Medicolegal Considerations in the Treatment of Psychosis With Second-Generation Antipsychotics

Psychiatric Times

December 2004

Vol. XXI

Issue 14

A quick Internet search using the terms "lawsuits and atypical antipsychotic medications," also known as second-generation antipsychotics (e.g., aripiprazole [Abilify], clozapine [Clozaril], olanzapine [Zyprexa], risperidone [Risperdal], quetiapine [Seroquel] and ziprasidone [Geodon]), returns hundreds of hits. Mostly, these hits are law firms seeking clients to sue physicians and/or pharmaceutical companies for serious side effects that may be linked with these medications. Top complaints of plaintiffs are diabetes, pancreatitis and wrongful death.

This wave of legal actions is occurring as a consequence of the marketing success of these compounds and amid the growing recognition, even among the general public, of the increased metabolic liabilities associated with them. It is likely that there will be many thousands of such diabetes cases in the United States. Several hundred will make it to the desk of a capable plaintiff's attorney, and several dozen will be so compelling that the painful sojourn through the tort system will be started in earnest. The astute among these attorneys will soon discover the need to apportion causality because of etiological vagueness and the enormous rates of obesity and diabetes that are unrelated to any introduced pharmaceutical. The goal for such attorneys is to causally tie the untoward outcome for a given patient to the manufacturer's negligence in either insufficient testing or inadequate labeling.

Both obesity and, as a direct consequence, diabetes are at epidemic crisis levels in this country and, of most concern, appear to be accelerating at a rate that is literally without precedent. Although the details accounting for and contributing to this pandemic among the general populace are not entirely known, the very existence of the pandemic has caused (or in some cases, has been used to promote) a delay in our collective recognition and acceptance of the substantial additional burden imposed by many second-generation antipsychotics on our already challenged patients. Our field is currently grappling (with insufficient information to date) to determine their impact on weight gain and diabetes, the liability with second-generation antipsychotics in comparison to (and in synergy with) other known risk factors, and the potential for differential risk between each second-generation antipsychotic. Much of our decision making at present is based on short-term clinical studies and epidemiological analyses. More informative, long-term, pharmacovigilant studies are awaited.

What is the reasonable psychiatrist supposed to do to optimize patient care and avoid the malpractice minefield? First and foremost, we must prioritize our relationship with the patient and do what is reasonable to inform patients about the risks of second-generation antipsychotics. Equally important, we must also monitor for side effects, keep ourselves informed, and try to prevent untoward events. Patients who wish to sue a doctor must prove that the doctor was negligent, and through this negligence, caused an injury.

Adverse drug reactions are a common reason for liability claims against physicians. The growing literature that associates second-generation antipsychotics with weight gain, obesity and its metabolic legacies (e.g., diabetes and changes in cholesterol and triglycerides) may be used as "evidence" that such adverse reactions can occur. Thus, clinicians must be familiar with the relative side-effect profiles of available second-generation antipsychotics and carefully weigh the risks and benefits of them before prescribing them. Unfortunately, the alternative of selecting first-generation antipsychotics, with their greater risk of tardive dyskinesia, a potentially irreversible movement disorder, also lands psychiatrists and patients squarely into further risk-benefit analyses. Tardive dyskinesia lawsuits were the second most frequent cause of legal action against psychiatrists in recent years, the first being suicide. New tardive dyskinesia lawsuits are less common now and they may be surpassed by the growing number of legal actions regarding what we now call "the tardive dyskinesia of the SGAs"--weight gain, diabetes and dyslipidemias (Wirshing et al., 2002). The Table explains a few of the current and proposed lawsuits regarding these side effects.

Standard of Care

Mossman and Lehrer (2000) addressed the issue of prescribing second-generation antipsychotics as opposed to first-generation antipsychotics and concluded that the "proper use of the older drugs is not a deviation from the standard of care." However, they concluded from case law that psychiatrists have a legal obligation to inform patients about the alternative of novel antipsychotics, considered in 2000 to have a more benign side-effect profile, at least with regard to extrapyramidal side effects and tardive dyskinesia. Now in 2004, does the standard of care suggest that psychiatrists must tell patients about the possibility of using the second-generation antipsychotics with the least weight gain potential, as some have more weight gain potential than others? More provocatively, will the standard of care swing back to using first-generation antipsychotics with low weight gain liability? As second-generation antipsychotics have overtaken the antipsychotic market in the United States, it is unlikely that psychiatrists will resort to prescribing these older agents to prevent weight gain; indeed, some first-generation antipsychotics have vast weight gain propensity themselves (e.g., chlorpromazine [Thorazine] and thioridazine [Mellaril]). Multiple drug company-sponsored trials suggest that two of the second-generation antipsychotics (aripiprazole and ziprasidone) may have, on average, less weight gain liability than the other agents; however, this has not been clearly established in head-to head trials comparing all the medications prospectively. Package insert information reveals that 10% and 8% of subjects treated with ziprasidone and aripiprazole, respectively, gained substantial amounts of weight in premarketing trials. Although these drugs are considered "weight neutral," because clinical trial data show low mean weights compared to some of the other second-generation antipsychotics, each patient is an individual and may be one of the minority who experiences a great deal of weight gain.

