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Biperiden for Excessive Sweating From Methadone

Biperiden for Excessive Sweating From Methadone
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  Letters to the Editor  Am J Psychiatry 160:2, February 2003 385  Omega-3 Fatty Acids for Depression in Pregnancy T O   THE  E DITOR : Recently, omega-3 polyunsaturated fatty acidaugmentation of antidepressant medications was demon-strated as providing significant benefit in a 4-week, parallel-group, double-blind study (1) and our 8-week study (unpub-lished data of K.-P. Su et al.).Depression during pregnancy affects both the mother andthe child. Most drugs pass from mother to baby through theplacenta in different degrees. Medicating depressed pregnantpatients is a clinical dilemma. Omega-3 polyunsaturated fatty acids, with a possible antidepressant effect (1) and a lack of teratogenicity for the fetus (2), seem to be a favorable treat-ment alternative. We report here what is to our knowledge thefirst case of successful treatment with omega-3 polyunsatu-rated fatty acid monotherapy of a pregnant patient with ma- jor depressive disorder. Ms. A was a 34-year-old married woman who came toour psychiatric service for a recurrent depressive episodeat the 24th week of pregnancy. She had had a first majordepressive episode 5 years earlier, when she was pregnantwith her first baby. Ms. A did not receive any drugs, andthe depressive episode remitted 9 months after child-birth. She had another two major depressive episodes be-tween these two pregnancies, and she responded well toparoxetine, 20 mg/day.When she came to our hospital, Ms. A refused antide-pressant agents because of possible teratogenic effectsand took only lorazepam, as needed, for insomnia. Shedid not have any history of substance abuse or any signif-icant medical condition that might account for her de-pression. The results of laboratory tests (CBC and bloodchemistry) were within normal limits.Ms. A signed our informed consent form and began totake 4 g of ethyl eicosapentaenoic acid (EPA) and 2 g of docosahexanoic acid (DHA) per day, beginning in the 25thweek of gestation. She was rated with the 21-item Hamil-ton Depression Rating Scale at every visit: weeks 0 (beforeEPA-DHA supplementation), 2, 4, 6, 10, and 18 (6 weeks af-ter delivery).Ms. A did not have any change in score between weeks0 (Hamilton depression scale score=28) and 2 (score=29)but showed improvement in depressed mood, anhedonia,feelings of worthlessness, hopelessness, and guilt at week 4 (score=18) and experienced the disappearance of sui-cidal ideation at week 6 (score=10). After that, only initialinsomnia and anxious feelings bothered Ms. A occasion-ally (week 10: score=6). She received paroxetine, 20 mg/day, after delivery, and her condition has remained stable(week 18: score=7). The baby was delivered and appearednormal in a general physical and neurobehavioral exami-nation at birth.  We have previously reported on a pregnant woman withacute schizophrenia who showed improvement after omega-3 polyunsaturated fatty acid monotherapy (3). We believe thatthis case is the first report of a pregnant patient with majordepressive disorder who was treated with omega-3 polyun-saturated fatty acid monotherapy. Since the patient receivedregular follow-up for 6 weeks before treatment with omega-3polyunsaturated fatty acids, it is unlikely that the remarkableimprovement was due to the clinical attention of regular vis-its. Because the patient had a depressive episode during herfirst pregnancy and after childbirth, we do not think that shehad a spontaneous remission from this episode. Her improve-ment of depression was likely due to omega-3 polyunsatu-rated fatty acid treatment.Reduced maternal DHA status after the second trimester(4) is associated with a high demand from the developing fe-tus for the rapid formation of its brain. Empirical studies of polyunsaturated fatty acids in the tissues (5), data from epide-miologic surveys (6), and results of therapeutic trials of poly-unsaturated fatty acids (1) suggest that a deficit in omega-3polyunsaturated fatty acids might cause major depressivedisorder (7, 8). Supplementation with omega-3 polyunsatu-rated fatty acids is thought to have protective effects for preg-nancy outcome in high-risk pregnancy (2). Because of itssafety and psychotherapeutic effects, as well as its promotionof health for mothers and their infants, treatment withomega-3 polyunsaturated fatty acids is a promising