The 2 main classes of antidepressants. major pharmacokinetic and pharmacodynamic. of Antidepressant Medications ...PRESENTATIONS...

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1 ...PRESENTATIONS... Pharmacokinetics and Pharmacodynamics of Antidepressant Medications Based on a presentation by C. Lindsay DeVane, PharmD Presentation Summary Antidepressants can be categorized by their pharmacodynamic and pharmacokinetic properties. Of the various types of antidepressants, selective serotonin reuptake inhibitors (SSRIs) have become the most often prescribed. Some major pharmacokinetic and pharmacodynamic differences among the SSRIs include half-life, ease of discontinuation of therapy, and the potential for involvement in metabolic drug-drug interactions. Antidepressants are also compared with respect to efficacy, although little difference is thought to exist in the efficacy of different SSRIs. Thus, managed care providers must consider the more subtle differences among the effects of SSRIs in order to rank-order the preferences for selecting a specific drug for a particular patient. The 2 main classes of antidepressants are tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs). Of these, SSRIs have become the most often prescribed. This class has a greater diversity in its structural characteristics than in its neurochemical effects, although chemical structure is not an important consideration for choosing a drug in this class. A comparison of the pharmacodynamic and pharmacokinetic properties of antidepressants is useful to clinicians and managed care providers who must select preferred SSRIs from a formulary. Physicochemical characteristics, which are also important, are seldom considered except when drugs are in the developmental stage. Pharmacodynamic properties describe the effects of drugs on the body. Efficacy, which is an essential pharmacodynamic criterion for formulary inclusion, is probably the most important factor from a patient s standpoint in deciding which drug to use. It is also a primary concern in drug development. Most study results on drug efficacy are based on shortterm randomized trials as opposed to actual clinical practice where clinicians may promote compliance, patient education, and supportive treatment, such as psychotherapy and family-oriented therapy. In trials, a 50% decrease in the Hamilton Depression Rating Scale response is often cited as the criterion for a drug s efficacy but it is not used consistently. Thus, it is possible for a severely depressed patient to have met the response criteria in one study and still qualify as being fully depressed and eligible to enter another clinical trial. VOL. 6, NO. 2, SUP. THE AMERICAN JOURNAL OF MANAGED CARE S39

2 ... PRESENTATIONS... It should be remembered that SSRIs and TCAs when used as part of a comprehensive program of depression management may be more effective in clinical practice than in controlled trials. In actual practice, efficacy rates generally range from 45% to 70%. Ongoing debate exists with regard to the level of effectiveness of SSRIs compared to TCAs, specifically the serotonergic tricyclics, in the treatment of depressive syndromes in inpatients and in those who are more severely depressed. Within the SSRI class, studies have shown little difference in efficacy. Pharmacokinetic properties are the result of the effects that the body exerts on administered drugs. There are many types of pharmacokinetic variables that may help clinicians select a particular drug. For example, a managed care provider who is prescribing an antidepressant or determining dosage may need to know Figure 1. Half-Life of Selective Serotonin Reuptake Inhibitors whether factors such as a patient s age or health-related habits like cigarette smoking affect drug performance. The following discussion will consider the following variables: medication half-life, discontinuation, and drug interactions. Significance of Half-Life Half-life as a measure of the rate of drug elimination is a pharmacokinetic variable familiar to most clinicians. 1 This measure is useful in the evaluation of antidepressants because it may help determine the most appropriate SSRI and provide guidelines for effective dosage regimens. For example, a drug with a very short half-life produces a rapid rate of accumulation on multiple dosing, but the accumulation of the drug may be fairly minimal, so that when dosing is stopped the washout (the elimination of the drug) occurs very quickly. Such an antidepressant may need to be administered more than once daily to be clinically effective. A drug with a long half-life, in excess of 24 hours, produces the opposite result. Drugs with a long half-life will continue to accumulate in the body for a week or more when they are administered once daily, and they require a similar period of time to elapse in order to be completely eliminated after discontinuation. The half-life of a medication is important in the treatment of some patients, for example, those with hepatic dysfunction and an impaired ability to metabolize drugs, and must be considered by clinicians when dosage and treatment regimens are determined. When a drug such as citalopram, which has a half-life of 24 hours, is given once a day, exactly half the amount of the drug in the body is eliminated S40 THE AMERICAN JOURNAL OF MANAGED CARE FEBRUARY 2000

