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Letters to the Editor

Naltrexone-Induced Panic Attacks TO THE EDITOR: Endogenous opioids have been related to anxiety disorders, and the opioid antagonist naltrexone has been reported to precipitate phobic behavior (1). We report a case of panic attacks precipitated by the administration of the opioid antagonist naltrexone. Ms. A was a 29-year-old woman with bulimia nervosa who was enrolled in a clinical trial designed to evaluate naltrexone (100 mg/day) in the treatment of eating disorders. This patient had a family history of anxiety, but she had never suffered from any psychiatric disorder other than bulimia. Any accidental, medical, and/or recreational exposure to opiates was definitely ruled out. Before being enrolled in the study, the patient gave her written informed consent. She received 100 mg of naltrexone orally, and some hours later she experienced a state of alarm, demonstrating marked anxiety, chest discomfort, shortness of breath, profuse sweating, nausea, derealization, and fear of dying and of losing control. She was unable to stay at home alone or to go out without being accompanied. During the following 3 days she continued to take 100 mg of naltrexone as previously scheduled. However, the frequency of the panic attacks increased progressively, reaching a pattern of successive short bursts. On the fourth day, she came to the hospital in a state of alarm, manifesting fear of dying and of going crazy. She was treated with alprazolam (0.5 mg) and experienced partial relief of the symptoms. However, the day after, following a further dose of naltrexone, she experienced a relapse into bursts of panic attacks. Withdrawal of naltrexone led to complete remission of the panic symptoms in a couple of days. Since then, she has never experienced panic episodes. Naltrexone is an opioid receptor antagonist that, like naloxone, has a marked affinity for opioid receptors. Since the late 1970s (2), several studies have suggested that panic attacks might be the consequence of hyperactivity of locus ceruleus noradrenergic cells. These neurons possess opioid receptors and are innervated by inhibitory fibers containing both enkefalins and endorphins (3). Similarly, exogenous opioid agonists, acting at receptors, produce inhibition of locus ceruleus cells (4). This pharmacological inhibition is reversed by opioid antagonists such as naloxone, which in turn produce hyperactivity of noradrenergic cells (5). In subjects in whom overactivity of endogenous opioids occurs, naltrexone might induce panic attacks by removing this inhibitory effect.
REFERENCES 1. Arntz A, Merckelbach H, de Jong P: Opioid antagonist affects behavioral effects of exposure in vivo. J Consult Clin Psychol 1993; 61:865870 2. Redmond DE Jr, Huang YH: Current concepts, II: new evidence for a locus coeruleus-norepinephrine connection with anxiety. Life Sci 1979; 25:21492162

3. Strahlendorf HK, Strahlendorf JC, Barnes CD: Endorphin-mediated inhibition of locus coeruleus neurons. Brain Res 1980; 191: 284288 4. Williams JT, Egan TM, North R: Enkephalin opens potassium channels in mammalian central neurones. Nature 1982; 299:74 76 5. Aghajanian GK: Tolerance of locus coeruleus neurones to morphine and suppression of withdrawal response by clonidine. Nature 1978; 276:186188 ICRO MAREMMANI, M.D. GIADA MARINI, M.D. FRANCESCO FORNAI, M.D. Pisa, Italy

Manic Reaction After Induction of Ovulation With Gonadotropins TO THE EDITOR: We wish to report a case of mania induced by hormone induction of ovulation for the treatment of infertility. Ms. A, a 34-year-old married woman with no significant psychiatric history or family psychiatric history, was undergoing ovulation induction for secondary infertility. Her obstetric history included two first-trimester spontaneous abortions. After complete evaluation by a gynecologist, she had been diagnosed with secondary infertility and had received clomiphene, with no response. Several months later she embarked on ovulation induction that used urofollitropin and human chorionic gonadotropin. Urofollitropin, a follicle-stimulating hormone (FSH) preparation, was given intramuscularly daily from day 8 to day 12 of the patients regular 4/24-day menstrual cycle. Estradiol levels were monitored and on day 12 attained the concentration of 2,171 pmol/liter (normal range=1102,202 pmol/liter), indicating ripe follicles. On days 13 and 14 of her cycle, chorionic gonadotropin, a luteinizing hormone (LH) preparation, was given to induce ovulation. Approximately midway through the course of ovulation induction, Ms. A experienced a rapid and dramatic heightening in mood. She described feeling high and energized, while friends observed that she was inappropriately happy, very talkative, and somewhat bizarre. Ms. A also described symptoms of reduced sleep, racing thoughts, and overactivity. In addition, she became hypersexual and preoccupied with sexual thoughts. She eventually had an extramarital affair with a man she met 1 week after her last hormone injection, and this led to the breakup of her 5-year marriage. After 2 months, the manic symptoms began to subside, and she recovered insight into her uncharacteristic behavior. She subsequently became clinically depressed and was hospitalized with suicidal ideation. She was treated with sertraline, 50 mg/day, with good response. Given the close temporal relationship of the exposure to reproductive hormone preparations and the development of