approachfor pregnant patients with major depressive disorder. References 1.Nemets B, Stahl Z, Belmaker RH: Addition of omega-3 fattyacid to maintenance medication treatment for recurrent uni-polar depressive disorder. Am J Psychiatry 2002; 159:477–4792.Olsen SF, Sorensen JD, Secher NJ, Hedegaard M, Henriksen TB,Hansen HS, Grant A: Randomised controlled trial of effect of fish-oil supplementation on pregnancy duration. Lancet 1992;339:1003–10073.Su KP, Shen WW, Huang SY: Omega-3 fatty acids as a psycho-therapeutic agent for a pregnant schizophrenic patient. EurNeuropsychopharmacol 2001; 11:295–2994.Hornstra G: Essential fatty acids in mothers and their neonates.Am J Clin Nutr 2000; 71(5 suppl):1262S–1269S5.Peet M, Murphy B, Shay J, Horrobin D: Depletion of omega-3fatty acid levels in red blood cell membranes of depressive pa-tients. Biol Psychiatry 1998; 43:315–3196.Hibbeln JR: Fish consumption and major depression (letter).Lancet 1998; 351:12137.Horrobin DF, Bennett CN: Depression and bipolar disorder: re-lationships to impaired fatty acid and phospholipid metabo-lism and to diabetes, cardiovascular disease, immunologicalabnormalities, cancer, ageing and osteoporosis: possible can-didate genes. Prostaglandins Leukot Essent Fatty Acids 1999;60:217–2348.Su KP, Shen WW, Huang SY: Effects of polyunsaturated fatty ac-ids on psychiatric disorders (letter). Am J Clin Nutr 2000; 72:1241 CHIH-CHIANG CHIU, M.D.SHIH-YI HUANG, Ph.D.WINSTON W. SHEN, M.D.KUAN-PIN SU, M.D. Taipei, Taiwan Electrolyte-Balanced Sports Drink for Polydipsia-Hyponatremia in Schizophrenia T O   THE  E DITOR : It is estimated that 10%–25% of patients withchronic schizophrenia develop polydipsia (1–4).   One-thirdbecome hyponatremic. Seizures, coma, and death may occur when sodium levels fall below 120 mmol/liter (1). It is unclear why these patients develop polydipsia; one possibility is thatenlargement of the ventricles impairs their baroreceptors.  386  Am J Psychiatry 160:2, February 2003 LETTERS TO THE EDITOR  Mr. A, a 56-year-old single white man with a 40-year his-tory of chronic schizophrenia, was being treated withstandard and atypical neuroleptics. He lived with his el-derly mother. He had had two life-threatening episodes of hyponatremia-induced coma and was incapable of stop-ping his polydipsia. Mr. A was encouraged to drink only anelectrolyte-balanced sports drink and also to take one saltpill with each meal.Urinary frequency and enuresis were first noted. Later,seizures and a coma resulted in hospitalization, and a di-agnosis of hyponatremia and rhabdomyolysis was made.His electrolyte level was stabilized, and he was then trans-ferred to a psychiatric hospital. Other causes of hy-ponatremia, including the syndrome of inappropriate an-tidiuretic hormone secretion, renal disease, and Addison’sdisease, were ruled out. A computerized tomography scansuggested a stroke involving the caudate nucleus and gen-eralized cerebral atrophy. Mr. A’s sodium level fluctuatedfrom 137 to 142 mmol/liter. He was discharged taking clo-zapine, olanzapine, and sertraline.Recurrence of seizures resulted in rehospitalization. Dur-ing Mr. A’s second hospitalization, his serum sodium levelfluctuated from 127 to 147 mmol/liter (four measurementswere between 127 and 129 mmol/liter). Hospital treatmentincluded behavior therapy, propranolol, fluoxetine, andolanzapine, but none of these benefited him (2).One month after discharge, Mr. A’s sodium levels werestill below normal (127 mmol/liter) and appeared to belife threatening. He did not understand the importance of limiting fluid intake. His elderly mother was unable tomonitor his drinking. Mr. A’s fluid intake was limited to anelectrolyte-balanced sports drink. He took one 19-mg saltpill with each meal. In the past year, his sodium levelshave been normal, there have been no seizures, and hismental status has improved.  