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We are pleased to publish an offering from our sister publication The Primary Care Companion to The Journal of Clinical Psychiatry about a topic of high importance to all physicians. This special commentary is Larry Culpepper. M.D.; Jonathan R. T. Davidson, M.D.; the first independent project undertaken by Allen J. Dietrich, M.D.; Wayne K. Goodman, M.D.; Kurt Kroenke, M.D.; and Thomas L. Schwenk, M.D. interests between psychiatry and primary uicide is a tragic but not uncommon outcome to psychiatric illness. The risk and rate of suicide among those who are mentally ill are published in Prim Care Companion J Clin higher than among the general population, and much effort has been made by researches and clinicians in both psychiatry and primary care to find ways to prevent suicide in these patients. However, reports that anti-depressant use can be associated with an increase in suicidal thoughts and behavior are cause for concern and have resulted in the public health advisory issued by the U.S. Food and Drug Administration (FDA) in March 2004. This advisory contained warnings relevant to 10 popular antidepressant agents (Table 1): for a summary of the warning information Issues Involved in the FDA's Assessment of
Drug Administration (FDA) issued a health Whether Antidepressants Are Associated With Increased Suicidality
Dr. Culpepper: Let me begin by posing some basic questions. What
are the issues involved in the FDA's assessment of whether antidepres- depressants have been asked to include a sants are associated with increased suicidality and potentially dangerous warning statement on product labeling. This behavior? What was this advisory based on, and why was it released now? Dr. Goodman: This investigation started with a focus on the pediatric
population during the meeting of the FDA Psychopharmacologic Advi- sory Committee and the Pediatric Subcommittee in February 2004. We monitored for worsening of depression or were presented with primarily unpublished data, particularly the results of emergence of suicidal behavior. The full text 15 clinical trials of antidepressants in pediatric depression, that were sub- mitted to the FDA. No child in those studies completed suicide. One might expect that worsening depression led to suicidal behavior and that this behavior would be more common in the placebo-treated groups, but that was not what was found. There was a stronger signal in some of the stud- ies for suicidal behavior or suicide attempts, depending on how it was defined, in the drug-treated groups compared with the placebo-treated groups. This result was not uniform, however. In addition, in contrast to what we see with adults, particularly with the selective serotonin reuptake inhibitors (SSRIs), the demonstrated improvement compared with pla- cebo in this pediatric population was not large. In fact, only 3 of 15 studies Primary Care Companion, assembled a submitted to the FDA were considered positive. Others were either failed Dr. Culpepper: In other words, there is a persistent trend that emerges
and advise clinicians how it will affect from these data, although these data were not collected specifically to Dr. Goodman: To put these events and findings in context, you have
to remember what happened more than 10 years ago with the1 report from Teischer and coworkers [Am J Psychiatry 1990:147:207-210] that Faculty affiliations and disclosures appear at raised concern about fluoxetine-induced suicidality in adults. Thereafter, careful large-scale studies examined suicidality in fluoxetine-treated Table 3. Symptoms of Activation Syndrome Panic attacks Akathisia (severe restlessness) Citalopram Mirtazapine a For more information about the advisory, go to Dr. Culpepper: How did the FDA, expand its focus
from children and adolescents to include adults as well? Table 2. Summary of Warning Information From Dr. Goodman: The initial focus was clearly on the
the FDA Public Health Advisory__________________________ pediatric population. However, 63 public testimonials Although no conclusion has been reached regarding the causal were also presented at the meeting. These were anecdotal relationship between antidepressant treatment and increased suicidality, health care providers should carefully monitor reports, and the most typical ones were by bereaved antidepressant-treated patients for worsening of depression or parents talking about their teenaged or young adult child emergence of Suicidality, especially at the beginning of treatment and after any change in dose who had committed suicide shortly after starting If depression worsens or suicidality emerges in an antidepressant treatment. My speculation is that there antidepressant-treated patient, health care providers should was some influence from those anecdotal reports, which evaluate the