Letters to the Editor
Posttraumatic Bell’s Palsy
Topiramate for Bulimia Nervosa in Epilepsy
TO THE EDITOR: Although Bell’s paralysis is common, in many TO THE EDITOR: Topiramate is a novel agent approved for the instances its pathogenesis remains unknown. We report on treatment of epilepsy; it has purported effects at voltage- an unusual case with a possible psychological origin.
activated sodium channels and γ-aminobutyric acid andglutamate receptors (1). In addition to its anticonvulsant Mr. A, a 36-year-old train driver, accidentally ran over a
properties, topiramate suppresses appetite, is associated with suicidal man as the train pulled into a station. Mr. A re-
weight loss (1), and may have mood-stabilizing properties (2).
acted with horror but continued working. Six weeks later
I will describe the history of a patient with partial complex ep- he suddenly noticed two young men standing on the
ilepsy and comorbid bulimia nervosa who had complete ces- tracks, obviously testing their courage, a few hundred
sation of her eating disorder with topiramate therapy.
yards in front of his train. No accident occurred, but he
was unable to work and called in sick. He felt weak and

Ms. A was a 34-year-old right-handed woman. Although
noticed a prickling on the right side of his face, followed
she did not walk until she was 19 months of age, her intel-
by numbness. The next morning he noticed that his right
lectual development was considered age-appropriate dur-
lip was drooping, saliva was dripping out of the right side
ing her school years. By age 8 she had began to experi-
of his mouth, and he was unable to blink his right eye.
ence a depressed mood, reduced motivation, compulsive
Two days later a neurologist discovered hypoesthesia of
overeating, excessive weight gain, and insomnia. She did
his right cheek, Bell’s phenomenon on his right side, and
not receive psychiatric treatment until age 16; that treat-
a loss of taste on the right side of his tongue; the neurolo-
ment consisted of individual psychotherapy. Despite re-
gist diagnosed Bell’s paralysis on his right side. Total recov-
current depressive and vegetative symptoms, she gradu-
ery took 3 weeks. During this period Mr. A did not go to
a ted fr om high sc ho ol and c o lle ge and en te red a
work; he suffered from nightmares and depression and
graduate-level professional school. While in professional
persistently relived the trauma.
school she began to induce vomiting with her fingers or
syrup of ipecac. She continued purging several times per

Then left facial paralysis appeared. Mr. A was admitted
week for the next decade. Her bulimic symptoms did not
to a university hospital, where peripheral facial palsy on
respond to treatment with fluoxetine, sertraline, or ven-
the left side was confirmed. An electrophysiological exam-
ination by means of neurography and testing of the orbic-
After graduation from professional school at age 29, Ms.
ularis oculi reflex revealed an incomplete lesion. The re-
A suffered two losses of consciousness. These were pre-
sults of a lumbar puncture and extensive laboratory tests
ceded by “altered visual perception” and an intense sen-
were negative, as were the results of magnetic resonance
sation of thirst. The second loss of consciousness was asso-
imaging. Examinations of serum and CSF provided no evi-
ciated with tonic posturing of all of her extremities.
dence of an infectious etiology (e.g., Lyme borreliosis, her-
Metabolic derangements secondary to her eating disorder
pes simplex, varicella-zoster virus, HIV, cytomegalovirus,
were suspected but could not be confirmed. An EEG re-
or Epstein-Barr virus). Recovery took 2 months. In the
vealed left temporal slowing and left anterior temporal
meantime, posttraumatic stress disorder was diagnosed.
sharp waves. The results of computerized tomography
Once during psychotherapy in a rehabilitation clinic,
and magnetic resonance imaging scans of her brain were
Mr. A was filled with tremendous fear before a treatment
unremarkable. She was prescribed phenytoin therapy.
session in which he expected to be confronted with what
Ms. A’s convulsions ceased when she had maintained
had happened to him. A prickling sensation on the right
adequate blood levels of phenytoin for about 5 years. She
side of his face reappeared, and according to his and his
experienced occasional auras, which often included the
therapist’s reports, temporary right facial paralysis re-
sensation of thirst. Phenytoin therapy had no effect on
mained for a couple of hours.
her binge eating or purging. She had recurrent depressive
episodes and one episode of self-mutilation with broken

To the best of our knowledge, the study by Goldberg and glass. After 5 years of phenytoin treatment, the auras be-
Harte (1) is the only report to systematically focus on emo- gan to appear more frequently, and she had a partial
tional factors as a possible cause for Bell’s paralysis. The au- complex seizure with clonic movements of the right arm
and leg, despite having a serum phenytoin level of 23.4

thors reported that facial paralysis resulting from severe emo- µg/ml. Topiramate was prescribed and gradually in-
tional trauma might range from a simple conduction block to creased to 150 mg/day. Her auras and convulsions disap-
almost complete neural degeneration. They assumed that peared. In addition, she experienced a reduced appetite
such palsy might result from a spasm of the vasa nervorum in and a 10-lb weight loss. She became less concerned about
the fallopian canal. In cases of otherwise unknown pathogen- her weight and had a reduced desire for binge eating,
esis, a past history of severe emotional trauma should be sus- purging, and self-mutilation. As of this writing, she has re-
mained free of these symptoms for 15 months.