At the time this treatment was initiated, hyponatremia,coma, and death appeared possible. Use of previously recom-mended behavioral and pharmacological treatments wereunsuccessful (1–4). While water restriction of a delusionalpolydipsic patient outside a hospital may not be feasible, anelectrolyte-balanced solution may be lifesaving. This anec-dotal observation requires replication. Of note is that this pa-tient’s mental status improved, as evidenced by enhanced ori-entation, with stabilized sodium levels. References 1.Jawetz RE: Water, water everywhere…the etiology and treatmentof polydipsia and hyponatremia. P&S Med Rev 1999; 6 ( C, de Leon J, Josiassen RC: Problems and progress inthe diagnosis and treatment of polydipsia and hyponatremia.Schizophr Bull 1996; 22:455–4643.Mercier-Guidez E, Loas G: Polydipsia and water intoxication in353 psychiatric inpatients: an epidemiological and psycho-pathological study. Eur Psychiatry 2000; 15:306–3114.Canuso CM, Goldman MB: Clozapine restores water balance inschizophrenic patients with polydipsia-hyponatremia syn-drome. J Neuropsychiatry Clin Neurosci 1999; 11:86–90 FREDERIC M. QUITKIN, M.D.AMIR GARAKANI, M.D.KATIE E. KELLY, B.A. New York, N.Y. Biperiden for Excessive Sweating From Methadone T O   THE  E DITOR : Methadone maintenance treatment is themost common pharmacological intervention for opioid de-pendence. In clinical trials (1, 2), about 45% of the patients inestablished methadone maintenance treatment sufferedfrom excessive sweating.Biperiden is an anticholinergic drug that is well knownfrom clinical use in parkinsonism and schizophrenia. Wepresent what we believe are the first reported cases of metha-done-induced excessive sweating that were successfully treated with biperiden. During the observation period, allthree patients had no additional medication, and none of them reported adverse effects such as sedation, dizziness,dryness of the mouth, or blurred vision. Mr. A was a 30-year-old computer technician who hadsuffered from excessive sweating since adolescence. Hetested different treatments, including Salvia tea, benzodi-azepines, carvedilol, and atropine drops, but none of them worked. After entering methadone maintenancetreatment (current dose: 50 mg/day), he suffered intolera-ble sweating, especially at business meetings. After he re-ceived biperiden during a psychiatric emergency to an-tagonize the extrapyramidal side effects of a typicalantipsychotic, he noticed a cessation of sweating for sev-eral hours. With a dose of 2–4 mg/day of biperiden 3–4days per week, we could reproduce and maintain this pos-itive effect.Mr. B was a 43-year-old electrician who had startedmethadone maintenance treatment 3 years earlier. Hehad never had a problem with sweating, but from the firstday of taking methadone and independently of the dose(20–90 mg/day, currently 40 mg/day), he had to changehis wet clothes numerous times a day and suffered fromnegative reactions at his workplace. Treatment with bi-periden resulted in a prompt and stable cessation of thegeneralized sweating (current dose: 2 mg/day).Mr. C was a 37-year-old man who had been taking meth-adone for 6 years (current dose: 18 mg/day). He had hada problem with sweating previously, but with methadone,it became much worse: “In the summer I felt like a hy-drant. It was really crazy.” Seeking help, he tried severalremedies without any success. Finally, biperiden (a 4-mgcontrolled-release tablet every morning) resulted in an ef-fective control of the symptom. Little is known about the exact mechanisms by whichmethadone influences autonomic thermoregulatory controland produces increased sudomotor activity. However, themainly centrally acting antimuscarinic agent biperiden ap-pears to antagonize this overactivation very efficiently.Recovery from opioid addiction can be a long-term processand requires prolonged periods of methadone maintenancetreatment. Excessive sweating due to methadone may be sodisturbing in the long run that the question arises if this is animportant and yet underestimated reason for prematuredropouts and treatment failures. Patients with a high level of psychosocial functioning seem to suffer from it especially. Wethink that the treatment of this important side effect needsmore concern and that biperiden in a dose of 2–4 mg/day could be a significant contribution toward overcoming thistreatment complication.   Am J Psychiatry 160:2, February 2003 387 LETTERS TO THE EDITOR  References 1.Langrod J, Lowinson J, Ruiz P: Methadone treatment and phys-ical complaints: a clinical analysis. Int J Addict 1981; 16:947– 9522.Yaffe GJ, Strelinger RW, Parwatikar S: Physical symptom com-plaints of patients on methadone maintenance. Proc Natl Conf Methadone Treat 1973; 1:507–514 CARLO CAFLISCH, M.D.BERND FIGNER, M.A.DOMINIQUE EICH, M.D.  