotic drugs ranked #1 in US sales (having moved up from the rank of #3 the year before), according to IMS Health, totaling $14.4 billion in 2008, up from $9.5 billion in 2004. In 2008, nearly 53 million prescriptions for antipsychotics were written in the U.S., up from nearly 44 million in 2004.
Meanwhile, with sales of $11.4 billion in the U.S. alone, the antidepressants ranked #5 among the top 15 therapeutic classes in 2008. While the 2008 dollar sales figure was down from an earlier high of $13.1 billion in 2004, this indicates growing demand for less-expensive generic antidepressants — not shrinking overall use, according to IMS. For instance, during the same time period (2004-2008), total U.S. prescriptions for antidepressants rose from 182 million in 2004, to 207 million in 2008, helping the antidepressants to become the third most widely dispensed prescription medications, on a volume basis, in 2008.
Similarly, the 15 top-selling drugs in 2008, by U.S. sales, according to IMS, included two antipsychotics and two antidepressants:
• The antipsychotic Seroquel (quetiapine) from AstraZeneca (#5 on the list), nearly doubled its sales over the last five years, recording 2008 sales of $3.9 billion, up from $2.1 billion in 2004
• The antipsychotic Abilify (aripiprazole) from BristolMyers-Squibb/Otsuka (#12), nearly tripled its sales over that same time period ($3.1 billion last year, up from $1.0 billion in 2004)
• The antidepressant Effexor XR (venlafaxine HCl) from Wyeth (#14) enjoyed 2008 sales of $3.0 billion, up from $2.6 billion in 2004
• The antidepressant Lexapro (escitalopram oxalate) from Forest (#15), saw its sales rise from $1.8 billion in 2004 to $2.7 billion last year.
Mental illness takes its toll
The symptoms associated with schizophrenia and other forms of mental illness — ranging from delusional thinking, thought disorder, and hallucinations, to social withdrawal, apathy and reduced ability to express emotion — exact a heavy toll not only on the afflicted, but on society, as well.
Direct costs associated with mental illness arise from increased medication use, clinic visits and hospitalization, lost earning potential, costs associated with Social Security disability payments, homelessness and incarceration, and more. According to an NIMH study published May 7, 2008, in the American Journal of Psychiatry, major mental disorders cost the U.S. at least $193 billion/year in lost earnings alone. “This estimate is probably conservative because [the study] did not assess people in hospitals or prisons, and included very few participants with autism, schizophrenia or other chronic illnesses that are known to greatly affect a person’s ability to work. The actual costs are probably higher than what we have estimated,” said Ronald Kessler, PhD, of Harvard University, author of the study.
Further, according to other NIMH data:
- Nearly one in four US adults suffer from a diagnosable mental disorder in any given year, and mental disorders are the leading cause of disability for people aged 18-44
- Major depressive order is a leading cause of disability in the U.S. for ages 15-44, affecting roughly 14.8 million American adults (6.7% of U.S. adults aged 18 and older)
Bipolar disorder affects roughly 5.7 million American adults (2.6% of U.S. adults)
Schizophrenia affects 2.4 million American adults (1.1% of U.S. adults)
- Anxiety disorders — including panic disorder, obsessive-compulsive disorder, post-traumatic stress disorder, generalized anxiety disorder and phobias — affect roughly 40 million American adults (18% of U.S. adults)
NIMH statistics indicate that depression is responsible for up to 70% of psychiatric hospitalizations and 40% of suicides. Currently the fourth most disabling illness worldwide, depression will be the second leading cause of disability by the year 2020, according to the World Health Organization.
The cost of depression in the U.S. in the year 2000 was estimated to be $83 billion, including both $26 billion in costs of treatment and $57 billion in losses related to absenteeism, reduced productivity at work, and earnings lost due to suicide-related deaths, according to NIMH.
With an overall rate of 10.9 suicide deaths per 100,000 people, suicide is considered to be a major, preventable public health problem. According to NIMH, in 2004 suicide was the eleventh leading cause of deaths in the U.S., accounting for 32,439 deaths.