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manic symptoms, and the lack of a premorbid history of mood disorder, we believe that the most likely explanation for this case is a medication-induced manic episode followed by a major depressive episode. The ovulation induction protocol described in this case is commonly used in reproductive medicine. Mood changes have been noted with clomiphene treatment (13), but to our knowledge, this is the first report of mania or hypomania induced by FSH and LH preparations. Previous research suggests that the hypothalamic-pituitary-ovarian axis is implicated in mood dysregulation (4). Hypoestrogenism and hypogonadotropic hypogonadism may be associated with depressive symptoms. Conversely, it is possible that elevations of estradiol levels, or gonadotropin administration, may result in elevated mood in susceptible women. Although this patients estradiol levels reached only the high normal range, the relative increase or rate of increase of estradiol may be important in mood changes, as estradiol has been reported to upregulate the serotonin transporter (5). In summary, it is likely that this patient experienced a manic episode induced by therapeutic ovulation induction. Although she had no risk factors for bipolar disorder, it is possible that the mood effects of gonadotropin administration are more marked in susceptible patients. Therefore, it may be prudent to monitor women with bipolar disorder or a family history of bipolar disorder for mood changes occurring during ovulation induction.
REFERENCES 1. Blum M, Zacharovitch D, Pery J, Gilerowitch M: Estrogen replacement therapy (ERT) by a special regimen in the years following menopause. Clin Exp Obstet Gynecol 1989; 16:911 2. Kapfhammer HP, Messer T, Hoff P: Psychotic illness during treatment with clomifen. Dtsch Med Wochenschr 1990; 115: 936939 3. Blenner JL: Clomiphene-induced mood swings. J Obstet Gynecol Neonatal Nurs 1991; 20:321327 4. Toren P, Dor J, Rehavi M, Weizman A: Hypothalamic-pituitaryovarian axis and mood. Biol Psychiatry 1996; 40:10511055 5. Weizman A, Morgenstern H, Rehavi M: Up-regulatory effect of triphasic oral contraceptive on platelet 3H-imipramine binding sites. Psychiatry Res 1988; 23:2327 RAINER N. PERSAUD, M.D. RAYMOND W. LAM, M.D. Vancouver, B.C., Canada

Six Deaths Linked to Misuse of Buprenorphine-Benzodiazepine Combinations TO THE EDITOR: The treatment of opiate abusers by substitution was introduced fairly late in France; high-dose buprenorphine became available in 1996. This synthetic morphinomimetic is a partial receptor agonist and a receptor antagonist. It binds lastingly to morphine receptors and has a duration of action of at least 24 hours. In France it is used as an analgesic under the trade name Temgesic at a dosage of 0.2 mg. For substitution treatment a high-dosage form is used, marketed under the trade name Subutex. The substitution dosage is between 2 mg and 8 mg. Because of the ceiling effect, this drug is considered to be particularly safe and has therefore become widely available in general medical practice. It is dispensed at a moderate level of control. Any physician may prescribe buprenorphine in a counterfoil book for up to 28 days. Any pharmacist may sup-