It is important to have and document informative discussions of the risks, benefits and treatment alternatives with the patient. It has been suggested that patients could be injured by legal advertisements because they may lead patients to discontinue their medications, resulting in the risk of relapse. Conceivably, a patient and family could sue a psychiatrist if they feel that the psychiatrist's concerns about diabetes precipitated an unnecessary switch of medications that resulted in relapse, rehospitalization or even death. Therefore, decisions to discontinue a medication in a stable patient must be made with extreme caution. Additionally, while we have several studies demonstrating favorable outcomes when a patient is switched from one drug to another, these are often open-label trials that do not account for the effect of time on outcome. Therefore, at the present time, we cannot adequately describe the risk-benefit profile of switching between the individual second-generation antipsychotics.

Although the risks of weight gain and its sequelae, such as diabetes, appear to exist for virtually all of the second-generation antipsychotics, most prospective research supports the notion that some of the medications have greater weight gain liability than others. The diabetes literature is less clear. It would be sensible to conclude that medications with the greatest weight gain liability are more likely to increase the risk of diabetes; however, the U.S. Food and Drug Administration does not fully concur with this inference and has asked that all second-generation antipsychotic manufacturers label their products with the warning that this class of agents can be associated with diabetes, diabetic ketoacidosis and possibly death. (Aripiprazole and ziprasidone have secured less demonstrative label changes.) This labeling is consistent with the FDA's actions in the past to label all medications of a particular group or class with the same warning. The FDA philosophy is conservative, reflecting the notion that it is better to be over-inclusive than under-inclusive. For example, all antipsychotics contain labeling information regarding the risk of tardive dyskinesia and neuroleptic malignant syndrome.

Duty to Inform

Good clinical practice dictates that we should provide adequate informed consent to patients taking second-generation antipsychotics regarding the various risks and benefits. Certainly, if a patient is doing well on a medication with known weight gain liability and they are obviously suffering from metabolic side effects, the decision of the psychiatrist to switch to a medication with lower weight gain liability should be made carefully. Maintenance of psychiatric well-being should be paramount, and the risks and benefits of switching a patient from a medication with more weight gain liability to one with less should be carefully discussed among the psychiatrist, patient and caregivers. No clear data exist demonstrating the superior efficacy of one second-generation antipsychotic over another, though a meta-analysis by Davis et al. (2003) makes a good case for the superior efficacy of clozapine compared to first-generation antipsychotics that exceed the effect sizes of other second-generation antipsychotics in such comparisons to first-generation antipsychotics. Clozapine's efficacy is, however, strongly mitigated by its problematic side effects, and it remains underutilized by U.S. psychiatrists in patients who have failed to respond to two other antipsychotic medication trials. On the other hand (and further illustrating the complexity of decision making) there is evidence that clozapine is effective for patients with schizophrenia who are suicidal (Meltzer et al., 2003). Similarly, evidence is accruing that second-generation antipsychotics may have antiaggressive effects (Buckley et al., 2003). These points are made to highlight the complexity of decision making for clinicians as the real potential of second-generation antipsychotics--both good and bad--evolves in our practices.

Side-Effects Prevention

Once informed consent has been obtained, the psychiatrist must follow a monitoring plan with the patient that will help manage the elevated risk of weight gain associated with these drugs. The extra monitoring plan should be doable, and physicians should provide information to the patient about ways to prevent weight gain, as well as about proper nutrition and exercise. At the very least, the psychiatrist should attempt to obtain a patient's weight and waist measurement at the beginning of treatment and at subsequent visits if possible. Minimally acceptable standards would be to obtain weights (either through in-office measurement or reliable reports) at each visit and at weeks 2 and 4 of treatment. Family and personal history of diabetes as well as glucose and lipid panels should be obtained at baseline. The lipids should be repeated at eight weeks, irrespective of weight gain. Diabetes monitoring should be associated with observed weight gain. Rapid weight gain (e.g., two pounds per week over the first eight weeks of treatment) observed in the early phases of treatment should signal to the clinician and patient the need for more aggressive monitoring, diet and exercise, or consideration of a medication switch. At the present time, there are insufficient data to advocate for adding anti-obesity agents to a patient's regimen. However, this may change as more studies occur and are published.