patient carefully to determine what intervention is needed (including stopping or changing the antidepressant If you read the FDA advisory carefully, it does not Activating symptoms (see Table 3) may be a signal of worsening establish a firm, causal connection between suicidality depression or increased suicidality in some patients. Health care providers should carefully evaluate any patient who develops these and these antidepressants. There is also a focus on the symptoms, especially if such symptoms were not pan of the original so-called "activation syndrome," which may or may not If an antidepressant medication needs to be discontinued, it should be be a precursor to suicidal behavior. It may be that the FDA realized that it needs to make all clinicians aware that pa- Before starting a patient on antidepressant treatment, the health care tients in all age groups may be sensitive to these drugs in provider should carefully screen that patient for bipolar disorder Health care providers need to educate patients and their families or other caregivers to be watchful for worsening depression. emergence of suicidality, and activation symptoms and encourage Activation Syndrome
them to report any changes to their health care provider Dr. Culpepper: From both psychiatric and primary
To see the complete advisory, go to amidepressants/default.htm and click on "Public Health Advisory."' care perspectives, is the concept of an activation syn-drome new, or are prior concerns being repackaged (Table 3)? patients [Leon AC, et al. Am J Psychiatry 1999:156: Dr. Dietrich: Thinking back to the age before SSRIs,
195-201; Khan A, et al. Int J Neuropsychopharmacol I remember in medical school being told that when you 2001:4:113-118: Storosum JG, et al. Am J Psychiatry prescribe an antidepressant, you had to monitor the pa- 2001;158:1271-1275], and any suspected relationship tient very carefully during the initial phases of treatment. was largely debunked. The difference now is the relative The effects of the antidepressant would sometimes allow strength of the pediatric data. We needed to consider patients the motivation and energy to act on an impulse or these data seriously and not just harken back to the previ- desire that their depression had previously kept them from acting on. This activation syndrome seems similar One result to consider is that the signal of suicidal be- but with increased specificity and a new label. havior was higher in drug-treated patients than Dr. Davidson: I agree to some extent. Even before
placebo-treated patients in some of the 15 studies SSRIs, we were told to be careful in the first week or two presented. It was not a consistent effect by any means. In of antidepressant treatment, including electroconvulsive fact, the risk ratio was elevated in only 3 of the studies. therapy. The activation preceded the improvement of de- Data from 25 pediatric studies were analyzed, pressed mood and suicidal thoughts, so suddenly patients comprising more than 4000 patients and including the J5 had the energy to carry out things that they had been depression studies and 1 other depression study, 4 somewhat inhibited from doing because of retardation or obsessive-compulsive disorder studies, 2 generalized anxiety disorder studies. 2 attention-deficit/hyperactivity There are a couple of factors to consider. One is that disorder studies, and 1 social anxiety disorder study. In any antidepressant treatment may, in the early phases, all, 109 patients experienced 1 or more events that were provoke suicidal behavior, but that doesn't really answer considered "possibly suicide related." the problem under discussion, because these reports of self-destructive behavior are not all early side effects. which we have all seen for the entire time we have been They seem to be scattered throughout the entire period of working with patients. This advisory does return our fo- cus to close follow-up and monitoring as well as making A second observation is that we have definitely known appropriate adjustments when treating depressed patients, for some time about what used to be called the but I am unconvinced that antidepressants regularly trig- antidepressant jitteriness syndrome. I have seen this ger some ominous, discrete event that spins into a high syndrome more in patients with panic disorder or somatizing anxiety; these patients may get very agitated and then become distressed by that agitation. In my Management of Patients
experience, they do not often become suicidal. Overall, if Already Taking Antidepressants
you see a patient with these symptoms, you have to Dr. Culpepper: We all have patients of a variety of