ply it. Urine assays can be performed but are not mandatory. However, it is recommended that the prescribing physician seek the advice of physicians in specialized drug abuse treatment centers and of experienced general physicians through a collaborative network. In April 1997, 34,000 patients were being treated with buprenorphine. Nevertheless, some drug abusers, and indeed some physicians, have not complied with the correct practice for prescribing and using this drug. This was not a problem until six deaths linked to misuse of benzodiazepines associated with high-dose buprenorphine were reported. The following postmortem research was conducted on these six cases. First, the blood and urine were submitted to exhaustive triple screening by immunochemical methods, high-performance liquid chromatography with diode detection, and gasphase chromatography coupled with mass spectrometry. The combination of all of these methods covers several thousand potentially toxic compounds and allows identification and assay of narcotics (opiates and derivatives, cocaine, amphetamines and derivatives, etc.) together with all of the psychotropics in the pharmacopeia (barbiturates, benzodiazepines, antidepressants, neuroleptics, carbamates, etc.). Other substances tested for included ethanol, volatile solvents, and cyanides (by gas-phase chromatography), carbon monoxide (by carboximetry), digitalis glycosides (by high-performance liquid chromatography/mass spectrometry), and arsenic and thallium (by atomic absorption spectrometry). Second, buprenorphine and its main metabolite, norbuprenorphine, were analyzed and quantified in all of the autopsy samples (blood, urine, stomach contents, liver, brain, kidney, heart muscle, etc.) by means of a high-performance liquid chromatography/mass spectrometry method described elsewhere (1). Blood concentrations of buprenorphine were in the therapeutic range (2.5, 1.1, and 1.7 ng/ml) in three subjects and higher than the therapeutic range (9.0, 12.6, and 17.7 ng/ml) in the other three, relative to known values in nonabusers. The exhaustive screening detected no traces of opiates (morphine, codeine, 6-monoacetylmorphine, etc.) in the postmortem blood. In contrast, all of the subjects displayed therapeuticrange levels of both demethyldiazepam and 7-aminoflunitrazepam. In all cases these concentrations were fairly low. The tissue concentrations were markedly higher than the blood levels. The levels of buprenorphine measured in the brain, kidney, and liver were, respectively, three to 12 times higher, one to 33 times higher, and two to 28 times higher than in the blood. Concomitant use of benzodiazepines seems to be strongly implicated in buprenorphine overdose. This association has been reported in a large number of clinical observations of respiratory depression involving buprenorphine at therapeutic doses (2, 3), but now this association is shown to be the cause of six deaths. It is necessary to evaluate the risks as precisely as possible by carrying out systematic blood assays of buprenorphine in every case of death of a drug abuser when drug misuse can be suspected and to review, if necessary, the provisions for dispensing high-dose buprenorphine.
REFERENCES 1. Tracqui A, Kintz P, Mangin P: HPLC/MS determination of buprenorphine and norbuprenorphine in biological fluids and hair samples. J Forensic Sci 1997; 42:112115 2. Faroqui MH, Cole M, Curran J: Buprenorphine, benzodiazepines and respiratory depression. Anaesthesia 1983; 38:1002 1003


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3. Sekar M, Mimpriss TI: Buprenorphine, benzodiazepines and prolonged respiratory depression. Anaesthesia 1987; 42:567568 MICHEL REYNAUD, M.D. ANTOINE TRACQUI, M.D. GEORGES PETIT, M.D. DENIS POTARD, M.D. PASCAL COURTY, M.D. Clermont-Ferrand, France