An expanding prescriber universe
Much of the growth in antidepressant and antipsychotic use in recent years can be attributed to a shift in the domain of prescribers who now freely prescribe both classes of psychiatric drugs. “I can tell you from my own clinical practice that this has completely changed since I completed my geriatric fellowship in 1993,” says Richard Stefanacci, DO, MGH, MBA, AGSF, CMD, Director, Institute for Geriatric Studies, Mayes College for Healthcare Business & Policy, University of the Sciences in Philadelphia. “At that time, these powerful psychotropic drugs were prescribed exclusively by psychiatric and neurological specialists, but this is no longer the case today.”
Views on the impact of this evolving prescriber domain are mixed. Advocacy groups argue that it invites potential problems, because it is helping to drive the “drug-centered treatment paradigm” that prevails today for many psychiatric conditions — whereby doctors and insurers overemphasize the use of prescription drugs as quick-fix solutions, while underemphasizing difficult, more-costly and more-time-consuming psychiatric intervention such as talk therapy and other forms of psychotherapy and occupational therapy.
Others argue that many of today’s primary-care physicians (PCPs) are not adequately trained to properly diagnose, prescribe and manage patients with psychiatric problems. “Today, many PCPs feel so comfortable with these medications that they call in verbal orders without even seeing the patient,” says Stefanacci. “Unfortunately, many PCPs have the perception that these medications are completely safe — which is ironic, given that they carry a Black Box warning.”
Expanding the prescriber base certainly puts the onus on the drug manufacturers to provide greater educational-outreach efforts that are geared toward non-specialty physicians. “The message and delivery of pharma outreach needs to be completely different for PCPs,” says Stefanacci.
Others argue that this paradigm shift is a good thing, because the broader base of prescribers casts a wider net to intervene on behalf of patients who might benefit from the use of an antidepressant or antipsychotic but are not likely to seek help from a psychiatrist. For instance, according to NIMH, research shows that many people who commit suicide are likely to have seen their physician in the year prior to their death; thus, improving the ability of PCPs to recognize and treat risk factors has been identified as one major way to help prevent suicide among these groups.
Similarly, in the April 2009 issue of Pediatrics, the United States Preventive Services Task Force, an independent, government-appointed medical panel that sets public health guidance for doctors on a variety of health-related issues, began urging doctors to perform routine screening on all American teenagers for depression. Today, an estimated 6% of American teenagers — nearly two million teenagers — are clinically depressed (a problem that can lead to persistent sadness, social isolation, problems in school and even suicide), and most are undiagnosed and untreated, according to the group. Evidence shows that detailed but simple questionnaires can accurately diagnose depression in the primary-care setting such as the pediatrician’ or primary-care physician’s office.
In a March 30 New York Times article, the panel stressed that it did not want its advice to lead to drug treatment alone, but should include psychotherapy, as well, particularly because some antidepressants have been linked to increase risks for suicidal thoughts. Meanwhile, because psychiatrists specializing in treating children and teens are scarce, a separate report (published in the same issue) notes that PCPs (including pediatricians and family physicians) will need to get more deeply involved in mental health care to carry out these latest recommendations.
“The willingness of PCPs (including internists, family physicians and geriatricians) to prescribe these medications is a healthy development overall, because it is helping more people to be properly screened and to begin treatment,” says Barney Spivack, MD, Medical Director of LifeCare (Shelton, CT). Spivack is a member of the American Medical Directors Assn. (AMDA; Columbia, MD), the national association representing more than 8,000 medical directors, attending physicians and others who practice in nursing homes and other long-term care (LTC) facilities, and currently serves on its clinical practice committee.
Managing depression is also an issue of interest for many employers and unions, because it has a big impact on worker productivity, says benefits consultant F. Randy Vogenberg, RPh, PhD, Principal for the benefits and training consultancy Institute for Integrated Healthcare (IIH; Sharon, MA). “When they are able to more effectively screen employees with mild to moderate depression, to make them more happy and productive workers, it’s a win-win for everybody.”
He notes that a growing number of the health and wellness initiatives being offered by employers and unions now include screening for depression. Drug companies can get involved here, by developing unbranded, education-oriented partnerships with employers and unions.