determine if there may be complicating symptoms of ages who are taking antidepressants, and many of them panic attacks or unrecognized anxiety, or, for that matter, have probably heard the news reports about the FDA ad- patients with undiagnosed bipolar disorder. These issues visory and other news stories about suicide and antide- are of some concern in determining what is meant by pressants. The advice from the FDA is that concerned pa- tients should call their physicians—we are the physicians Dr. Culpepper: I was perplexed about the activation
in question, so what do we tell patients who are concerned syndrome because as I read the FDA's description of symptoms (see Table 3). I was reminded of an idiosyn- Dr. Schwenk: Early, close follow-up has always been
cratic reaction that I have seen in some patients—for ex- recommended but has not always been done as it should ample, an anxiety patient started on treatment with be. We must take these issues seriously and remember that full-dose fluoxetine who comes in for a follow-up visit these are powerful medications used to treat a powerful pacing and reporting inability to sleep. In other words, I disease. However, what primary care physicians do well are substantive and detailed discussions of side effects Dr. Goodman: I think for the most part, the committee
and functioning. We need to have these discussions with was talking about early side effects on the basis of clinical our antidepressant-treated patients as often as necessary impressions, including the anecdotal reports of parents in until we—doctor and patient—are both convinced which suicide seemed to be a problem in the early phases of the treatment. If this is the case, it would coincide with Dr. Culpepper: It does seem like we have moved
what Drs. Davidson and Culpepper mentioned, the need from a time when a new patient with depression came to be careful with the anxious patient and to start such a in weekly at the beginning of treatment to now, when patient with a low dose, monitor carefully, and raise the we will telephone a new patient for follow-up and then see that patient in the office 3 or 4 weeks after initiating In addition, multiple mechanisms might account for treatment, if not up to 6 or 8 weeks. Is this a wake-up call this activation syndrome or behavioral toxicity. In fact, that our treatment paradigm may have gotten too slack? during the 1991 committee meetings that followed Dr. Kroenke: With the older antidepressants, I think
Teischer and coworker's original report on part of the reason that we might have had them return ear- fluoxetine-induced suicidality. Dr. Teicher presented a list lier was often for something other than monitoring for ac- of possible mechanisms to explain suicidality. An tivation. We had to titrate the older drugs more often, and example is the rollback phenomenon, which is an older the newer ones have lulled us into thinking that one dose term that describes a patient with melancholic depression may fit all and, even if it does not, we usually find we or psychomotorically retarded depression who becomes need to adjust the dosage less often. Second, the older activated after treatment. However, the committee felt agents are toxic and possibly lethal if overdosed, so we that this phenomenon probably occurs rarely in the were very cautious in following up with new patients and pediatric population, in which few depressed children are gave them limited amounts of the drug. The SSRIs and psychomotorically retarded. Another item on this list is newer antidepressants have decreased a lot of that fear of stage shifts from depression to mixed or manic states in patients with undiagnosed bipolar disorder. Dr. Dietrich: Doling the medicine out carefully was
Dr. Culpepper: Other mechanisms on that list are
certainly much more a part of my practice with the paradoxical worsening of depression, akathisia, and tricyclic antidepressants (TCAs) than it is with the insomnia, in addition to induction of anxiety and panic at- SSRIs. I have also found that my patients are less tacks. The activation syndrome, then, may cover a set of interested in coming back for an office visit 1 or 2 weeks behaviors that may have several different origins. after starting an antidepressant. Many of these patients are Dr. Schwenk: We are dealing with a very loosely