Comments on Review of Book on Hysteria TO THE EDITOR: In her review of my book The Analysis of Hysteria: Understanding Conversion and Dissociation, 2nd ed. (1), Dr. Judith Gold alleges that my opinions are not well supported by references. It is not always clear where she is claiming evidence for this view, but in several instances there are strong indications of misjudgment on her part, if not bias. Among the examples she gives, one (from p. 110 of my book) referring to hysterical personality characteristics in patients with anorexia nervosa is a conclusion at the end of a detailed discussion of more than a dozen sources that support my comment. Figures from two of those sources are cited. She says that many comments are subjective, and she offers as a typical example my discussion of the DSM-IV criteria for dissociative identity disorder where I say, Thus, it is possible for a personality to take partial control, or for two or more personalities to share this control, according to this definition. How this can happen while memory is lost may puzzle the thoughtful (p. 272). She slightly misquotes my original comment, but how indeed can two personalities share this control and have amnesia for each other at the same time? Apparently, Dr. Gold is not willing to consider my question. Dr. Gold similarly objects to my comment on Putnam when I said that there is a likelihood that the therapist will produce the phenomenon. I quoted Putnam at length, showing how he interviews patients in order to elicit multiple personality disorder. Dr. Gold says, The data supporting . . . [my] statement are absent. As with the previous example, I was quoting a text and commenting directly upon it. The segment of citation and critique was complete in itself in each of these cases, and Dr. Golds statements misrepresent the nature of my remarks. These examples are joined to a claim that my chapters touching on suggestion lack references. It is difficult in the space of a letter to demonstrate the carelessness with the facts that this statement evinces. More than 20 references deal variously with the effects of placebos, data concerning suggestibility and suggestion, and the conclusions on suggestion of such authors as William James, Freud, Ernest Jones, Baudouin, T.X. Barber, Hilgard, and Ellenberger, as well as the results of physiological studies. The chapter on epidemic or communicable hysteria to which Dr. Gold refers is replete with references. All of the nine reviews of the first edition of this book that I have seen were highly positive. The difference in the second edition is that I have had the temerity to assess critically the recovered memory movement and multiple personality disorder.
REFERENCE 1. Gold JH: Book review, Merskey H (ed): The Analysis of Hysteria: Understanding Conversion and Dissociation, 2nd ed. Am J Psychiatry 1997; 154:284 HAROLD MERSKEY, D.M. London, Ont., Canada

TO THE EDITOR: I am writing to protest the highly unfair comments on Dr. Merskeys book by Dr. Judith Gold. The reviewers obvious bias is particularly objectionable. Dr. Merskey is well-known as a critic of the construct of dissociative disorders and of its purported link to childhood trauma (1). Why, then, did the Journal choose as a reviewer Dr. Gold, who is known to be passionately committed to these very ideas? The result was predictable. Dr. Gold dismisses Dr. Merskeys scholarly review as arguments put forward by the supporters of the False Memory Syndrome Foundation. The readers of the Journal deserve better than this. I recommend that anyone who is interested in conversion and dissociation will benefit from consulting Dr. Merskeys text.
REFERENCE 1. Merskey H: The manufacture of personalities. Br J Psychiatry 1992; 160:327340 JOEL PARIS, M.D. Montreal, Que., Canada

Dr. Gold Replies TO THE EDITOR: In reply to Dr. Merskeys letter regarding my review of his book, I have little further comment. While, as noted in the review, a number of areas are well covered in the book, the topics of conversion, dissociation, memory, and trauma are discussed more thoroughly in the special supplement to this journal that was published in July 1996. I did my best to review the book in a totally impartial manner. I do not know why Dr. Paris asserts that I am passionately committed to these very ideas, as I have no knowledge of this passion myself. I believe that there are a lot of questions to be answered in the field of dissociation and a need for much more reasoned discussion on the issue surrounding memories of trauma. I had looked forward to reading Dr. Merskeys book in the hope that some of this would be elucidated and tried therefore to review it in a very objective manner.
JUDITH H. GOLD, C.M., M.D., F.R.C.P.(C) Halifax, N.S., Canada

Readmission as an Indicator of Quality of Care TO THE EDITOR: The March 1997 article by John S. Lyons and associates (1) recommended not using readmission as an indicator of quality of care. Their study advances our understanding of readmission but is based on three potentially controversial underlying assumptions and methods that merit further discussion. First, the authors downplay the notion that excellent inpatient care can prevent readmission. The hospitals studied offer short-term psychiatric hospitalization with the treatment goals of crisis stabilization rather than longer-term treatment of the psychiatric disorder. The authors claim that once the hospital has arranged for a referral, prevention of readmission is likely the responsibility of the community care provider. They partially reinforce this model by demonstrating a lack of associations between index admission characteristics and readmission. If both providers and payers agree that treatment is not a goal, then the authors are correct to suggest that we abandon prevention of readmission as an indicator of high-quality care.

