Academic Psychiatry 29:162-166, June 2005
© 2005 Academic Psychiatry
Old Versus New Medications: How Much Should Be Taught?
James W. Jefferson, M.D.
Dr. Jefferson is with Madison Institute of Medicine, Inc., Madison, Wisconsin and Clinical Professor of Psychiatry at the University of Wisconsin Medical School, Madison, Wisconsin. Address correspondence to Dr. Jefferson, Healthcare Technology Systems, 7617 Mineral Point Rd., Madison, WI 03717; jjefferson{at}healthtechsys.com (E-mail). Copyright © 2005 Academic Psychiatry.
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ABSTRACT
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OBJECTIVE: To address the issue of how much psychiatric residents should be taught about older medications. METHODS: Selective use of the literature, including historical overview, was employed to compare and contrast old and newer generation medications. RESULTS: While many old drugs are truly antiquated, medications such as typical antipsychotics, tricyclic and monoamine oxidase antidepressants, and lithium should remain integral parts of a psychopharmacology teaching program. CONCLUSION: A proper blending of knowledge about older and newer medications and the use of older and newer medications is in the best interest of patients in need of psychopharmcotherapy.
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INTRODUCTION
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Better a tried remedy than a newfangled one.
—Ambrose Paré
Consider the following scenario:
The senior faculty member peers over his bifocals and asks, with some optimism, ‘How many of you residents have used monoamine oxidase inhibitors [MAOIs]?’ Response, if you would call it response, involves blank looks of incomprehensibility. The faculty member, now feeling a bit like an old-timer, asks, ‘Well, what about tricyclics [TCAs]?’ The residents respond as a group: ‘We do not prescribe TCAs and never will, they are not well-tolerated and they sometimes kill—especially in the elderly.’
The faculty member tries once more, ‘Well, I suppose that lithium has been displaced by divalproex [Depakote] and the new anticonvulsants as a treatment for bipolar disorder.’ The residents’ response is rather harsh: ‘You suppose—we know.’ Why use a drug that is less well-tolerated, more toxic, more likely to interact with other drugs and diet, and is never promoted by a sales force? (2).
The issue at hand is not whether residents (and unenlightened others) should be taught about new medications, but whether it is prudent to indiscriminately replace the old with the new. In a global sense, most would agree that the therapeutic modalities of yesteryear have deservedly been relegated to the archives of history. After all, who would champion a return to the days of Benjamin Rush, whose treatment of choice for mania in 1812 was copious blood-letting (20–40 oz for starters) (3). Rush’s intervention came complete with justification based on etiological theory and clinical experience, which are justifications similar to those that we put forth today to allow us to embrace the latest fashionable medicinal marvel.
If one skims through literature on the history of psychopharmacology, it becomes abundantly clear that there are many old medications about which nothing should be taught. For example, Feldman (4) points out that in 1803, John Ford claimed success in treating hypomania with granulated tin preparations. And in an 1887 book, Spitzka championed conium as "the best and safest drug for mania." By the way, conium or Conium maculatum may be more familiar to you as poison hemlock. [If I might appear to be a tin skeptic, allow me to note that it has not been shown ineffective for treating hypomania, as far as I know. Additionally, another metal, chromium, has recently shown promise for treating depression (5)].
In his historical review of psychiatric pharmacotherapy, Ban (6) mentions morphine, potassium bromide, and chloral hydrate as three widely used and therapeutically effective drugs of the nineteenth century. Should we waste our time teaching about these old-timers? Probably not. First, let us discard the bromides, once used by the ton in psychiatric hospitals for their sedative effects [MacLeod wrote of the "bromide sleep" to treat acute mania (7)] and widely available over-the-counter (e.g., Peacock’s Bromides, Miles Nervine) but now rightly displaced because of their toxicity. Chloral hydrate, first synthesized in 1832, has faded from the scene as a hypnotic and now has limited availability. Opiates, one would think, have no role in the psychopharmacological arsenal, yet they pop up periodically as alternatives for dealing with treatment-resistant depression (8) and obsessive-compulsive disorder (9). These are best left in the hands of the specialist and, consequently, should not be part of a basic teaching curriculum.
Ban’s second period of pharmacotherapy covered the first half of the twentieth century—a period dominated by the barbiturates and amphetamines (used therapeutically for the most part). He reports that about 50 different barbiturates were on the market by mid-century, competing in terms of onset and duration of action (a competition repeated among the benzodiazepines when they took center-stage). Today, the barbiturates have virtually disappeared from the psychiatric scene, and any teaching of them would be of historic value only. But a point to be made in today’s era of "benzodiazepine bashing" is that the benzodiazepines displaced the barbiturates, in part, because the latter were potent enzyme inducers and potentially lethal respiratory depressants. The benzodiazepines represent true progress in the anxiolytic/hypnotic arena and continue to be prescribed widely today. They must remain part of our teaching agenda.