managing to work in spite of the depression and are defined and heterogeneous group of problems, many of Table 4. Timeline of Regulatory Action on Antidepressants in event was the decision by the regulatory body in the United Kingdom to contraindicate or discourage the use The Medicines and Healthcare Products Regulatory Agency of all SSRIs except fluoxetine in the pediatric population. (MHRA) in the United Kingdom issued a warning The reason given was that few data supported the use about the use of paroxetine in children younger of these agents in children, and therefore the risk-benefit The FDA recommends that paroxetine not be used ratio was unfavorable. In a sense, the decision that the in children or adolescents due to increased risk FDA came to was a compromise that indicated that, on one hand, they realized there are insufficient data to es- Labeling for venlafaxine changed to clarify that the tablish a direct connection between these medications agent is not recommended for use in children; "Dear Health Care Professional" letter sent by and suicidality, yet on the other hand, they also realized that there has been insufficient attention paid to some of MHRA advised against the use of venlafaxine in the early side effects of antidepressant treatment that may or may not be precursors to suicidal behavior. MHRA advised against the use of a l l SSRIs except fluoxetine in children: paroxetine. venlafaxine One of the presentations made at the February sertraline, citalopram, and escitalopram are 2004 FDA meeting was by David Shaffer, F.R.C.P., contraindicated in this age group, while the use of F.R.C.Psych. He presented suicidal trend data for the adolescent population and showed very clearly a reduc- Committee and the Pediatric Subcommittee of the tion in suicide from 1995 to 2000, the period in which Ami-Infective Drugs Advisory Committee held a SSRIs became the first-line treatment for depression public meeting to review data and reports of (Ftgure1). The introduction and increased use of SSRIs antidepressant-induced suicide in children and may not solely account for this decrease, but Dr. Shaffer FDA issued a public health advisor) warning was unable to exclude them as contributing to the lower clinicians to observe child and adult patients suicide rate (go to closely to monitor for worsening depression and/or suicidality. ac/04/slides/4006S l_03_Shaffer.htm to view the slide Abbreviations: FDA = U.S. Food and Drug Administration. SSRI = selective serotonin reuptake inhibitor. Overall, even in the pediatric population, these drugs have done more good than harm and have saved lives. However, a cautionary note is warranted to remind physi- work again so soon after the first office visit. Williams cians, patients, and family members that some and colleagues conducted a national survey of primary patients-children in particular—have adverse behavioral care physicians and discovered that the average time to reactions in the early phases of treatment. Everyone follow-up visit was almost a month for patients with involved in the patient's care and treatment should look major depression and longer than a month for patients out for these reactions and the physician should alter with dysthymia and minor depression [Arch Fam Med the treatment as needed—adjust the dose of the 1999:8:58-67]. For whatever reason, follow-up visits medication, stop the medication, or add another occur less often than many of us would like to see. Dr. Kroenke: One thing that confused me is that the
Dr. Culpepper: Let us narrow this down to some
FDA is recommending a label change for these 10 newer pragmatic advice. One of your patients who have been antidepressants (see Table 1) but not for the older agents taking an antidepressant for some time asks you. "I've such as the TCAs. Does this mean that the FDA considers read this stuff in the newspaper: should I stop taking my this issue of activation irrelevant with the TCAs? Another antidepressant?" What do you tell him or her? question is how do you separate common initial side ef- Dr. Schwenk: I would first ask the patient if he or she
fects of an antidepressant, which many of these symptoms has been experiencing any of the side effects or symp- that we have discussed are, from an actual syndrome that toms that are described in the health advisory. If so, I would ask the patient to come in so that we can assess the Dr. Davidson: This advisory started with data on
situation. If not, reassurance is all that is necessary. children, and my impression is that TCAs are used in-frequently in children because of some of the earlier stud- Management of Patients
ies showing cardiovascular risks. These agents certainly Who Need Treatment With an Antidepressant
should have been included in the FDA advisory, which Dr. Culpepper: Let us move on to discuss patients
who need treatment with an antidepressant. For example, Dr. Goodman: The FDA's action in issuing the health
you evaluate a patient who scored a 20 on the depression advisory was of course preceded by the action of the section of the Patient Health Questionnaire (PHQ-9), British counterpart to the FDA (Table 4), The seminal which indicates severe depression, but who has never re- ceived antidepressant treatment. How do you proceed? Figure I. Changes in Youth (aged 15-24 years) Suicide Rates in the United States During the 20th Century" "Modified from David Shaffer's slide presentation "Suicide and "Related Problems in. Adolescents," given at the Feb. 2. 2004, meeting of the Psychopharmacologic Advisory Committee and the Pediatric Subcommittee of the Anti-Infective Drugs Advisory Committee of the U.S. Food and Drug Administration [FDA]. Available on the FDA Web site at: l-03-Shaffer.htm. Dr. Kroenke: I would have a conversation with the pa-