Zurich, Switzerland  Real-Life Research T O   THE  E DITOR : We commend Ann A. Hohmann, Ph.D., M.P.H.,and M. Katherine Shear, M.D. (1), on their attention to impor-tant issues in translating efficacy research to real-life researchin the community. We are completing a trial of community-based support-education groups for single mothers (2), apopulation facing high poverty rates and an elevated risk of mental health problems, particularly depression. We consid-ered similar issues before our trial. For example, we under-took feasibility work to determine appropriate identificationand enlistment of study participants, adequate retention ingroups, and acceptability and completion of evaluations. Wecontemplated the generalizability of the study setting, thesimilarity of the participants to those most in need, and therelevance of the outcome goals to the participants. We wish to emphasize four specific issues arising from ourtrial. First, despite strong expressed community support forour trial, study recruitment is difficult. Readiness to change(3) and engage in treatment activities appears to be muchlower in the community than in clinical settings, where moth-ers have been mobilized to ask for help with specific prob-lems. Clinic participants anticipate assessment question-naires, but community participants do not have the sameexpectations and may be less ready to complete question-naires. It is not clear if we attract those most   in need (most de-pressed? poorest?), but we attract mothers with expected so-ciodemographic and mental health characteristics who areready to engage in the treatment process.Second, we want to highlight the importance of the firstcontact with potential study participants. The person charged with engaging potential subjects must be able to describe thestudy in a clear, comprehensible manner and be inviting andencouraging. In our study, this person plays a critical role inreminding participants about group sessions and booking evaluations and has turned out to be a key person in both re-cruitment and maintenance.Third, putting in place a standard outcome protocol is es-sential, but an openness to recognizing other relevant out-comes during the trial is important. We examine maternal well-being (mood, social support, self-esteem) and parent-ing—important outcomes to participants and those working  with these mothers and their children. Preliminary qualitativeresults suggest that participating mothers may use the groupas a stepping stone to other mainstream activities and ser-vices after participation. This was not identified as a relevantoutcome at the outset but possibly constitutes one that ismore important.Fourth, the authors suggested that investigators undertak-ing community-based trials consider what is needed beforecontinuing an intervention after the study if it is successful.This may be difficult to do in advance, since community re-search may provide model programs not easily replicated be-cause of personnel or costs. Creating opportunities for aca-demic-community partnerships may upgrade the relevanceof academic studies and the scientific usefulness of commu-nity-based studies. References 1.Hohmann AA, Shear MK: Community-based intervention re-search: coping with the “noise” of real life in study design. Am J Psychiatry 2002; 159:201–2072.Lipman EL, Secord M, Boyle MH: Moving from the clinic to thecommunity: the Alone Mothers Together Program (letter). Can J Psychiatry 2001; 46:6573.Prochaska JO, Velicer WF, Rossi JS, Goldstein MG, Marcus BH,Rakowski W, Fiore C, Harlow LL, Redding CA, Rosenbloom D,Rossi SR: Stages of change and decisional balance for 12 prob-lem behaviors. Health Psychol 1994; 13:39–46 ELLEN L. LIPMAN, M.D., F.R.C.P.MICHAEL H. BOYLE, M.S.W., Ph.D. Hamilton, Ont., Canada Dr. Shear Replies T O   THE  E DITOR : We thank Drs. Lipman and Boyle for their in-teresting comments on our article. This work does indeedsound like exactly the kind of study we were trying to outline.The observations about difficulties recruiting people anddrawing attention to the importance of the first contact willbe very useful for others embarking on community studies.The admonition that an intervention may have unpredictedeffects is also very well taken. We disagree about the finalpoint, however. We argue instead that one of the purposes of research in community settings is to calibrate the interven-tion to the realistic possibility of its poststudy implementa-tion. To use an exaggerated metaphor, if a poor community ishaving transportation problems and a researcher wishing tosolve the problem brings in a fleet of limousines to demon-strate that the problem can be solved, this is a study hardly  worth doing. Limousines are not likely ever to be available inthis community. Documentation that if they exist, people willride in them is not helpful. M. KATHERINE