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Second, the authors seem to support the notion that poorquality inpatient service can make it harder for a client to live in the community. They found no association between readmission and length of stay and concluded that the shortening of hospital stays . . . does not appear to result in a revolving door model of inpatient care. This analysis demonstrates how readmission can be used as a quality indicator when it interprets lack of association as adequate program functioning. Readmission is a direct measure of our goal of clients living in the community. Other measures, such as length of stay or clinical status at discharge, are indicators of the process for attaining this goal. We may overlook declines in quality if we follow Lyons and associates recommendation to ignore readmission, since it is unlikely that a list of process indicators will always be complete and accurate. Considering that routine quality analyses are secondary analyses, the likelihood of unreliable data is especially high, and measuring direct client outcomes becomes even more important (2). Third, different analytic techniques may increase readmissions descriptive power. The authors used dichotomous models that assign all readmissions equal weight, but 40% (N=18 of 45) of their study groups readmissions occurred within the first 30 days of a 6-month follow-up. Statistical methods that incorporate person-time, such as Poisson distribution or proportional hazards regression, can indicate factors that cause faster readmission. For example, one factor causing readmission on day 5 of follow-up is clearly more harmful than another causing readmission on day 30. Assigning the outcomes equal weight could bias results toward the null. Armed with more accurate tools, payers and providers should continue to use changes in adjusted readmission rates to make comparisons either of one facility over time or between facilities in a network.
REFERENCES 1. Lyons JS, OMahoney MT, Miller SI, Neme J, Kabat J, Miller F: Predicting readmission to the psychiatric hospital in a managed care environment: implications for quality indicators. Am J Psychiatry 1997; 154:337340 2. Druss B, Rosenheck R: Evaluation of the HEDIS measure of behavioral health care quality. Psychiatr Serv 1997; 48:7175 NEIL M. THAKUR, M.PHIL. New Haven, Conn.

dence that poor-quality inpatient service can make it harder for a client to live in the community. The actual association we were testing (by controlling for severity of illness) was whether persons discharged sooner than expected (on the basis of admission characteristics) were more likely to be readmitted. This was done to study the common criticism that utilization management results in sicker and quicker discharges. One claim is that these individuals are more likely to need more services later. We found no evidence of that for psychiatric inpatients, and we used this as additional evidence that readmission was not related to inpatient outcome. Mr. Thakurs idea of using the absence of association as an indicator in and of itself is intriguing but seems problematic conceptually. A letter does not provide space for the full elaboration of the inherent difficulties with this idea, but a large subset of the logical problems are similar to those of proving a null hypothesis. Demonstration of the presence of a relationship based on inductive statistics has a different standard of evidence than does demonstration of the absence of a relationship. Mr. Thakur is not correct when he argues that readmission is a direct measure of our goal of clients living in the community. Community tenure is a direct measure, as are many quality-of-life measures. Hospital admissions generally can be used as indirect measures of community tenure, but then so can nursing home placements and other institutional options. A focus on hospital readmissions as a quality indicator is not likely to help people with severe and persistent mental illness remain in the community. When used inappropriately, it can create disincentives for providers to take on the challenge of managing the cases of difficult-to-treat patients. Mr. Thakur makes some excellent statistical suggestions about more sophisticated approaches to the analysis of these data. These techniques require large samples and a statistically sophisticated readership. We are working toward incorporating survival analysis and decision-tree analyses into a growing database. However, given the current emphasis on implementing outcome measures now, we felt that the analytic approach used in our study was both appropriate to the study group and understandable to our primary audience.
JOHN S. LYONS, PH.D. Chicago, Ill.

Consequences of Involuntary Treatment TO THE EDITOR: The study reported by John A. Kasper, M.D., and colleagues in the April 1997 issue of the Journal (1) does not adequately address the consequences of involuntary treatment (and hospitalization) for patients. To do this, a study would have to follow patients for a substantial period after discharge to see how they fare in terms of functioning, rehospitalization rates, and cooperation with follow-up plans. Barbara Grumet and I reported a study in 1984 (2), a period during which New York had a four-step administrative procedure for dealing with treatment refusal. We found that refusers who later agreed to be treated at some point during the administrative review stayed out of the hospital nearly twice as long as a matched group of patients who complied with medication. We speculated that perhaps [this group of refusers] retained a healthy skepticism about doctors, medicine, and psychiatry and some sense of themselves as not without power and control over their lives. These qualities may have helped the refusers to better cope with life outside the hospital. The Virginia administrative scheme, which allows cli-