Meanwhile, because PCPs and other medical specialists “tend to see a high prevalence of anxiety and/or depression in people being treated for chronic medical illnesses, these physicians are in a good position to help patients to manage these issues,” says Peter Winn, MD, CMD (Okahoma City, OK), who is board-certified in family medicine and geriatrics. Winn is a Medical Director for a long-term-care facility and hospice, and is a member of the AMDA Board of Directors.
The expansion of the prescriber domain has other advantages, as well. For instance, Vogenberg notes that “insurance often limits the number of visits a patient may make to a psychiatrist, so it’s common for psychiatrists to initiate prescriptions of antidepressants and antipsychotics but then refer the patient to his or her PCP to continue therapy and ongoing monitoring.”
This shift is especially apparent in long-term care facilities, nursing homes and assisted-living facilities, “where geriatric psychiatrists tend to be few and far between,” says Spivack. “It’s often the nurses (including advance practice nurses, APRNs) and other members of the interdisciplinary care team who have the closest contact with the residents, and are thus in the best position to evaluate and recommend condition-specific treatment, and these individuals often direct, drug-related recommendations to the attending physicians, prompting them to act on the described symptoms,” adds medical director Winn.
Improved marketing outreach
“The fact that the bulk of the treatment can be appropriately instituted by PCPs today is an excellent development, but drug companies need to do everything they can to reinforce the idea of using antidepressants and antipsychotics appropriately,” says Spivack. “Too often, physicians jump around and switch medications before appropriate doses or recommended duration of treatment even reached. It should be incumbent on PCPs to have a good working knowledge of these complex medications.”
Given the many parallel issues that are at play in both drug classes, industry observers agree that it’s in the brand team’s best interest to develop meaningful, educational outreach — rather than heavy-handed product promotion — to support the most responsible prescribing (both approved and off-label) by both generalist physicians and specialists in the field of psychiatry.
“To support all of these clinicians, drug makers should develop good, creative, interactive programming that can help them to recommend the right drug for the right patient at the right dosage, and enhance their own ability to better manage mood and behavior problems among the elderly,” adds Spivack.
“Drug companies should be more proactive about publishing evidence-based studies, articles and critical evaluations not just in medical journals aimed at generalists and family physicians, but in practitioner journals aimed at nurses and mid-level practitioners such as nurse practitioners (NPs) and physician assistants (PAs),” says Winn of AMDA.
He also notes that “pharma sales reps need to be forthright with prescribers during detailing efforts — for instance, including balanced information from studies and/or editorials, especially those that challenge the results of drug studies as to the general applicability to certain patient populations such as older adults and those in long-term care settings.”
Specifically, experts suggest that educational outreach efforts aimed at general physicians should help them to:
- Recognize symptoms and diagnose problems related to depression, schizophrenia and bipolar disorder and other forms of mental illness
- Evaluate and prescribe the most appropriate initial treatment options (to match patients with the most appropriate drug options), and to understand the evidence-based protocols for moving patients through successive treatment options in each drug class
- Carry out appropriate ongoing monitoring to track metabolic and extrapyramidal side effects (such as movement disorders including tardive dyskinesia and dystonia)
- Know when to refer the patient to a psychiatric specialist.
Similarly, Stefanacci points out that outreach aimed at psychiatrists and other mental health experts should provide evidence-based research that can help them to manage difficult cases, where, for instance, the patient may need to move through a succession of alternative drugs in response to issues related to tolerability, efficacy or side effects. Unbranded outreach should also encourage psychiatrists to develop and maintain relationship with the PCPs of their patients, so they can support the patient with appropriate prescription refills, ongoing adherence and monitoring efforts, once the psychiatrist has been referred the patient back to his or her doctor for long-term treatment management. This is especially important considering the need for ongoing bloodwork and monitoring that is required when using these potent psychotropic drugs (discussed below).
“In terms of the antipsychotics, the burden of side effects must be clearly communicated to all stakeholders,” he adds. “Evidence-based, academic detailing can be coupled with more creative marketing outreach to support this broader domain of prescriber,” says Spivack.