Table 5. Questions to Ask Depressed Patients Who Express Suicidal Thoughts __________ ___ tient that focuses specifically on suicidality, rather than a Have you made a plan for committing suicide? broad array of symptoms, to determine whether he or she How seriously are you thinking about it? had thoughts of death or dying and active thoughts about What is stopping you from committing suicide? planning it—in other words, I would try to determine Do you have weapons in your home? What kind of emotional support system do you have? if there was risk of suicidality. I would have this discus-sion on the day treatment begins. The higher the risk, the more likely it would be that I would involve mental health Managing Antidepressant-Treated Patients
Who Report Increased Suicidality
Dr. Culpepper: What if, when you inquire about sui-
Dr. Culpepper: From a psychiatrist's perspective,
cidality, the patient says, "Oh no, I would never do that. how would you now handle referrals from primary care I haven't had any serious inclination that way." Do you physicians of depressed patients who have become sui- simply start medication treatment? Do you now, since the cidal? For example, let us say that I have a patient who advisory, want to get a written consent before starting one day remarks to me that she has been thinking about medication? What do you tell the patient about the FDA suicide, that one of her aunts committed suicide by over- dosing on pills, and that that option is looking appealing Dr. Dietrich: If I am satisfied that the suicide assess-
to her. I refer her for psychiatric consultation. What are ment is negative and that the patient has neither passive you going to do as my psychiatric consultant for this pa- nor active thoughts of death at this time, I would next tient? In particular, how might you deal with her differ- go into the business of patient preferences—whether the patient prefers a counseling approach or a medication Dr. Davidson: First, I would be sure to do a careful
approach. Assuming that the patient prefers medication evaluation of suicide risk (Table 5). If there appears to be either alone or in addition to counseling, I would review a fairly serious risk, I would consider hospitalizing the pa- side effects, as usual, but now I would call the patient's tient or at the very least entering into a contract with her in attention to the recent FDA warning and tell him or her which she promises not to commit suicide and to call me what symptoms to watch out for. I would inform the pa- or another person if and when Serious thoughts about it tient that, for this reason, I will be monitoring his or her cross her mind. If the risk does not seem acute, then I response to medication closely, and I would also ask the would tell her that she needs immediate treatment. The patient to touch base with me the following week. more suicidal the patient is, the more compelling the case help prevent this tragic outcome. We all—psychiatrists for prescribing a medication as opposed to counseling, in and primary care physicians alike—must be careful in the my opinion, I would talk about the medications with her early phases of treatment, particularly when treating chil- and say. "You probably have heard about the concerns in the media and from the FDA about whether these drugs can make you more suicidal, and in my judgment, it is un- Managing Antidepressant-Treated Patients
likely to happen.” I would reassure her that it is more Who Report Activation Syndrome
likely that she will improve with antidepressant treatment, Dr. Culpepper: What about patients who report not
but that we would need to stay in close contact, especially overt suicidality but symptoms of activation syndrome? during the first few weeks of treatment. I would also in- For example, what course of action do you take with a volve a spouse, family member, or close friend in her care patient who has been taking an antidepressant for 2 weeks to make sure someone is always available as support. and who calls you to report feeling unbearably on edge Dr. Culpepper: What if the patient is a 16-year-old
boy with some symptoms of obsessive-compulsive disor- Dr. Schwenk: Assess suicidality and make a decision
der and other anxiety in addition to the suicidal thoughts? on that basis. If the patient has been on treatment for only Dr. Goodman: Dr. Davidson's answer was compre-
2 weeks, I would probably tell him or her to stop taking hensive, but I would add that with a patient with anxiety, the medication and see me as soon as possible. it may be wise to start at a lower dosage than you nor- Dr. Culpepper: Would anybody taper medication?