This case is interesting for a number of reasons. Although Reference
psychiatric symptoms are commonly reported in patients 1. Goldberg MJ, Harte S: Emotional factors contributing to facial with epilepsy, the association of epilepsy with eating disor- paralysis. J Am Geriatr Soc 1972; 7:324–329 ders is less clear. Although the patient’s eating disorder pre- dated her clinical epilepsy by several years, the fact that her seizure auras included sensations of thirst suggests that her uncontrolled epileptiform activity could have been related to Am J Psychiatry 158:2, February 2001 LETTERS TO THE EDITOR
The complete resolution of her bulimic symptoms with disorder and matched controls. J Affect Disord 1999; 56:195– topiramate therapy also appears to be a novel observation.
Selective serotonin reuptake inhibitors are normally pre- 2. Esposito S, Prange AJ Jr, Golden RN: The thyroid axis and mood scribed for bulimia nervosa. This practice is supported by a disorders: overview and future prospects. PsychopharmacolBull 1997; 33:205–217 controlled study with fluoxetine (3). Anticonvulsants such as 3. Crantz FR, Silva JE, Larsen PR: An analysis of the sources and phenytoin (4) and carbamazepine (5) have had limited suc- quantity of 3,5,5′-triiodothyronine specifically bound to nu- cess in the treatment of bulimia nervosa. This case suggests clear receptors in rat cerebral cortex and cerebellum. Endocri- that the pharmacological actions of topiramate might be use- ful in the treatment of bulimia nervosa and that controlled tri- 4. Dratman M, Crutchfield F, Gordon J, Jennings A: Iodothyronine homeostasis in rat brain during hypo-hyperthyroidism. Am JPhysiol 1983; 245:185–193 References
5. Puig-Domingo M, Guerrero JM, Vaughan MK, Little JC, Reiter RJ: 1. Privitera MD: Topiramate: a new anti-epileptic drug. Ann Phar- Activation of cerebrocortical type II 5′-deiodinase activity in Syrian hamsters kept under short photoperiod and reduced 2. Marcotte D: Use of topiramate, a new anti-epileptic, as a mood ambient temperature. Brain Res Bull 1989; 22:975–979 stabilizer. J Affect Disord 1998; 50:245–251 6. Mason GA, Walker CH, Prange AJ Jr: L-Triiodothyronine: is this 3. Fluoxetine Bulimia Nervosa Study Group: Fluoxetine in the peripheral hormone a central neurotransmitter? Neuropsy- treatment of bulimia nervosa: a multi-center, placebo-con- trolled, double-blind trial. Arch Gen Psychiatry 1992; 49:139– 7. Gordon JT, Martens DA, Tomlinson EE, Greenberg J, Dratman MB: Desmethylimipramine, a potent inhibitor of synaptoso- 4. Wermuth BM, Davis KL, Hollister LE, Stunkard AJ: Phenytoin mal norepinephrine intake, has diverse effects on thyroid hor- treatment of the binge-eating syndrome. Am J Psychiatry 1977; mone processing in rat brain, II: effect on in vivo 5′-deiodina- tion of [125I]thyroxine. Brain Res 1994; 634:96–104 5. Kaplan AS, Garfinkel PE, Darby PL, Garner DM: Carbamazepine 8. Mason GA, Bondy SC, Nemeroff CB, Walker CH, Prange AJ Jr: in the treatment of bulimia. Am J Psychiatry 1983; 140:1225– The effects of thyroid state on beta-adrenergic and serotoner- gic receptors in rat brain. Psychoneuroendocrinology 1987; 9. Mason GA, Walker CH, Prange AJ Jr: Modulation of gamma-ami- nobutyric acid uptake of rat brain synaptosomes by thyroidhormones. Neuropsychopharmacology 1987; 1:63–70 Thyroid Hormones and Seasonal Mood Change
O THE EDITOR: Several studies of peripheral thyroid economy in seasonal affective disorder have shown inconsistent results(1). However, measurements of the peripheral thyroid state Thalamic Alterations in Schizophrenia
may not provide a reliable index of the central thyroid state (2).