SHEAR, M.D. Pittsburgh, Pa. Change in Brain Function With Placebo T O   THE  E DITOR : I read the intriguing report by Andrew F.Leuchter et al., M.D. (1), of a comparison of brain quantitativeelectroencephalography (QEEG) in depressed subjects whoreceived placebo and in those who received an antidepres-sant (fluoxetine or venlafaxine). For unknown reasons, theauthors described the collection of QEEG measures at the endof the 1-week placebo lead-in period (1 week after baseline)but neglected to report these data. According to the Hamilton Depression Rating Scale scoresgiven in the article, much of the clinical improvement oc-curred early (by 1 week after baseline). If this is true, thenQEEG data collected temporally closest to that transitioncould be the most informative. The most informative datafrom this study should not be left out of this article.  388  Am J Psychiatry 160:2, February 2003 LETTERS TO THE EDITOR  Reference 1.Leuchter AF, Cook IA, Witte EA, Morgan M, Abrams M: Changesin brain function of depressed subjects during treatment withplacebo. Am J Psychiatry 2002; 159:122–129 ANDREW P. HO, M.D. Beverly Hills, Calif. Hagiographic Treatment of C.G. Jung T O   THE  E DITOR : While it is understandable that space limita-tions prevented Sam C. Naifeh, M.D., from providing greaterdetail on C.G. Jung (1), the biographic information provided was so one-sided that it verged on the hagiographic. WhileJung undoubtedly was a pioneer at a time when organic psy-chiatry was on hiatus, most of his ideas have not stood the testof time, and it is difficult to believe that psychiatry today owesany significant debt to his contribution. All of his life Jung was obsessed with the idea of a collectiveunconscious, stemming from the notorious (and discredited)solar phallus dream (2). This spilled over into racial theories,and his more-than-tacit support for Nazi psychiatry was con-veniently forgotten or blurred over after World War II (3). He wrote indiscriminately or wildly about a range of paranormalphenomena—such as astrology, alchemy, and telekinesis— without any attempt to challenge their irrational basis.Furthermore, in his relationships with colleagues and pa-tients, Jung’s behavior was often unethical. After his split withFreud, his anti-Semitic utterances increased considerably. Hehad few qualms about sleeping with patients (to gauge the ex-tent of Jung’s malevolence, readers need only learn of his well-documented affair with the tragic Sabina Spielrein; see refer-ence 4) and, furthermore, inflicted his lovers on his long-suf-fering wife and family. All leaders or pioneers have their feet of clay, but the extentto which Jung’s followers eulogize their hero is unacceptable.No less an authority than Henri Ellenberger used the fiction of a creative neurosis to explain away a psychotic illness (5).Psychiatry needs more history, tinctured with respect forthe difficulties of an earlier time when there were fewer cer-tainties. However, ignoring Jung’s appalling behavior, bizarreideas, and extreme irrationalism does not provide a balancedpicture or do the situation justice. References 1.Naifeh SC: Carl Gustav Jung, M.D., 1875–1961. Am J Psychiatry2001; 158:19732.Noll R: The Jung Cult. London, Fontana Press, 19963.Maidenbaum A, Marten S (eds): Lingering Shadows: Jungians,Freudians and Anti-Semitism. Boston, Shambhala, 19914.Kerr J: A Most Dangerous Method: The Story of Jung, Freud andSabina Spielrein. New York, Alfred Knopf, 19935.Ellenberger H: The Discovery of the Unconscious. New York,Basic Books, 1970 ROBERT M. KAPLAN, M.B.Ch.B., F.R.A.N.Z.C.P., M.A. Wollongong, N.S.W., Australia Diabetes and Atypical Neuroleptics T O   THE  E DITOR : In their survey of diabetes mellitus in patientsreceiving neuroleptics, Michael J. Sernyak, M.D., et al. (1) re-ported that the prevalence was 9% higher in those treated with atypical neuroleptics than in those treated with typicalneuroleptics. Dr. Sernyak et al. acknowledged some of thelimitations of their study, including the fact that it was retro-spective, there was no attempt to determine diabetes status atbaseline, and the screening period was only 4 months long.They acknowledged that this narrow time frame yielded a vir-tual cross-sectional group, precluding determination of thetemporal relationship between neuroleptics and the develop-ment of diabetes mellitus—a basic requirement when assess-ing causality. Thus, they showed an association between atyp-ical neuroleptic treatment and diabetes, but they did notestablish