3 ... PHARMACOKINETICS AND PHARMACODYNAMICS OF ANTIDEPRESSANT MEDICATIONS... every day (See Figure 1 for half-life of several SSRIs). 2 In contrast, less of fluoxetine, which has a very long half-life, is eliminated from the body over the same time period. The sustained effects from such a drug may be advantageous in some patients. Drug Discontinuation Another clinical implication of the half-life differences among SSRIs pertains to discontinuance. In clinical practice, it has been observed that some SSRIs, particularly fluvoxamine and paroxetine, are sometimes more difficult to discontinue than drugs such as sertraline and citalopram. The latter drugs have longer half-lives and appear to have a lower propensity to cause withdrawal effects because of their slower elimination from the body when dosing is abruptly discontinued. 3 To avoid a discontinuation syndrome from a drug with a short half-life, the clinician might need to initiate a slow drug taper. That syndrome might also occur when antidepressants other than SSRIS are used. The discontinuation symptoms of SSRIs are listed in Table 1. Drug Interactions Today, drugs are infrequently given as monotherapy, and a relationship clearly exists between the number of drugs a patient takes and the potential for drug interactions. Drug interactions can produce variable effects or no effect on the clinical state of patients. Some possible consequences of drug interactions include changes in the duration or intensity of the desired effect, emergence of a new adverse effect, or worsening of an existing adverse effect. Drug interactions are divided into 2 categories: pharmacokinetic and pharmacodynamic interactions (Table 2). 4 The serotonin syndrome, which is an example of a pharmacodynamic interaction, is a liability shared by all SSRIs. The serotonin syndrome, which requires immediate treatment, occurs with an increase in or the addition of a known serotonergic agent to an established medication regimen. It can be identified by the presence of any 3 of the following symptoms: mental status changes, agitation, myoclonus, hyperreflexia, diaphoresis, shivering, tremors, diarrhea, incoordination, or fever. 5 The major mechanisms of a pharmacokinetic interaction are illustrated in Figure 2. Such interactions frequently occur as a result of enzyme inhibition or induction. Enzyme inhibition might occur in a patient who is taking 1 drug in a long-term regimen to which an enzyme inhibitor is added. The drug that is present in the Table 1. Discontinuation Symptoms of Selective Serotonin Reuptake Inhibitors Dizziness, incoordination Paresthesia electric shocks Flulike symptoms Confusion, disorientation GI distress Sleep disturbance Agitation Symptoms develop within 48 hours of discontinuation Symptoms may last up to 10 to 14 days Risk is higher if drug is taken for more than 1 month Agents with longer half-life protect against symptom emergence Table 2. Drug-Drug Interactions Pharmacokinetic altered plasma or tissue concentration of previous or concurrent therapy Pharmacodynamic altered pharmacologic/behavioral effects due to receptor site interactions VOL. 6, NO. 2, SUP. THE AMERICAN JOURNAL OF MANAGED CARE S41

4 ... PRESENTATIONS... highest concentration with the greatest enzyme affinity may actually compromise the metabolism of the other drug and may increase the concentration of the previous therapy. This Figure 2. Mechanisms of Pharmacokinetic Drug Interactions Table 3. Inhibition of Human CYP 450 Isoenzymes by Selective Serotonin Reuptake Inhibitors CYP450 Isoenzymes SSRIs 1A2 2C9 2C19 2D6 3A3/4 Fluvoxamine Fluoxetine / /++ Paroxetine Sertraline + + +/ Citalopram 0/+ 0 0/+ 0/+ 0 Source: References 2, 4. interaction, which requires the presence of the 2 drugs at the same enzymatic site of the liver, can occur immediately after an enzyme inhibitor has been administered. A slower onset of a drug interaction occurs in enzyme induction. In that type of interaction, an enzyme inducer