In contrast to the peripheral tissues, where most of the nu- O THE EDITOR: Erin A. Hazlett, Ph.D., et al. (1) illustrated ana- tomic and metabolic alterations in the left anterior and me- clear-bound triiodothyronine ( T3) is imported from the diodorsal thalamic nuclei in schizophrenic patients. Dorsal plasma pool, in the brain the supply of T3 depends mostly on thalamic nuclei are smaller and contain fewer neurons in the cellular uptake and intracellular deiodination of thyroxin schizophrenic patients than in comparison subjects (2). An- by type II 5′-iodothyronine deiodinase (3). The existence of a dreasen et al. (3) suggested that symptoms and signs of separate pathway in the brain for thyroxin deiodination sug- schizophrenia may derive from dysfunction in the thalamus gests that the adult central nervous system has the ability to and its circuitry. Infarctions in the anterior tuberothalamic ar- tery region produce clear-cut thalamic lesions and memory A short photoperiod and low ambient temperature are di- impairments (4) resembling those observed in schizophrenic rect stimuli that could affect type II 5′-iodothyronine deiodi- nase activity (5). Other effects of temperature and photope- We studied seven patients with strokes in the left anterior riod (e.g., decreased pituitary and gonadal hormones) could thalamus by recording auditory-evoked fields and magnetic be indirect factors that stimulate type II 5′-iodothyronine spontaneous brain activity (4). Two had delusions at disease deiodinase activity. Thus, seasonal changes in light and- onset. Auditory-evoked fields induced by tones delivered at a temperature may affect the metabolism of brain thyroid 2-second interstimulus interval were normal. However, an in- crease in the length of the interstimulus interval failed to en- T3 may itself be a neurotransmitter, and it may have an an- hance auditory-evoked fields in a fashion observed in com- tidepressant effect (6). It enhances the effects of norepineph- parison subjects. Mismatch fields, elicited by infrequent rine (7), serotonin (8), and γ-aminobutyric acid (9). Small al- deviant tones among regular standard tones, were signifi- terations of brain thyroid e conom y, inde pende nt of cantly smaller in patients than in comparison subjects. Pari- peripheral changes in thyroid status, may produce significant eto-occipital spontaneous brain activity was slowed. It is of behavioral effects. Therefore, it is reasonable to suggest that interest that these electrophysiological alterations resembled brain thyroid hormones might be involved in the mecha- those described previously in schizophrenic patients, who nisms of seasonal changes in mood and behavior.
have lower mismatch responses (6) and a lower peak fre- References
quency of parieto-occipital spontaneous activity (7). A 1. Sher L, Rosenthal NE, Wehr TA: Free thyroxine and thyroid- smaller interstimulus interval effect on auditory-evoked re- stimulating hormone levels in patients with seasonal affective sponses is implicated by an animal model (8).
Am J Psychiatry 158:2, February 2001 LETTERS TO THE EDITOR
Resemblances in findings among patients with thalamic Withdrawal reactions appear to be especially common when infarctions and patients with schizophrenia support the hy- atypical neuroleptics are abruptly withdrawn (6, 7). Until the pothesis of thalamic alteration in schizophrenia. Further re- authors provide additional data (e.g., on concomitant medi- search on correlations of neuropsychological and electro- cations prescribed and withdrawn, on withdrawal-emergent physiological findings and the severity of alterations in the extrapyramidal symptoms, on speed of response to reinstitu- left anterior thalamus among schizophrenic patients is tion of neuroleptics), their study underscores the clinical need for gradual, patient-centered drug withdrawal and thescientific need to distinguish between neuroleptic with- References
drawal reactions and psychotic relapses.
1. Hazlett E, Buchsbaum MS, Byne W, Wei TC, Spiegel-Cohen J, Geneve G, Kinderlehrer R, Haznedar MM, Shihabuddin L, References
Siever LJ: Three-dimensional analysis with MRI and PET of the 1. Kumra S, Briguglio C, Lenane M, Goldhar L, Bedwell J, Venu- size, shape, and function of the thalamus in the schizophrenia chekov J, Jacobsen LK, Rapoport JL: Including children and ad- spectrum. Am J Psychiatry 1999: 156:1190–1199 olescents with schizophrenia in medication-free research. Am J 2. Harrison P: The neuropathology of schizophrenia: a critical re- view of the data and their interpretation. Brain 1999: 122:593– 2. Viguera AC, Baldessarini RJ, Hegarty JD, van Kammen DP, To- hen M: Clinical risk following abrupt and gradual withdrawal of 3. Andreasen N, Arndt S, Swayze V, Cizadlo T, Flaum M, O’Leary D, maintenance neuroleptic treatment. Arch Gen Psychiatry Ehrhardt J, Yuh W: Thalamic abnormalities in schizophrenia vi- sualized through magnetic resonance image averaging. Sci- 3. Gilbert PL, Harris J, McAdams LA, Jeste DV: Neuroleptic with- drawal in schizophrenic patients: a review of the literature.
4. Mäkelä JP, Salmelin R, Kotila M, Salonen O, Laaksonen R, Hok- kanen L, Hari R: Left thalamic infarctions modify neuromag- 4. Baldessarini RJ, Viguera AC: Neuroleptic withdrawal in schizo- netic cortical signals. Electroencephalogr Clin Neurophysiol phrenic patients. Arch Gen Psychiatry 1995; 52:189–192 5. Perenyi A, Frecska E, Bagdy G, Revai K: Changes in mental con- 5. Aleman A, Hijman R, de Haan EH, Kahn RS: Memory impair- dition, hyperkinesias and biochemical parameters after with- ment in schizophrenia: a meta-analysis. Am J Psychiatry 1999: drawal of chronic neuroleptic treatment. Acta Psychiatr Scand 6. Javitt D, Doneshka P, Grochowski S, Ritter W: Impaired mis- 6. Shiovitz TM, Welke TL, Tigel PD, Anamd R, Hartman RD, Sramek match negativity generation reflects widespread dysfunction JJ, Kurtz NM, Cutler NR: Clozapine rebound and rapid onset of working memory in schizophrenia. Arch Gen Psychiatry psychosis following abrupt clozapine withdrawal. Schizophr 7. Canive J, Lewine J, Roberts B, Edgar C, Davis J, Orrison WJ: Mag- 7. Goudie AJ, Smith JA, Robertson A, Cavanagh C: Clozapine as a netoencephalographic assessment of spontaneous brain activ- drug of dependence. Psychopharmacology 1999; 142:369–374 ity in schizophrenia. Psychopharmacol Bull 1996: 32:741–750 8. Jayachandra M, Schroeder C, Lindsley L, Javitt D: Auditory N1 refractoriness in a primate model of schizophrenia. Soc Neuro- Diagnosing Personality Disorders
TO THE EDITOR: Using a large representative national sample, Mark Zimmerman, M.D., and Jill I. Mattia, Ph.D. (1), at-tempted to disconfirm a hypothesis my colleagues and I ad-vanced and corroborated (2). I asserted that clinicians do not Medication-Free Minors With Schizophrenia
rely primarily on the direct-question format used in struc- TO THE EDITOR: In their conclusions on schizophrenia research tured interviews to assess personality disorders (e.g., “Have with medication-free minors, Sanjiv Kumra, M.D., F.R.C.P., you ever been told that you seemed like a shallow or superfi- and colleagues (1) may have underestimated the clinical im- cial kind of person?” to assess histrionic personality disorder).