mally would in depression without a concomitant anxiety Dr. Goodman: It might be only necessary to lower the
disorder. I would also warn patients like this that they dose. That is an individual decision, whether to stop treat- might feel a little bit anxious or jittery when they first start ment or taper the dose. You should not increase the dose at the medication and that they should call me if they feel uncomfortable. This is assuming that I have come to some It seems somewhat analogous to the situation of differ- sort of agreement with them, as Dr. Davidson recom- entiating akathisia from worsening of psychosis—you mended, and that they can be maintained on an outpatient cannot assume that the symptoms represent a worsening of the underlying condition without first testing to see if With an adolescent, we also need to realize that the they are due to the medication. You conduct this test by efficacy of these agents may be different. The thrust of the stopping the medication, adding an adjunctive agent, or regulatory action in the United Kingdom, after all, was lowering the dose of the original medication. that the data demonstrating the efficacy of the SSRIs Dr. Culpepper: In the primary care setting, how do we
(except fluoxetine) in younger patients were weak or non- differentiate this activation syndrome in an existent. It was that lack of evidence that made the antidepressant-treated patient from undiagnosed bipolar risk-benefit ratio weighted more on the risk side, given disorder? Symptoms of activation syndrome seem similar the signals of suicidal behavior in this age group. A to those of antidepressant-induced mania or rapid cycling. recent article reviewed those data, published and Is that a diagnostic issue that we can deal with in primary unpublished, in more detail [Whittington CJ, et al. Lancet 2004:363: 1341-1345]. Dr. Schwenk: A key point here is that primary care
When treating adolescents, it is also important to re- physicians like myself must become more expert in the member that they may not be as effective as adults in verbalizing their experiences. They may feel diagnosis and treatment of patients with bipolar disorder, uncomfortable or anxious but unable to describe those which has become much more prevalent in our practice sensations adequately. I think you need to go out of your than it used to be. In the past, most patients with bipolar way with adolescents to urge them to contact you early in disorder were referred to a mental health specialist, but the stages of treatment—even before their next office now, for a variety of reasons, many are being treated by visit—if they feel worse in any way, and then it will be primary care physicians. I try to be much more attentive your job to determine whether those feelings indicate to these symptoms of agitation, irritability, and worsening depression or are side effects of the medication. My suspicion is that some young adults and Dr. Dietrich: When I initiate treatment with an antide-
children have considered or even committed suicide pressant, I try to gather a careful history in terms of both because they did not have a way of understanding that the patient's own previous episodes that might have been what had happened to them was a result of negative hypomanic and family history. I warn at-risk patients to effects of the drug. Perhaps if we can share more be watchful for these symptoms, and when I see a patient information with young patients to help them recognize who appears to be switching into a manic episode, 1 have that unpleasant sensations and feelings might be the luxury of getting a quick psychiatry consultation that many primary care physicians may not have. 1 can easily get help from one of my psychiatry colleagues in sorting out whether a patient may be on the verge of a bipolar especially if these informants are educated about the ill- ness and asked to watch out for certain types of changes. Dr. Culpepper: What about the primary care physician
who has few if any opportunity for psychiatry consultations, Concluding Thoughts
for example, a doctor who works in a rural area and may be Dr. Davidson: One point that we need to make is the
a hundred miles from the nearest psychiatrist? What are fact that there are good trials in children and adolescents other possibilities for managing a patient who is with anxiety disorders—obsessive-compulsive disorder, experiencing activation symptoms? Would you ever think social phobia, and generalized anxiety disorder—that about prescribing atypical antipsychotics to this type of have reported a positive signal in favor of the efficacy of the newer antidepressants. There is virtually no evidence Dr. Schwenk: Absolutely. We as primary care physi-