stimulates the liver to synthesize more enzymes that metabolize drugs. Carbamazepine and rifampin induce the activity of cytochrome (CYP) 3A4. A case example that illustrates enzyme induction follows. A patient taking 200 mg of sertraline became infected with a methicillin-resistant Staphylococcus aureus from his line of work and was prescribed rifampin for 10 days. 6 The patient presented with a change in his antidepressant s efficacy. He experienced a loss of therapeutic effects, increased anxiety, and the appearance of new symptoms near the end of his 10-day antibiotic therapy. His plasma concentrations of sertraline and its metabolite were tested at presentation and again after he had finished taking rifampin. The second test showed that sertraline concentrations had increased, probably because of the removal of the inductive effect of rifampin on the patient s metabolism of sertraline. When the interaction occurred, loss of therapeutic effects and the appearance of withdrawal symptoms resulted. As a result of drug interaction reports, studies have been undertaken to examine the extent to which SSRIs inhibit human CYP 450 isoenzymes. Overall study data reveal that fluvoxamine is more likely to participate in a metabolic drug reaction and that citalopram has the lowest profile and propensity for participating in such interactions (Table 3). 2,4 Some drug interactions are advantageous for the patient. For example, the pharmacodynamic interaction of pindolol with SSRIs enables the patient to experience a rapid onset of S42 THE AMERICAN JOURNAL OF MANAGED CARE FEBRUARY 2000

5 ... PHARMACOKINETICS AND PHARMACODYNAMICS OF ANTIDEPRESSANT MEDICATIONS... antidepressant effects. Also, the combination of SSRIs with atypical antipsychotics will result in an increased concentration of antipsychotic effects, which is not always a disadvantage to the patient. Although drug interactions occur infrequently in clinical practice, clinicians must be prepared to manage adverse effects. For example, when clinicians are concerned about potential drug interactions with SSRIs, they should choose an SSRI that has a low liability for such an effect or they should initiate a low dose of a potentially interacting drug and then carefully monitor the patient. Studies on drug interactions and the mechanisms that create them have promoted the knowledge that drug metabolism, disposition, and pharmacokinetics can help explain patient situations and prevent negative drug reactions. With this knowledge, drug interactions can be minimized by changing the time at which a medication is taken so that sufficient time elapses before another drug is administered, prescribing a drug that does not produce an adverse interaction, altering the dose if an inducer or inhibitor is added, discontinuing one of the medications, monitoring drug interactions therapeutically, or monitoring the patient to detect problems.... DISCUSSION HIGHLIGHTS... Dr. DePaulo: Do you think the differences in enzyme inhibition have caused problems in your patients? Dr. Jefferson: Yes. I can go through case after case of patients who are genetically or pharmacologically induced CYP 2D6 slow metabolizers. Their tricyclic blood levels would be quite high in spite of relatively modest doses. Dr. DePaulo: Many patients are so anxious about taking psychotropic drugs that they have panic attacks and faint when they take their medication. They attribute everything that happens after they take the antidepressant to side effects of the drug. How do you deal with that? Clinicians must be prepared to manage adverse effects. Dr. Jefferson: Ideally, you could compile a drug s side-effect history before it is administered. Some clinicians have checklists of side effects, and others share the data on the package inserts with the patient. I try to assess the patient s level of anxiety before I prescribe a medication. This helps me to decide the dosage level at which to start. Costs Dr. Kroenke: I want to mention the issue of the cost of depression. In spite of excessive absenteeism and loss of productivity, there is still not much incentive for a managed care system to try to reduce that cost because it does not affect the monthly per-member capitation rate. Until a partnership exists between the employer and the payer that focuses on the cost savings of treating depression, not much is going to happen. Studies still have not shown a cost offset in the direct costs of treating depression. Dr. DePaulo: The expectation of a full cost offset, such as recouping the costs of care, suggests our motivation for treating depressed patients is that of saving money. Treating patients in a cost-effective manner is a necessity, but treatment effectiveness is the primary goal. C. Lindsay DeVane, PharmD VOL. 6, NO. 2, SUP. THE AMERICAN JOURNAL OF MANAGED CARE S43