pact of the speed of tapering neuroleptic medications in chil- Clinicians of all theoretical orientations have reported that dren and adolescents, who are usually more sensitive to the they diagnose personality disorder pathology by listening to adverse effects of psychotropics. The authors stated that the their patients’ narratives about significant interpersonal ex- subjects were tapered “over 1 to 2 weeks.” Whether or not this periences and observing their behavior in the consulting schedule conforms to routine clinical practice, common sense and guidelines for the tapering of most psychotropics Drs. Zimmerman and Mattia hypothesized that if clinicians taken for prolonged periods suggest that this schedule be hear the results of structured interviews for borderline per- considered an abrupt withdrawal.
sonality disorder (including information on particular crite- And contrary to what the authors implied in their article, ria, such as self-mutilation), this influences their diagnoses— the study they cited (2) and another meta-analysis of neuro- a hypothesis with which no one, myself included, would dis- leptic withdrawal (3, 4) actually show that abrupt withdrawal agree (unless the clinicians have reason to distrust the data increases the probability of recurrence of psychotic symp- provided by the interviewer). In one-half of their sample, cli- toms. In that light, the “rapid and severe deterioration” of nicians made diagnoses as they normally would, on the basis symptoms that followed drug discontinuation in 26% of their of an initial intake interview of unspecified length. In this sit- subjects points to a withdrawal reaction, as psychotic re- uation, clinicians diagnosed only 0.4% out of 500 outpatients lapses rarely occur during the first weeks of withdrawal (5).
entering their clinic with borderline personality disorder. In Am J Psychiatry 158:2, February 2001 LETTERS TO THE EDITOR
the other one-half of the sample, researchers conducted 2. Westen D: Divergences between clinical and research methods structured interviews, then “presented the case to a psychia- for assessing personality disorders: implications for research trist who reviewed the findings of the evaluation with the pa- and the evolution of axis II. Am J Psychiatry 1997; 154:895–903 tient,” and then made a diagnosis. Under these conditions, 27 3. Westen D, Arkowitz-Westen L: Limitations of axis II in diagnos- ing personality pathology in clinical practice. Am J Psychiatry out of 59 patients diagnosed as having borderline personality disorder by structured interview were diagnosed with border-line personality disorder by a psychiatrist, and seven more were given a rule-out diagnosis of borderline personality dis-order.
The investigators largely replicated a well-known psycho- Spontaneous Depression Versus
logical finding: that biasing observers with prior information Biphasic Cycling
(particularly a label) affects the way they subsequently view a TO THE EDITOR: The recent randomized study of bipolar de- person. What is perhaps more striking is that fewer than one- pression by L. Trevor Young, M.D., Ph.D., et al. (1), document- half of the psychiatrists who were biased in this way gave the ing a superior antidepressant response after adding paroxet- patients the borderline personality disorder diagnosis! In the ine rather than a second mood stabilizer to an existing mood least, from a methodological point of view, the psychiatrist stabilizer, addressed a critical and unresolved area of research should have been presented with the results of the structured in the treatment of bipolar disorder. Because studies such as interviews after spending some time with the patients, prefer- this are scarce, clinical decisions about when to introduce an- ably at least two or three sessions, so that the psychiatrist tidepressants for the treatment of bipolar depression remain would have had time to assess the patients’ personalities.