Amphetamines (and methylphenidate) have survived. While they are certainly not new medications (first used in the 1930s and immortalized shortly after World War II by Harry "the Hipster" Gibson in his memorable tune, "Who Put the Benzedrine in Mrs. Murphy’s Ovaltine") (10), they are still alive and well in psychiatry. Despite being Schedule II controlled substances with abuse potential, they remain first-line treatments for attention deficit hyperactivity disorder (ADHD) and narcolepsy, and they remain valuable adjuncts for managing certain aspects of depression. Along with the benzodiazepines, they must remain on the "teach about" list.
Currently, there are three major areas of old versus new medication contention: namely, typical versus atypical antipsychotics; MAOIs and tricyclics versus selective serotonin reuptake inhibitors (SSRIs) and other new generation antidepressants; and lithium versus anticonvulsant and other mood stabilizers. It is in these areas that resident knowledge about and utilization of the old has been shrinking in the direction of disuse atrophy. At issue is whether this atrophying process will cripple the ability of younger clinicians to provide comprehensive treatment or whether insisting that older drugs retain a prominent place in teaching programs will needlessly dilute more appropriate teaching about the new. Dwight-Johnson et al. recently came down very much in favor of the former as they decried the underuse of evidence-based pharmacotherapies for affective disorders (11).
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Typical (Old, First Generation) Versus Atypical (New, Novel, Second Generation, and Beyond) Antipsychotics
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Even though debate continues about how to define an "atypical" antipsychotic (D2/5HT2A antagonists, fast-off preparations, low risk of extrapyramidal symptoms (EPS)/ tardive dyskinesia (TD), more effective for negative symptoms, etc.), we all know that this rather heterogeneous cluster is currently composed of (in the U.S.) aripiprazole, clozapine, olanzapine, quetiapine, risperidone, and ziprasidone. With the exception of clozapine, none has been shown to be outstandingly more effective than other antipsychotics for treatment-resistant schizophrenia. In fact, a recent well-designed study found aripiprazole and the old standby, perphenazine, to be equally effective in a treatment-resistant population (12).
Should we continue to teach about the typical antipsychotics (at least a few of them)? The answer here is yes, for several reasons. First, there are many patients who have both benefited from and tolerated the older antipsychotics and who have no need to switch to something new for the sake of newness. Second, treatment resistance and partial response are all too common in schizophrenia, which has led to the frequent use of combination therapies despite a paucity of research to justify this approach. Nonetheless, combinations of atypical and typical or two or more atypical antipsychotics are quite common (just as combinations of typical antipsychotics once were). Third, many would argue, albeit without research support, that a patient should not be defined as treatment resistant without having failed an adequate trial of at least one typical antipsychotic. Finally, while, on the whole, the atypicals are better tolerated, they are not without their own blemishes. For example, there is growing concern about the metabolic syndrome and its complications with the long-term use of at least some of the new generation drugs (13).
Expert opinions based on systematic overviews, meta-analyses, and metaregression analyses suggest a certain disharmony in the field. Geddes et al. (14) concluded that, "Conventional antipsychotics should usually be used in the initial treatment of an episode of schizophrenia unless the patient has previously not responded to these drugs or has unacceptable extrapyramidal side effects." Davis et al. (15) reported that, "Consequently, at this time efficacy and EPS advantage necessitate the consideration of olanzapine, risperidone, and amisulpride as first-line drugs." Most recently, Leucht et al. reported that, "of the new generation drugs, only clozapine was associated with fewer EPS and higher efficacy than low-potency conventional drugs" (16). None of these metaanalyzing experts have suggested that teaching about first generation antipsychotics be relegated to oblivion. Overall, the newer antipsychotics seem to be leading the pack, although it would be premature to abandon the far less expensive typical antipsychotics.
A recent 12-month, double-blind comparison of olanzapine and haloperidol for schizophrenia found similar efficacy and study retention, although olanzapine was associated with more weight gain and "significantly greater VA costs, ranging from $3,000 to $9,000 annually." Societal costs, however, were not significantly different, and haloperidol was associated with more akathisia, more TD symptoms and more neurocognitive impairment (17). These findings left ample room for continued risk/benefit debate.
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MAOIs and TCAs Versus New Generation (SSRIs and Beyond) Antidepressants
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How much should be taught about monoamine oxidase inhibitors (MAOIs)? I say somewhat reluctantly, not much. Of course, there are still three nonselective, irreversible MAOIs on the U.S. market (phenelzine, tranylcypromine, and isocarboxazid), and the reversible inhibitors of monoamine oxidase A (RIMAs) continue to poke about on the horizon. We have all heard the adage that true treatment resistance must include failure to respond to at least one MAOI. Nonetheless, there are so many better tolerated, safer alternatives available that few patients will need an MAOI and few clinicians will have occasion to prescribe one. That said, these very same clinicians still need to know enough about these drugs to appreciate their benefits and risks, and to know when and how to refer patients to the few specialists who have the expertise to use them appropriately.