from the available database that the incidents mentioned cians have to be much smarter about using mood stabiliz- in the FDA advisory have taken place in the anxiety popu- ers and atypical antipsychotics and not be as averse to us- lation. We need to keep this very much in mind because we are obligated to help our teenaged patients who de- Dr. Culpepper: Would you consider ordering a toxicol-
ogy screen in this type of patient? I have seen patients with Dr. Kroenke: I am concerned about generalizing
increased irritability and agitation who denied using alco- study results and treatment strategies regarding hol or illegal drugs, but their toxicology results were children to adults and vice versa. For example, it may be positive for cocaine, which of course can explain those easier to involve an informant with a young patient whose symptoms. Has anyone else had that experience? parents are involved in every level of treatment. With an Dr. Davidson: In many of the clinical scenarios we
adult patient, however, you often see the patient as an have discussed, we need to make sure that the patient is adult alone. The logistics of trying to contact a family avoiding alcohol and illegal drugs. I have certainly seen member to participate in treatment and negotiate the patients who have appeared to be irritable and impulsive and then discovered that they have mixed alcohol with Dr. Culpepper: Those are both good points. When
their medication. We should always inquire about alcohol I think about suicidality, I am reminded of the Institute of Medicine's report on preventing suicide [http:// Dr. Culpepper: Earlier in the discussion, we touched on id=3843]. One of the points in contracting for safety. Does the FDA advisory about ac- that report is that depression is often in the background of tivation and suicidality alter your perspective on the suicidal behavior, but that anxiety is often there as well. effectiveness of contracting for safety? Two other critical ingredients that heighten the risk of sui- Dr. Schwenk: I believe that contracting is something
cide are impulsivity and substance abuse, which become that primary care physicians have been taught to have quite lethal when combined. How can clinicians quickly some faith in, but my sense is that psychiatrists may not Dr. Dietrich: With patients whom I have been treating
Dr. Culpepper: I have been unable to pinpoint any sci-
for years and see fairly often, I have an intuitive sense entific evidence that said that contracting works or does not of their baseline level of impulsive behavior and can de- work. Is it something that is unique to primary care, as Dr. tect changes. The challenge comes with a new patient who may evoke some concern in this area. In that case, I would Dr. Goodman: I have some hesitations about contract-
ask many of the same assessment questions that Dr. ing. If you accept the possibility that in some individuals, Davidson suggested (see Table 5), about emotional sup- by whatever mechanism, these medications can induce a port systems, use of drugs or alcohol, and availability of state change, then you have to wonder how good a safety firearms and other means of harming oneself. I would also contract with one of those individuals will be. In that situa- ask that patient about his or her decision-making process tion, you will not be dealing with a patient in the same state to determine if the patient tends to make snap decisions. as when you wrote the contract with him or her. We should When treating somebody new, I try to be careful about try to discuss the patient's state of mind with an infor- understanding those issues and where they fit into the mant—a spouse, close friend, or, in the case of a child or patient's life and try to explore them in a nonjudgmental adolescent, a parent. Certainly in the case of an adolescent, if you are able to get information from a parent that the pa- In some situations, even with patients I think I know tient has been acting strangely, more hostile, or more well, I will ask directly about impulsivity. Patients have irritable since the medication was started, that would be surprised me with their answers, especially those whom I see as nonimpulsive but who see themselves as impulsive Dr. Davidson: It is important to involve a significant