The use of intake diagnoses recorded in the patients’ charts Little attention has been paid in the literature to the dis- as an index of the clinician’s diagnostic impressions was also tinction between depression that arises spontaneously (i.e., an unfortunate methodological choice. The authors report after remission from a prior mania) and depression that arises that only two patients out of 500 received an intake diagnosis soon after the resolution of a manic episode (i.e., biphasic).
of borderline personality disorder in the naturalistic condi- Biphasic episodes of mania followed by depression have been tion. This is so far below the norms reported in any study of reported to occur in as many as 58% of bipolar disorder pa- which I am aware that I agree with the authors’ casual obser- tients (3), although even expert clinicians fail to reach con- vation that “clinicians were very reluctant to diagnose border- sensus on the optimal first-line treatment strategy for depres- line personality disorder during their routine intake diagnos- sion that occurs immediately after a manic episode (2).
tic evaluations” (1, p. 1572). And I applaud the clinicians’ Because depression that occurs as part of a biphasic episode reluctance: giving a patient a stigmatizing diagnosis in an of- could reflect a more cyclical overall disease process than de-pression that arises spontaneously in the course of bipolar ficial record available to third-party payers after seeing the disorder, the utility (and safety) of antidepressants, rather patient only briefly (presumably spending most of the inter- than more aggressive anticycling agents, remains an open view inquiring about axis I diagnoses, suicidality, and other issues relevant to triage) would be inappropriate in most cir- Although the size of the group studied by Dr. Young et al. (1) cumstances. In a similar study in which clinicians made precluded a definitive subanalysis of spontaneous versus bi- anonymous diagnoses (3), Arkowitz-Westen and I found that phasic depression, their data may nonetheless help shed light 14.5% of the patients received a borderline diagnosis.
on this topic by generating hypotheses. Their exclusion of pa- Finally, the choice to study only one personality disorder, tients with known rapid cycling furthermore makes theirs an borderline, was unfortunate. As I noted in the article to which ideal group to address this issue, as they are unconfounded by the authors were responding (2), borderline personality disor- the idiosyncracies of rapid cycling and possible previous anti- der and antisocial personality disorder are the two diagnoses depressant-induced changes in cycle frequency. In light of for which structured interviews have the best validity and re- other data suggesting that depression that follows manias liability data; that is precisely because they are the ones with may portend a more favorable response to lithium treatment the most objective behavioral indices (e.g., cutting, suicide at- than depression that precedes manias (4), it would be a valu- tempts, and arrests). A more conservative test of their hypoth- able added dimension to their study to provide preliminary esis would have been to select a disorder such as narcissistic personality disorder, for which criteria are not so accessible References
by direct questioning. Whether clinicians would have founddiagnoses made after 5–10 minutes of direct questioning by 1. Young LT, Joffe RT, Robb JC, MacQueen GM, Marriott M, Patelis- Siotis I: Double-blind comparison of addition of a second interviewers (some of whom were only bachelor’s-level re- mood stabilizer versus an antidepressant to an initial mood search assistants) compelling enough to accept one-half of stabilizer for treatment of patients with bipolar depression. Am the time, as they apparently did with borderline personality 2. Sachs GS, Printz DJ, Kahn DA, Carpenter D, Docherty JP: The Ex- pert Consensus Guideline Series: Medication Treatment of Bi- References
polar Disorder 2000. Postgrad Med 2000; special number, pp 1. Zimmerman M, Mattia JI: Differences between clinical and re- search practices in diagnosing borderline personality disorder.
3. Winokur G, Clayton PJ, Reich T: Manic Depressive Illness. St Am J Psychiatry 158:2, February 2001 LETTERS TO THE EDITOR
4. Maj M, Pirrozi R, Starace F: Previous pattern of course of the ill- tion. If the finding is confirmed, determining the illness pat- ness as a predictor of response to lithium prophylaxis in bipo- tern that precedes the onset of depression in bipolar disorder lar patients. J Affect Disord 1989; 17:237–241 may help clinicians identify those patients for whom the risk- benefit ratio of antidepressant treatment is most favorable.
Dr. MacQueen and Colleagues Reply
TO THE EDITOR: Our initial study examined whether bipolar pa- tients who became depressed while taking a mood stabilizerwere more likely to improve after the addition of a second Female Sexual Dysfunction
mood stabilizer or an antidepressant. In his comment to the and Antidepressant Use
editor, Dr. Goldberg questioned whether our data set could beused to assess whether the patients who became depressed TO THE EDITOR: David Michelson, M.D., et al. (1) appropriately after a period of sustained euthymia differed in treatment re- demonstrated that neither buspirone nor amantadine was sponsivity from patients who became depressed after a manic more effective than placebo in the treatment of antidepres- episode. As Dr. Goldberg noted, our group size precluded a sant-induced sexual dysfunction in women. Their results ap- definitive examination of this issue; however, we were able to parently are not in agreement with those of Landén et al. (2), determine the preceding mood state for 23 out of 27 subjects who showed the superiority of buspirone to placebo for anti- in our group. We could not confidently ascertain whether four depressant-induced sexual dysfunction, particularly in subjects who had been referred only for participation in the women. However, this discrepancy suggests the possibility study had been euthymic for the 2 months preceding the on- that the effects of buspirone on sexual dysfunction might set of depression; therefore, we did not include these subjects abate with continued treatment, owing to the desensitization in the analyses. We defined the euthymia-depression group as of serotonin1A autoreceptors, because Dr. Michelson et al. ad- patients who had had no evidence of manic or hypomanic ministered buspirone for a longer period (8 weeks) than symptoms within the 2 months preceding the onset of the de- pressive episode. In contrast, the mania-depression patients On the other hand, although the study by Dr. Michelson et had been either manic or hypomanic within the 2 months al. (1) was not primarily aimed at evaluating the efficacy of the preceding the onset of depression. Of the 14 patients treated combination of fluoxetine and buspirone in treating affective with two mood stabilizers, 10 were assigned to the euthymia- symptoms, I will comment on this issue. Several case studies depression group, while four were assigned to the mania-de- and open trials showed the efficacy of buspirone added dur- pression group. Of nine patients treated with a mood stabi- ing antidepressant augmentation (3). In the first controlled, lizer plus an antidepressant, four were in the euthymia-de- double-blind trial (4), however, buspirone augmentation of a pression group, and five were in the mania-depression group.