Winn suggests that drug companies can do more to showcase valuable information that already exists — such as prevailing guidelines and recommendations from AMDA, CMS, FDA, various medical societies, and even Beer’s List (a widely used reference that provides evidence-based recommendations for drugs that are potentially inappropriate for use among older patients) — to develop user-friendly tools that PCPs can use to more effectively recognize and screen/diagnose the symptoms of depression and other psychiatric conditions in the office setting. “Doctors and drug companies should continue to get the message out there that ‘it’s not normal to be depressed,’ and they should remind patients that the treatment of depression often requires drug therapies to continue for a year or more,” he adds.
When it comes to psychiatric medications, the question of which drugs get preferential treatment in the eyes of insurers often plays out like this: “Payors of all sorts — managed-care organizations, PBMs and insurers — tend to manage this class of drugs through out-of-pocket (OOP) expense assignments — setting relatively low OOP expenses for generics, higher OOP for preferred brands, and much higher for non-preferred branded medications,” says Stefanacci. “This leaves the decision of valuing the specific products in the hands of the patient. If the patient believes that a specific product is worth X, then they are willing to pay at least that. If the OOP is greater than X (their perceived value), then they will opt for the generic.” Such a system underscores the importance of ongoing DTC outreach efforts that are aimed at educating and influencing consumers, both to build name recognition and convey the full value proposition for individual drugs.
Similarly, Stefanacci notes that when it comes to their efforts to influence tier status on insurance and other managed-care formularies, “drug makers need to push to gain preferred status for their products, articulate the value proposition of their products to patients and their caregivers via DTC and other educational outreach efforts, and articulate the value proposition of their products to prescribers through educational programs, so they can advocate acceptance by their patients.” PC
BOX: Shedding Light on Black Box Warnings
Experts agree that neither the antipsychotics nor the antidepressants should be used without full consideration of the heavy side effects burden that both classes of drugs bring. For instance, FDA requires both the newer atypical antipsychotics (since April 2005) and the older typical (since June 2008) to carry a Black Box warning, to notify healthcare professionals and patients that the use of both classes of drugs is associated with an increased risk of mortality when used to treat behavioral problems in elderly patients with dementia-related psychosis (a widely used but off-label indication for these drugs).
Specifically, patients with dementia-related psychosis who are treated with the newer atypical antipsychotic drugs are at increased risk of cardiovascular events such as stroke, sudden death of unknown cause, and life-threatening infections (such as pneumonia).
All second-generation atypical antipsychotics must also include Black Box warning labels alerting prescribers to additional side effects, such as increased risk of hyperglycemia and diabetes.
When it comes to antidepressants, FDA began requiring a Black Box warning for all antidepressants in 2004, after a thorough review of published and unpublished data revealed a slight increase in suicidal thoughts an actions among children and adolescents taking antidepressants, compared to those taking a placebo.
In May 2007, FDA called for makers of all antidepressant medications to update the existing Black Box warnings, to include warnings about increased risks of suicidal thinking and behavior in young adults (ages 18-24) during initial treatment, as well.
Despite these warnings, the use of both types of psychotropic drugs to treat a variety of off-label indications among pediatric and geriatric patients continues to grow. Similarly, a New York Times article (published June 24, 2008) asserts that a third of all nursing home patients are given antipsychotic drugs.
When it comes to the elevated risk of suicidal ideation in children, teenagers and young adults patients taking antidepressants, things can get very tricky because young patients suffering from depression, if left untreated, already face an elevated risk of suicide.
In fact, in mid-2007, NIMH released a study that suggested that a 2004 spike in suicide rates may have coincided with a drop in the use of antidepressants among youths that followed warnings from U.S. and European regulatory agencies that the medications might trigger suicidal thoughts. According to the study, SSRI prescriptions for youth dropped by 22% in both the U.S. and Netherlands during 2003-2004 (following months of public hearings and preliminary warnings, which resulted in FDA requiring the Black Box warning in 2004). Over the same time period (2003-2005), youth suicides in the Netherlands increased by 49%. In the U.S., such rates increased by 15% in 2005 — the largest change in adolescent suicide rates since data collection began in 1979, according to NIMH.
Such complexity underscores the need for need for better training of all medical practitioners (both generalists and specialists), to improve screening and diagnosis, and encourage the proper use and ongoing monitoring of drugs, especially where successive drugs may need to be tried to achieve desired results. PC