If a psychiatrist demonstrates concern about these side-effect issues, informs the patient, attempts to monitor and reverse these problems, and refers to internists for assistance as necessary for glucose regulation or dyslipidemias, then the psychiatrist is doing their best by the patient. The standard of care is evolving as this article is being written; doctors can be sued for any number of untoward events. The American Diabetes Association et al. (2004) have published a good set of monitoring suggestions. By no means is this monitoring guideline the standard of care, rather it is a position piece generated by experts from the diabetes and psychiatry communities. Monitoring guidelines are also being published by other groups and organizations (e.g., American Psychiatric Association [2004]). Each set of guidelines has common elements of a thorough baseline assessment and of regular monitoring. They differ in the recommendations of frequency and detail of monitoring. Prospective trials are underway to provide even better data on which to base our clinical monitoring decisions. A recent survey by Newcomer and colleagues (2004) suggested that, as a field, we have a long way to go to achieve monitoring as a consistent part of practice.

Documentation

Formal requirements for adequate documentation for informed consent and appropriate monitoring for these adverse effects of second-generation antipsychotics have yet to be established. In such a vacuum, it would be prudent to document, at the very least in general terms, that the patient was informed of the risks and benefits of the selected medication.

There should also be documentation of ongoing consideration of this risk-benefit ratio during the course of treatment. The emergence of and the efforts to deal with these adverse effects should be carefully documented, as should joint patient-doctor decisions to switch to another agent. Some systems of care are now giving consideration to forms (paper or electronic) to assist in documentation.

Doctor-Patient Relationship

The basic principle we train our psychiatry residents with is to deliver the best possible care you can to your patients. Treat patients the way you would like a family member to be treated--with dignity and respect. A good relationship with patients and their families is key to preventing an adversarial relationship from developing, even in the event of the worst possible outcomes. Although it is normal for people to be angry in cases with bad outcomes, even in the best relationships, the family's anger over a death due to an unexpected medication side effect may land on the psychiatrist.

Staying Informed

Stay informed about these issues by reading medical and psychiatric journals, attending professional meetings, keeping up-to-date on grand rounds, and staying current on FDA bulletins. The pharmaceutical companies can also provide information if you have a particular concern or are seeking more information about a drug and its side effects. Staying informed will help you deliver the best possible care to your patients.

Dr. Donna Wirshing is associate professor of psychiatry at the David Geffen School of Medicine at the University of California, Los Angeles (UCLA), and is co-chief of both the Schizophrenia Inpatient Treatment Unit and the Schizophrenia Research Outpatient Clinic of the Veterans Affairs Greater Los Angeles Healthcare System.

Dr. William Wirshing is professor of psychiatry in the department of psychiatry and biobehavioral sciences at the David Geffen School of Medicine at UCLA, chief of the Schizophrenia Treatment Unit, chief of Schizophrenia Research Outpatient Clinic, and director of the Brentwood Movement Disorders Laboratory at the West Los Angeles VA Medical Center.

Mr. Nystrom is currently working toward his M.D. at UCLA.

Dr. Buckley is professor and chairperson of the department of psychiatry and health behavior at the Medical College of Georgia in Augusta.

References

American Diabetes Association, American Psychiatric Association, American Association of Clinical Endocrinologists, North American Association for the Study of Obesity (2004), Consensus development conference on antipsychotic drugs and obesity and diabetes. Diabetes Care 27(2):596-601.

American Psychiatry Association (2004), Practice Guideline for the Management of Schizophrenia, 2nd ed. Available at: www.psych.org/psych_pract/treat/pg/prac_guide.cfm. Accessed Nov. 2.

Buckley PF, Noffsinger SG, Smith DA et al. (2003), Treatment of the psychotic patient who is violent. Psychiatr Clin North Am 26(1):231-272.

Davis JM, Chen N, Glick ID (2003), A meta-analysis of the efficacy of second-generation antipsychotics. Arch Gen Psychiatry 60(6):553-564.

Meltzer HY, Alphs L, Green AI et al. (2003), Clozapine treatment for suicidality in schizophrenia: International Suicide Prevention Trial (InterSePT). [Published erratum Arch Gen Psychiatry 60(7):735.] Arch Gen Psychiatry 60(1):82-91 [see comment].

Mossman D, Lehrer DS (2000), Conventional and atypical antipsychotics and the evolving standard of care. Psychiatr Serv 51(12):1528-1535.

Newcomer JW, Nasrallah HA, Loebel AD (2004), The Atypical Antipsychotic Therapy and Metabolic Issues National Survey: practice patterns and knowledge of psychiatrists. J Clin Psychopharmacol 24(5 suppl 1):S1-S6.

Wirshing DA, Boyd JA, Meng LR et al. (2002), The effects of novel antipsychotics on glucose and lipid levels. J Clin Psychiatry 63(10):856-865.