selective serotonin reuptake inhibitor (citalopram or paroxe- Analysis of Hamilton Depression Rating Scale scores re- tine) in patients with refractory depression failed to demon- vealed a significant interaction between week and prior mood strate any difference in efficacy from placebo augmentation.
state (F=2.20, df=6, 114, p<0.05); euthymia-depression pa- The study of Dr. Michelson et al. (1) seems to be a second tients treated with a mood stabilizer plus an antidepressant such study, although most of their patients were almost re- demonstrated the greatest improvement in Hamilton depres- covered, as indicated by their Hamilton depression scale sion scores across treatment weeks. This differential improve- scores. Nonetheless, the results of visual analogue scales ment in euthymia-depression patients treated with a mood measuring mood and energy did not indicate their complete stabilizer plus an antidepressant was mirrored in their Global recovery. The fact that amantadine added to fluoxetine signif- Assessment of Functioning Scale scores (F=2.27, df=6, 114, icantly improved energy levels and approached statistical sig- p<0.03), which also showed the greatest improvement in the nificance for mood improvement strongly supports the possi- bility of at least subjectively insufficient recovery of the It is interesting that despite the small group size and post patients’ depression at baseline. The mean mood changes in hoc exploratory nature of this analysis, there was a demon- the visual analogue scales from baseline (higher values repre- strable difference in improvement for the euthymia-depres- sent greater improvement) were 8.7 (amantadine added), 1.4 sion group treated with a mood stabilizer plus an antidepres- (buspirone added), and 0.6 (placebo added); the mean energy sant. Speculatively, Dr. Goldberg might have predicted this changes were 9.5, 2.1, and –3.2, respectively. There was no dif- pattern of results, as he points out that even non-rapid-cy- ference between the addition of buspirone and the addition cling patients with mania and depression may have a greater of placebo in mood or energy change, although the addition tendency toward cyclicity and be less likely to benefit from of amantadine was significantly better than the addition of antidepressant treatment. As there were no patients in our placebo, particularly in energy change. Also, there was no dif- study who became manic or hypomanic after acute treatment ference among the groups in changes measured by the Beck with a mood stabilizer plus an antidepressant, it was not pos- Depression Inventory. These findings suggest that buspirone sible for us to comment on the relative safety of antidepres- added to fluoxetine cannot improve subjective mood or en- sant use in the euthymia-depression group versus the mania- depression group. Nonetheless, our results suggested that Although Dr. Michelson et al. (1) did not mention this sug- prior mood state may influence treatment responsivity in de- gestion because it was not their purpose, I believe that this is pressed bipolar patients; this clearly warrants further explora- important information to note until further placebo-con- Am J Psychiatry 158:2, February 2001 LETTERS TO THE EDITOR
trolled, double-blind studies clarify the role of buspirone in for me to get close to people”). In an ongoing study in our clinic, 20 patients with generalized social phobia had a meandetachment score of 25.5 (SD=3.8, range=19–35). Nineteen References
(95%) of the 20 patients had scores exceeding the median 1. Michelson D, Bancroft J, Targum S, Kim Y, Tepner R: Female score of 19 found among healthy subjects by Dr. Laakso and sexual dysfunction associated with antidepressant administra- colleagues (1). The detachment scale therefore may be sensi- tion: a randomized, placebo-controlled study of pharmaco- tive to social avoidance related to anxiety in social phobia. Al- logic intervention. Am J Psychiatry 2000; 157:239–243 2. Landén M, Eriksson E, Ågren H, Fahlén T: Effect of buspirone ternatively, the detachment scale may have detected aloof- on sexual dysfunction in depressed patients treated with selec- ness as an unexpected element (or consequence) of social tive serotonin reuptake inhibitors. J Clin Psychopharmacol Because social phobia is highly prevalent in the community 3. Sussman N: Anxiolytic antidepressant augmentation. J Clin Psy- yet is frequently missed by clinicians, studies recruiting healthy subjects may inadvertently include persons with so- 4. Landén M, Björling G, Ågren H, Fahlén T: A randomized, dou- cial phobia unless they are systematically screened out. Be- ble-blind, placebo-controlled trial of buspirone in combination cause two articles regarding detachment and dopamine (1, 2) with an SSRI in patients with treatment-refractory depression. J did not include the methods used to exclude subjects with psychiatric disorders, some of their subjects with elevated de- tachment scores may have had social phobia. Future studies of detachment should systematically assess the presence ofsocial phobia among subjects.
Dr. Michelson Replies
TO THE EDITOR: We appreciate and note Dr. Terao’s comments.