causality.Some other limitations are worth noting. No matched com-parison subjects were used in this retrospective study. A his-tory of alcoholism was significantly more common in theatypical neuroleptic group than in the typical neurolepticgroup, and alcohol-induced pancreatitis may have accountedfor at least part of the higher prevalence of diabetes in theformer group.Finally, the numbers of patients taking each agent varied widely, making statistical analyses difficult. For example, thepercentage of patients taking quetiapine was so small that theodds ratio for diabetes in this group was higher than normalin the 40–49-year age range but lower than normal in the 60–69-year age range—a finding that is the opposite of what one would expect to see clinically (2).The possibility that patients taking neuroleptics may de-velop diabetes is a valid question, but because of design limi-tations, the current study did not yield any answers regarding causality.The authors are employees of AstraZeneca Pharmaceuti-cals. References 1.Sernyak MJ, Leslie DL, Alarcon RD, Losonczy MF, Rosenheck R:Association of diabetes mellitus with use of atypical neurolep-tics in the treatment of schizophrenia. Am J Psychiatry 2002;159:561–5662.American Diabetes Association: Clinical practice recommenda-tions 2002. Diabetes Care 2002; 25(suppl 1):S1–S147 WAYNE K. GELLER, M.D.WAYNE MacFADDEN, M.D. Wilmington, Del. T O   THE  E DITOR : Dr. Sernyak et al. compared the presence of di-abetes mellitus among schizophrenia patients within the De-partment of Veterans Affairs system who were treated withatypical neuroleptics (clozapine, risperidone, olanzapine,and quetiapine) and those who were treated with typical neu-roleptics. Diagnostic data covered the period October 1998through September 1999, and prescription data covered the4-month period from June through September 1999. Associa-tions between diabetes mellitus and neuroleptic treatment were made within this 4-month period, with index neurolep-tics being essentially identified on the basis of the last neuro-leptic prescription written during the period. While the study controlled for several confounding factors, limitations in de-sign may have undermined the validity of its findings.Patients were not screened for preexisting diabetes melli-tus, although it appears that this could have been done withavailable data. Identification and exclusion of preexisting cases would have avoided the possibility of assigning to spe-cific neuroleptics cases of diabetes mellitus due to previous   Am J Psychiatry 160:2, February 2003 389 LETTERS TO THE EDITOR  causes, including prior neuroleptic use. There is reason to be-lieve that the likelihood of preexistence was not the same forall neuroleptics. For example, in a study on this subject by meand my colleagues (unpublished study by F.D. Gianfrancescoet al.), we found that 76% of the diabetes mellitus observedduring treatment with quetiapine already existed within the 4months before treatment, versus 70% for risperidone, 67% forolanzapine, and 71% for typical neuroleptics. Also, in 49% of the quetiapine-treated patients, treatment with quetiapine was immediately preceded by treatment with another neuro-leptic, often olanzapine, whereas treatments with risperi-done, olanzapine, and typical neuroleptics were immediately preceded by treatment with other neuroleptics in only 16%,18%, and 13% of patients, respectively.Exclusive use of ICD-9-CM codes to identify diabetes melli-tus cases could have further affected results, especially giventhat preexisting diabetes mellitus cases were not removedfrom study. The presence of diabetes mellitus in a patient ismore definitely determined if there is treatment, as evidencedby prescriptions for antidiabetics or insulin. An ICD-9-CMcode for diabetes mellitus does not necessarily mean that apatient has tested positive or tested sufficiently positive to warrant more than monitoring. In some instances, ICD-9-CMcodes for diabetes mellitus may have reflected follow-up ex-aminations for patients whose diabetes mellitus had already disappeared because of a change in neuroleptics, for example.Last, the study did not control for differences in treatmentduration among the neuroleptic categories, which may havefurther biased its findings. It is reasonable to assume that thelikelihood of acquiring diabetes mellitus from a neuroleptictreatment increases with exposure to that neuroleptic. Treat-ments with index neuroleptics could have started at any timebefore or during the 