Are we ready to discard the tricyclics? Here the answer is a more emphatic "no." Anderson (18) reviewed 18 meta-analyses of comparative trials of antidepressants. Some of the conclusions he reached with "high confidence" include: "little difference in efficacy between most new and old antidepressants and a different side effect profile of SSRIs to TCAs, with superior general tolerability of SSRIs over TCAs." With a "lower level of confidence," Anderson found TCAs more efficacious than SSRIs in in-patients, amitriptyline more effective than SSRIs and no tolerability difference between the two classes in the elderly. Few would suggest that TCAs should be used in preference to the newer antidepressants—even in in-patients—especially because of better tolerability and safety of the latter. But few would fail to consider tricyclics as viable treatment alternatives both as monotherapy and in combination with newer antidepressants. It should be quite clear, however, that with growing emphasis on the long-term treatment of depression, compliance becomes an even larger issue and tolerability plays a major role in promoting compliance. Here, the tricyclics are losers, although not to the extent that is often portrayed by proponents of the newer antidepressants. Finally, when it comes to the treatment of chronic pain conditions, the tricyclics have, thus far, more than held their own in comparison to the newer generation drugs (19). Whether this remains so as better tolerated nontricyclic mixed uptake inhibitors (e.g., venlafaxine, duloxetine) evolve remains to be seen.
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Lithium Versus Anticonvulsant and Other Mood Stabilizers
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Europeans must look somewhat quizzically at the prescribing pattern for bipolar disorder in the U.S. Geddes and Goodwin (20) refer to the U.S. as being "the most unusual" among the extreme variations in mood stabilizer prescribing patterns seen from country to country. This, according to Geddes and Goodwin, is in part due to "the widespread and dramatic increase in the use of valproate... and the decrease in the use of carbamazepine and lithium." Goodwin (21) remarks that the dramatic shift in bipolar prescribing toward anticonvulsants in the U.S. (at the expense of lithium) "more closely reflects marketing and continuing medical education (CME) discrepancies than it does differences in effectiveness." Baldessarini et al. (22) state that, "No other treatment has performed as well as lithium in as many aspects of long-term care of bipolar disorder patients, and despite some risks and limitations, lithium remains the standard against which all proposed alternatives are compared." Add to these observations the rather convincing evidence that lithium reduces suicidal behavior in bipolar patients (23), and it becomes difficult to accept that many residents are completing training without sufficient knowledge and experience to feel comfortable using this drug.
There is no question that lithium is now considered an old drug, even in the U.S., where it was first approved for the treatment of acute mania in 1970 and for maintenance therapy in 1974. There is also no question that other medications have well-established roles in the treatment of bipolar disorder [Food and Drug Administration (FDA) approval of divalproex for mania in 1995; olanzapine for mania in 2000; lamotrigine for maintenance in 2003; and still more recently aripiprazole, quetiapine, risperidone, ziprasidone, and extended-release carbamazepine for mania; olanzapine and aripiprazole for maintenance; and olanzapine/fluoxetine combination for bipolar depression]. In addition, a vast amount of clinical experience as well as anecdotal reports and case series strongly support benefits from divalproex beyond acute mania. Nonetheless, there is no rational explanation for the apparent fade of lithium into the background of bipolar prescribing practices in the U.S. Less than reasonable explanations include: its unjust portrayal as an extremely dangerous, neurotoxic, nephrotoxic substance; its generic availability and, hence, its lack of marketing muscle; the premature glorification of the newest of the new based only on case reports and anecdotal experience (remember that writing and publication biases favor articles with positive outcomes); and the general tendency of the young to view the old with distrust.
The final areas to address with regard to "old versus new: how much should be taught" have to do with the total amount of time a training program devotes to formal psychopharmacology teaching and the availability of postgraduate education. A training program that minimizes the value of psychopharmacology will direct its minimization at older drugs. A training program trapped by today’s financial incentives to see more and more patients in less time will find it difficult to devote sufficient didactic teaching to psychopharmacology in general and to older drugs more specifically. The situation becomes even worse when it comes to postgraduate education, which is heavily dependent on industry support. It is not that industry support is necessarily bad for education (where we be without it?), but, to quote Healy (24), "there is a real sense at present then, that knowledge in psychopharmacology does not become knowledge unless it has a certain commercial value." In general, old drugs are generic drugs and generic drugs are relatively inexpensive. However effective they may be, there is little commercial incentive to promote them in contrast to the moneymakers still under patent protection.
The American Society of Clinical Psychopharmacology (ASCP) has developed a comprehensive psychopharmacology treatment program available to psychiatric residencies (for a fee) that provides a reasonable balance between the old and the new. Stating so here is intended to be less of a sales pitch (I have contributed to this program) and more a reminder that the proper balance of old and new is essential to the effective teaching and practice of psychopharmacology. When faced with complex, treatment-resistant patients, primary care physicians will continue to refer to psychiatrists for help. Psychiatrists, in turn, will be best equipped to meet these challenges if they are able to adeptly integrate the use of new and old drugs. The hope of the future is that better and better, safer and safer (and less and less expensive) medications will continue to evolve and will, therefore, be completely justified in displacing their older and less perfect counterparts. Until then, at least some of the old must coexist with the new. After all:
Is it progress if a cannibal uses a knife and fork?
—Unkempt Thoughts, 1962
Stanislaw Lec 1909–1966 (25, p 415, #10)
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ABSTRACT
INTRODUCTION