1. Laakso A, Vilkman H, Kajander J, Bergman J, Haaparanta M, So- With respect to the discrepancy between our results and lin O, Hietala J: Prediction of detached personality in healthy those of Landén et al. (1999), we note that in addition to dif- subjects by low dopamine transporter binding. Am J Psychiatry ferences in length of treatment, their findings derive from a study primarily designed to assess antidepressant efficacy 2. Farde L, Gustavsson JP, Jonsson E: D2 dopamine receptors and rather than sexual function. The interpretation of their report personality traits (letter). Nature 1997; 385:590 is, consequently, limited by a number of methodological is- 3. Breier A, Kestler L, Adler C, Elman I, Wiesenfeld N, Malhotra A, sues. Conversely, our study was not designed to assess the ef- ficacy of buspirone augmentation of fluoxetine for residual ment in healthy subjects. Am J Psychiatry 1998; 155:1440– depressive symptoms, and indeed, we selected patients with- out such symptoms to avoid confounding the analysis of sex- 4. Tiihonen J, Kuikka J, Bergstrom K, Lepola U, Koponen H, Leino- ual function. In that context, our findings with amantadine nen E: Dopamine reuptake site densities in patients with socialphobia. Am J Psychiatry 1997; 154:239–242 were suggestive and consistent with those of several previous 5. Schneier FR, Liebowitz MR, Abi-Dargham A, Zea-Ponce Y, Lin S- reports and merit further investigation. Nonetheless, our H, Laruelle M: Low dopamine D2 receptor binding potential in study is not a fair assessment of augmentation therapies social phobia. Am J Psychiatry 2000; 157:457–459 among patients who have an incomplete response to fluoxe- 6. Schalling D, Asberg M, Edman G, Oreland L: Markers for vulner- tine therapy, nor was it intended to be.
ability to psychopathology: temperament traits associated with platelet MAO activity. Acta Psychiatr Scand 1987; 76:172– Detachment and Generalized Social Phobia
TO THE EDITOR: We read with great interest the finding of Aki Laakso, M.D., Ph.D., and colleagues (1) that the personalitytrait of “detachment” is associated with low dopamine trans- Drs. Laakso and Hietala Reply
porter binding in healthy subjects, complementing priorfindings of its association with low dopamine D2 receptor TO THE EDITOR: We would like to thank Drs. Schneier, Liebow- density (2, 3). These results parallel findings in generalized so- itz, and Laruelle for their comments regarding our article, cial phobia of low dopamine transporter binding (4) and low which described the association between low dopamine D2 receptor binding (5). The authors suggested that “detach- transporter binding and detached personality. Indeed, it may ment,” as measured by the detachment scale of the Karolin- be difficult to discern the psychological basis for avoidant be- ska Scales of Personality (6), relates to a behavioral pattern of havior with a self-rating instrument such as the Karolinska withdrawal and aloofness and that the findings may be rele- Scales of Personality. Patients with either social phobia or vant for schizoid personality disorder. We would caution, schizoid personality disorder do experience discomfort when however, that “detachment” is also associated with general- interacting socially, although this is because of anxiety (often ized social phobia and may represent social avoidance due to in the presence of a desire to socialize) in the former and more because of a lack of interest in the latter. Although many of the Most of the 10 items of the detachment scale could easily detachment items in the Karolinska Scales of Personality do apply to persons who avoid social situations because of fear reflect more aloofness than phobic anxiety about socializa- of embarrassment, rather than aloofness (e.g., “It is [not] easy tion (e.g., “I am [not] deeply moved by other people’s misfor- Am J Psychiatry 158:2, February 2001 LETTERS TO THE EDITOR
tunes,” “I [do not] want to confide in someone, when I am dic descendants and other citizens in Winnipeg may be due to worried and unhappy”), we agree that the association be- a cultural tradition of fish consumption, rather than differ- tween detached behavior and low dopaminergic transmis- ences in genetic predisposition. Our proposition is consistent sion reported by us and others (Farde et al., 1997; Breier et al., with the finding in a cross-national analysis that greater sea- 1998) may relate to similar findings on social phobia (Tii- food consumption predicted lower prevalence rates of major honen et al., 1997; Schneier et al., 2000). However, we also re- depression (r=–0.84, p<0.005) (3).
ported a strong positive correlation between scores on the so- Seafood is rich in the omega-3 essential fatty acids eicosap- cial d esirability subscale of the Karolinska Scales of entaenoic and docosahexaenoic acids. Docosahexaenoic acid Personality and dopamine transporter binding, which sug- is selectively concentrated in synaptic membranes, where it gests also that motivational aspects of social behavior play a has a crucial role in maintaining the biophysical properties part in the described phenomenon. It is also worth noting determining receptor conformation (4). Mechanisms through that up to 60% of patients with social phobia also fulfill the which eicosapentaenoic and docosahexaenoic acids may di- DSM-IV criteria for avoidant personality disorder (1). This has minish depressive symptoms have recently been reviewed (5) not been fully addressed in previous studies examining and include modulation of serotonin turnover, phosphoino- dopaminergic neurotransmission in social phobia (Tiihonen sitol-mediated signal transduction, and L-type calcium chan- et al. 1997; Schneier et al., 2000).