4-month study period. Neuroleptics withlonger treatment durations may have been disadvantaged by the study design.In summary, a more careful study would have controlledfor preexisting diabetes mellitus and for differences in neuro-leptic exposure and would have used more definite indicatorsof this condition, such as prescriptions for antidiabetic medi-cations and insulin. FRANK D. GIANFRANCESCO, Ph.D. Montgomery Village, Md. Dr. Sernyak and Colleagues Reply T O   THE  E DITOR : We welcome the opportunity to respond to thequestions raised by Drs. Geller, MacFadden, and Gian-francesco about our recent article reporting an associationbetween prescription of atypical neuroleptics and diagnosisof diabetes mellitus in a group of nearly 40,000 patients. Al-though data on matched comparison subjects were not ob-tained, a multivariate adjustment procedure was employed.This statistical procedure is more appropriate in situations in which multiple agents are compared. While the number of patients did vary from group to group, we do not think that this invalidates our analysis. To take theexample offered by Drs. Geller and MacFadden, we suggestthat, given the small numbers of patients receiving quetia-pine (probably because of the short amount of time that que-tiapine had been available at the time of the study), our find-ings of an association of the diagnosis of diabetes mellitus with quetiapine appear all the more striking. Indeed, thelarger problem in studies of this kind is that a large number of patients increases the probability of finding statistically sig-nificant findings that are not clinically significant. We agree with Drs. Geller and MacFadden that observa-tional nonexperimental designs do not support causal con-clusions, although their strength is that they allow evaluationof the outcomes of large numbers of patients treated underreal-world conditions. However, we point out that a recentstudy designed to investigate just this causal connection be-tween atypical neuroleptics and diabetes mellitus (1) pro-duced findings consistent with many of ours.Dr. Gianfrancesco reiterates several limitations that westated in our article. Still, although we know very little aboutDr. Gianfrancesco’s data, they do appear to validate our sup-position that some neuroleptics were much more likely to beswitched to after the development of diabetes. However, thereliable determination of preexisting diabetes was beyondour capability at the time. Our group is working on anotherdata set in an attempt to address this necessary compromise.The suggestion of controlling for treatment duration is also well taken. However, it seems that this would tend to bias theresults in favor of the newest available antipsychotic—at thetime, quetiapine—having the lowest odds ratio for the diag-nosis of diabetes mellitus, which did not appear to occur. While changing the case definition of diabetes would cer-tainly change the number of patients so classified, how this would introduce biases against any particular antipsychoticsis not clear, and, in fact, an analysis of prescriptions for hy-poglycemic agents yielded substantially the same results asreported in the article.The authors of both letters raise legitimate concerns aboutsome of the limitations of our study that should, of course, benoted. However, we do not believe that these either representa lack of care or substantively challenge the conclusionsreached in our article. Reference 1.Newcomer JW, Haupt DW, Fucetola R, Melson AK, Schweiger JA,Cooper BP, Selke G: Abnormalities in glucose regulation duringantipsychotic treatment of schizophrenia. Arch Gen Psychiatry2002; 59:337–345 MICHAEL J. SERNYAK, M.D.DOUGLAS L. LESLIE, Ph.D.RENATO ALARCON, M.D.MIKLOS LOSONCZY, M.D., Ph.D.ROBERT ROSENHECK, M.D. West Haven, Conn. Brain Changes and Placebo T O   THE  E DITOR : Helen S. Mayberg, M.D., et al. (1) observed thatthe patients in their study whose depression relented aftertreatment with either fluoxetine or placebo had nearly identi-cal positron emission tomography (PET) brain scans. They concluded that the “facilitation of specific adaptive reciprocallimbic-cortical changes is necessary for depression remis-sion, regardless of the mode of treatment” (p. 734). Why “necessary”? This study shows only an association be-tween the remission of depressive symptoms and regionalchanges in brain glucose metabolism, which representchanges in blood perfusion at these sites. No one knows why 
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