or report times in their life when they have been impulsive. other to determine if there have been changes in behavior. Disclosure of off-label usage: The chair has determined that, to the best Table 6. Web Sites With Information About the of his knowledge, bupropion, citalopram, escitalopram, mirtazapine, U.S. Regulatory Actions on Antidepressants nefazodone, paroxetine, sertraline, venlafaxine, and fluvoxamine are not Antidepressant use in children, adlescents, and adults: approved by the U.S. Food and Drug Administration for the treatment of pediatric depression. If you have questions, contact the medical affairs department of the manufacturer for the most recent prescribing FDA statement regarding the antidepressant Paxil for the From the Department of Family Medicine, Boston Medical Center, Antidepressant medications for children; information for parents Boston, Mass. (Dr. Culpepper); the Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, N.C. (Dr. Davidson); the Department of Community and Family Medicine, Dartmouth Medical School, Hanover, N.H. (Dr. Dietrich); the Depart- ment of Medicine, Regenstrief Institute, Inc., and Indiana University, Indianapolis (Dr. Kroenke); the Department of Psychiatry, University of Florida, Gainesville (Dr. Goodman); and the Department of Family Medicine, University of Michigan Medical Center, Ann Arbor (Dr. Schwenk). Dr. Culpepper: Is impulsivity a steady state or is it
In the spirit of full disclosure and in compliance with all ACCME Dr. Davidson: It can change and, in my experience,
Essential Areas and Policies, the faculty for this CME activity was SSRIs do alter impulsivity. They tend to control it rather asked to complete a full disclosure statement. The information received is as follows: Dr. Culpepper is a consultant for Cephalon, Forest, Eli than loosen it. However, we need to ask patients not only Lilly, Pfizer, Somerset, and Wyeth. Dr. Davidson has received speaker about suicidal impulses but aggressive impulses in gen- fees from Solvay, Pfizer, GlaxoSmithKline, Wyeth, American Psychiatric Association, Forest, and Eli Lilly; is a scientific advisor for eral, and we need to monitor patients closely to determine Solvay, Pfizer, GlaxoSmithKline, Forest, Eli Lilly, Ancile, Roche, how antidepressant treatment changes impulsivity in each Novartis, Organon, Boehringer Ingelheim, UCB Pharma, Pharmacia, Johnson & Johnson, Boots, Bristol-Myers Squibb, Cephalon, Nutrition 21, and Sanofi-Synthelabo; has received research support from Pfizer, Dr. Culpepper: We as physicians must of course avoid
Solvay, Eli Lilly, GlaxoSmithKline, Wyeth, Organon, Forest, Pure doing harm to our patients with the treatments we pre- World, Allergan, Nutrition 21, Bristol-Myers Squibb, UCB Pharma, and scribe. However, we must balance that with the possibility Cephalon; has had drug supplied for NIH and other studies by Eli Lilly, Schwabe Pharmaceutical, Pure World, and Pfizer; and has received of inflicting harm by withholding possibly beneficial or royalties from MultiHealth Systems, Guilford Publications, American lifesaving medications. The points we have emphasized Psychiatric Association, and Penguin Putnam. Dr. Dietrich is on the speakers/advisory boards for Forest, Pifzer, and Wyeth. Dr. Goodman here are neither new nor ominous, but reflect good clini- is an employee of the University of Florida Department of Psychiatry, cal practice: begin antidepressant treatment carefully, has received grant/research support from Eli Lilly, Forest, monitor patients closely, and watch for signs of untoward GlaxoSmithKline, Pfizer, and Wyeth; and is a consultant/speaker for Bristol-Myers Squibb, Eli Lilly, Forest, Janssen, Pfizer, Roche, and side effects, worsening symptoms, and increased Solvay. Dr. Kroenke has received grant/ research support from Eli Lilly suicidality. More information about the FDA advisory and and Wyeth, has received honoraria from Pfizer, and is on the regulatory action in the United States can be found at the speakers/advisory board for Eli Lilly. Dr. Schwenk is a consultant for Eli Lilly. Drug names: bupropion (Wellbutrin and others), citalopram (Celexa), escitalopram (Lexapro), fluoxetine (Prozac and others), mirtazapine (Remeron and others), nefazodone (Serzone and others), paroxetine (Paxil), sertraline (Zoloft), venlafaxine (Effexor). For the CME Posttest for this article, see pages 885-8S7. For more CME activities, visit——————————————— ————



LABORATORIO DI CHIMICA E TECNOLOGIA DEI RADIOELEMENTI Reazioni dì metallocarbonili del VI B con leganti orto -fenilenici Reazioni di metallocarbonili del gruppo VI B con leganti para -fenilenici. R.Portanova, A.Cassol, L.Magon e G.Tomat: Complessi organostagno(IV)-tiocianato in soluzione acquosa. Chimica delle Radiazioni e dei Radioelementi, Roma, 30-31 Marzo 1967, 81 (1968) Chimica delle

Patient instruction/consent sheet for allergy skin testing

PATIENT INSTRUCTION/CONSENT SHEET FOR ALLERGY SKIN TESTING Skin Test: Skin tests are a method of testing for allergic antibodies. A test consists of introducing small amounts of the suspected substance, or allergen, into the skin and noting the development of a positive reaction (which consists of a wheal, or swelling, or flare in the surrounding area of redness). The results are read 15

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