6 ... PRESENTATIONS... Employer-Provider Alliance Dr. Goodman: I would like to emphasize Dr. Kroenke s point because it s crucial. An alliance between the employer and the healthcare provider makes it possible to undertake an overall assessment of the reduction in the cost of treating a depressed patient. Such costs are the employers burden rather than that of the insurance industry. If an alliance exists and the employer can determine the extent of absence or sickness caused by depression, that employer can decide whether treating depression is cost effective. Mr. Vodoor: It s fine to talk about cooperation between employers and managed care, but it may not happen. Managed care companies are trying to get employers cooperation, which is necessary to ensure managed care will continue as an entity to provide care for the patient. When Dr. DePaulo says that we should not treat depression simply to save costs, I agree with him. Unfortunately, business is also a concern. I think certain employers are beginning to work with managed care companies. The burden should be shared equally by employers and managed care. Insurers may have to decide if they must walk away when an employer does not prefer value over the bottom line when premium costs are considered. Prescription Preferences Mr. Urick: Prescription choices are a question of what providers perceive as valuable for the patient, and they are based on a perception of the comfort level of primary care physicians and specialists. Employers do not invest more time and effort in finding the value of treating employees for depression because they feel that such treatment is the responsibility of the health maintenance organization and the clinician, and that it is part of what they re buying. We need to help employers realize the return on the investment of treating depressed patients. It was mentioned today that $6 billion was spent through salesmanship and advertising to consumers to make physicians more comfortable with prescribing one drug as opposed to another. Managed care organizations and the pharmaceutical industry should direct more effort toward making employers more aware of the value of treating depression. Dr. Schreter: We don t generate data that are persuasive enough to payers. An article by Claxton and associates in the July issue of the Journal of Occupational and Environmental Medicine addresses the issue of whether antidepressant use reduces the number of missed workdays. 7 In that study, researchers compared the rates of absenteeism in 630 depressed workers before and after the initiation of antidepressant drug therapy. The authors discovered that on average the rate of absenteeism among depressed patients increased steadily from 1.5 days per month to 5.5 days per month during the 6 months before drug therapy was begun. After the initiation of drug therapy, the absenteeism rate began to decline. After 6 months of therapy, absenteeism had decreased to the point at which patients had returned to predepression levels of functioning. If we can generate such data, then we could demonstrate the value of providing drug therapy for depression. Hurdles to Treatment of Depression Dr. DePaulo: Providing treatment for depression can be difficult for several reasons. One is that most psychiatric care is carved out, it is not delivered S44 THE AMERICAN JOURNAL OF MANAGED CARE FEBRUARY 2000

7 ... PHARMACOKINETICS AND PHARMACODYNAMICS OF ANTIDEPRESSANT MEDICATIONS... by the provider who has the contract for providing general healthcare. As a result, providers of psychiatric care will be required to seek reimbursement from a separate management company. The majority of insurance plans in this country have management that is independent of both the insured and the care provider. Small employers will insist they cannot offer coverage for the treatment of depression because it will bankrupt them. You never hear that argument about providing treatment for cancer. Dr. Schoenbaum: What you do hear about is enhancing coverage for certain kinds of treatment and the resultant effect of the ability of small businesses to pay for health insurance. Dr. DePaulo: However, there are few diseases that accompany psychiatric illnesses where the disease is not covered. People don t argue that insurers shouldn t cover cancer, but they may say that insurers shouldn t cover expensive ineffective treatments. Mr. Urick: I think coverage legislation probably favors the treatment of mental illness as opposed to other