Dr. Lyons Replies TO THE EDITOR: I would agree with Mr. Thakur regarding the basic assumptions of our article on readmission to the psychiatric hospital. I do have concerns regarding some aspects of his suggestions. First, it is accurate to state that our research was based, in part, on the assumption that providers and payers agree that treatment is not a goal of inpatient care. There is little time during brief hospitalizations to engage in treatment, particularly of severe and persistent mental illness. I do not think this is a particularly controversial assumption, at least in the United States. However, it is important to note again, as we stated in the article, that this logic does not hold for systems of care. There may be circumstances in which readmission rates to the psychiatric hospital are useful quality indicators for integrated systems of care. On the second point, I do not think that the absence of an association between length of stay and readmission is evi-


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nicians to override their patients refusal without recourse to appeal at a higher level, completely disregards the potential psychological benefit for patients in retaining some sense of personal autonomy.
REFERENCES 1. Kasper JA, Hoge SK, Feucht-Haviar T, Cortina J, Cohen B: Prospective study of patients refusal of antipsychotic medication under a physician discretion review procedure. Am J Psychiatry 1997; 154:483489 2. Hassenfeld IN, Grumet B: A study of the right to refuse treatment. Bull Am Acad Psychiatry Law 1984; 12:6574 IRWIN N. HASSENFELD, M.D. Albany, N.Y.

Dr. Hoge Replies TO THE EDITOR: Dr. Hassenfeld raises several important points in his letter. His observation that our study did not address the long-term consequences of antipsychotic medication refusal and involuntary treatment is, of course, correct. It has been suggested that involuntary treatment may have considerable psychological effects and that some patients may become alienated from treatment as a result. This claim has not been empirically substantiated. In the only study to date, Cournos and colleagues (1) compared state hospital patients who were involuntarily medicated under New York States judicial review system with patients who were compliant with treatment; they failed to find any differences in rates of discharge, subsequent outpatient compliance, or rehospitalization. While that study is an important contribution to the literature on refusal of treatment, I agree with Dr. Hassenfeld that many questions about the long-term course of refusers remain unanswered. We need to know more about the course of patients who refuse treatment and are not taken to review. A prospective study conducted in Massachusetts, a jurisdiction with a judicial review system, found that only 18% of refusing patients reached review (2). Of particular concern are patients who

are discharged from the hospital untreated; approximately one-fourth of the group in the Massachusetts study fell into this category. Given his recognition that there is a paucity of such data, it is particularly puzzling that Dr. Hassenfeld criticizes the Virginia scheme under which psychiatrists have the discretion to override patients refusals. He believes that it completely disregards the potential psychological benefit for patients in retaining some sense of personal autonomy. Implicit in his criticism is the assumption that patients would fare better under some other system of review. There is no evidence that this is so, although the hypothesis is testable. Having practiced and researched treatment refusal in Massachusetts and Virginia, I can offer my own impressions on this point. The most important variable in the administration of involuntary treatment is the therapeutic relationship. Psychiatrists who maintain a therapeutic relationship with noncompliant patients have the best chance to maximize autonomy-enhancing treatment effects and to minimize negative psychological impact. Patients must continue to be treated respectfully and to be involved in treatment decision making to the greatest extent possible. In my experience, clinicians in the two jurisdictions are equally successful in practicing this difficult art. In the minority of cases, a subset of clinicians will interpret treatment refusal as a signal that the therapeutic relationship is over and that their sole course of action is to file a petition or to write an involuntary treatment order. These patients are not receiving our best, and it is my hypothesis that as a result, they do not achieve the best outcomes.
REFERENCES 1. Cournos F, McKinnon K, Stanley B: Outcome of involuntary medication in a state hospital system. Am J Psychiatry 1991; 148:489494 2. Hoge SK, Appelbaum PS, Lawlor T, Beck JC, Litman R, Greer A, Gutheil TG, Kaplan E: A prospective, multicenter study of patients refusal of antipsychotic medication. Arch Gen Psychiatry 1990; 47:949956 STEVEN K. HOGE, M.D. Charlottesville, Va.

Reprints of letters to the Editor are not available.

Correction In lines 910 of the third full paragraph on page 1788 of the review by Esther SomerfeldZiskind, M.D., M.A., of volumes I and II of Otto Klemperer: His Life and Times in the Book Forum (December 1997, pp. 17871789), the artist Kokoschka should have been identified as Austrian rather than Polish.

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