diseases. The Mental Health Parity Act implies that companies cannot limit visits for the treatment of mental illness, so I don t believe we are missing the issue in terms of coverage. There are other areas more prone to progress. From a pharmaceutical perspective, most prescriptions for antidepressant drugs are written by primary care physicians. Psychiatry might be better served by educating other providers about better diagnosis and management of depression in the primary care environment as a way to control utilization. Time as a Barrier to Treatment of Depression Dr. Kroenke: In primary care, time is a barrier to the treatment of depression. Depression takes longer to treat, because in addition to educating the patient you often must reattribute the presenting symptoms to a psychiatric cause that you must destigmatize. After all, the patient came to you with a physical complaint. Psychiatry might be better served by educating other providers about better diagnosis and management of depression in the primary care environment as a way to control utilization. Even if over time you improve identifying an appropriate medication and initiating therapy, monitoring the patient s progress takes time. To meet the Agency for Health Care Policy and Research guidelines, at least 4 follow-up visits are required. In the primary care setting, depression is just another problem like diabetes or hypertension. I am not convinced that primary care physicians alone should be doing all the work, and I m not sure that all depressed patients should be referred to mental health professionals. Having a collaborative care model [CCM] in managed care as well as better systems to relieve the primary care physician of some of the responsibility of depression management would be very helpful. Dr. Jefferson: You re talking about the underrecognition, underdiagnosis, undertreatment, and inappropriate treatment of depression, but some psychiatrists apply the same errors to the treatment of panic disorder, social anxiety disorder, and obsessive-compulsive disorder by primary care physicians. Paul Urick, RPh VOL. 6, NO. 2, SUP. THE AMERICAN JOURNAL OF MANAGED CARE S45

8 ... PRESENTATIONS... Treatment Priorities Dr. DePaulo: All of us must be very critical in our reasoning about the priorities in the treatment of illness, whether we re talking about rheumatoid arthritis and depression or depression with obsessive-compulsive disorder, or anything else. Of the anxiety and depressive disorders, unipolar and bipolar depression and panic disorder have the greatest impact. The other problems can be treated without heavy involvement of the primary care physician. Many people experience a major depressive disorder [MDD], and the country s psychiatrists cannot provide treatment for all of them. Patients tend to segregate themselves; they don t all go to mental health providers when they are depressed. Those with the least severe depression tend to seek treatment from nonpsychiatrists. Mr. Vodoor: The managed care industry is not suggesting that primary care physicians should not provide care for depressed patients, but it is concerned about whether primary care physicians have the proper information to diagnosis depression correctly. Need to Motivate Stakeholders Dr. Kroenke: I think you re talking about systems support, as it is represented by the CCM, which is not widely disseminated outside research circles. We need to get other stakeholders motivated. Workplace studies must be conducted to determine whether treating depression has a beneficial effect on productivity. To date, it has not been convincingly demonstrated that treating depression reduces direct medical costs. Dr. Schreter: The burden is on us as researchers to demonstrate to employers that treating depression increases productivity, so that we can convince those employers to become more involved in that treatment.... REFERENCES DeVane CL, Jusko WJ. Dosage regimen design. Pharmacol Ther 1982;17: DeVane CL. Differential pharmacology of antidepressants. J Clin Psychiatry 1998; 59(suppl 20): Gilman PK. Serotonin syndrome: History and risk. Fundam Clin Pharmacol 1998;12: DeVane CL, Nemeroff CB. Psychotropic drug interactions: Primary Psychiatry 1999;6: Rosenbaum JF, Zajecka J. Clinical Management of antidepressant discontinuation. J Clin Psychiatry 1997;58(suppl 7): Markowitz JS, DeVane CL. Rifampin induction of sertraline metabolism and possible precipitation of SSRI withdrawal symptoms. J Clin Psychopharmacol In press. 7. Claxton AJ, Chawla AJ, Kennedy S. Absenteeism among employees treated for depression. J Occup Environ Med 1999;41: S46 THE AMERICAN JOURNAL OF MANAGED CARE FEBRUARY 2000