nel regulation. Depletions of docosahexaenoic acid in RBC We feel that it is unlikely that the association we reported phospholipid membranes have been reported in depression could be caused by subjects in our study group with social (6). A placebo-controlled study in bipolar disorder (7) showed phobia. First, any direct comparisons of scores on the Karo- that supplementation with docosahexaenoic and eicosapen- linska Scales of Personality between diagnostic groups taenoic acids had marked mood-stabilizing and antidepres- (healthy versus social phobic) from different populations (Eu- sant activity. Thus, high levels of fish consumption should be ropean versus United States) without normative transforma- considered a potential etiology for the finding of a lack of sea- tion of the personality data should be made with caution. Sec- sonal affective disorder among the Icelandic population.
ond, although social phobia was not excluded with a References
structured instrument such as the SCID (a thorough clinical 1. Magnusson A, Axelsson J, Karlsson MM, Oskarsson H: Lack of interview for axis I diagnoses), a medical history focused on seasonal mood change in the Icelandic population: results of a psychiatric and neurologic illness was obtained from healthy cross-sectional study. Am J Psychiatry 2000; 157:234–238 volunteers. In addition, the recruitment procedure did not fa- 2. Fish and Fishery Products: World Apparent Consumption vor subjects with social anxiety. Considering that the point Based on Food Balance Sheets (1961–1993): FAO Fisheries Cir- prevalence of social phobia in the general population is be- cular 821, revision 3. Rome, Food and Agriculture Organization tween 5% and 10% (2), the risk for including persons with so- cial phobia in our screened group of 18 healthy subjects was 3. Hibbeln JR: Fish consumption and major depression (letter).
low. However, we certainly agree that a detailed psychiatric examination of the subjects is highly important in studies on 4. Mitchell DC, Gawrisch K, Litman BJ, Salem N Jr: Why is docosa- hexaenoic acid essential for nervous system function? Bio-chem Soc Trans 1998; 26:365–370 References
5. Hibbeln JR, Umhau JC, George DT, Shoaf SE, Linnoila M, Salem 1. Fahlén T: Personality traits in social phobia, I: comparisons N Jr: Plasma total cholesterol concentrations do not predict with healthy controls. J Clin Psychiatry 1995; 56:560–568 cerebrospinal fluid neurotransmitter metabolites: implications 2. Stein MB: Phenomenology and epidemiology of social phobia.
for the biophysical role of highly unsaturated fatty acids. Am J Int Clin Psychopharmacol 1997; 12(suppl 6):S23–S26 6. Peet M, Murphy B, Shay J, Horrobin D: Depletion of omega-3 fatty acid levels in red blood cell membranes of depressive pa- tients. Biol Psychiatry 1998; 43:315–319 7. Stoll AL, Severus E, Freeman MP, Rueter S, Zboyan HA, Dia- mond E, Cress KK, Marangell LB: Omega-3 fatty acids in bipolar Lack of Seasonal Mood Change in Icelanders
disorder: a preliminary double-blind, placebo-controlled trial.
Arch Gen Psychiatry 1999; 56:407–412 TO THE EDITOR: The finding of a lack of seasonal affective disor- ders in Iceland, from a study by Magnusson et al. (1), is strik- ing, especially when compared with findings from other countries of similar latitude. One reason for this finding maybe the high content of fish in the Icelandic diet (225 lb per per- Antidepressant Use Among Elderly Patients
son per year) (2). The authors noted a similar and unexpectedprevious finding of a low prevalence of seasonal affective dis- TO THE EDITOR: Muhammad M. Mamdani, Pharm.D., M.A., orders in Japan, which also has a high per capita intake of fish M.P.H., et al. (1) recently reported that the prevalence of anti- (147 lb per person per year) (2). Despite a greater exposure to depressant use among the elderly population of Ontario in- light in winter, most other countries have higher rates of sea- creased from 9.3% in 1993 to 11.5% in 1997—a 24% increase sonal affective disorder. Per capita fish intake in pounds per from baseline. Annual antidepressant costs in this population person per year is as follows: Canada, 51; Finland, 72; Nether- increased by 150%, from $10.8 million in 1993 to $27 million lands, 25; Sweden, 59; Switzerland, 30; United Kingdom, 41; in 1997. These increases were mainly accounted for by steady and the United States, 48 (2). We suggest that the difference in growth in the use of selective serotonin reuptake inhibitors the prevalence of seasonal affective disorders between Icelan- (SSRIs). The authors lauded the increased use of antide- Am J Psychiatry 158:2, February 2001 LETTERS TO THE EDITOR
pressants (on the assumption that more cases of late-life Dr. Mamdani and Colleagues Reply
depression are now being treated) but questioned the cost-effectiveness of prescribing SSRIs in favor of the less expen- TO THE EDITOR: Drs. Flint and Silveira have raised several im- sive tricyclic antidepressants. In particular, they argued that portant issues that warrant further consideration. As dis- there is little evidence from meta-analyses of controlled trials cussed in our study, the use of tricyclic antidepressants in the that SSRIs and tricyclic antidepressants differ in efficacy or elderly should be limited to secondary amine tricyclic antide- overall frequency of adverse effects (1).
pressants, such as nortriptyline, given their favorable adverseeffect profile relative to tertiary amine tricyclic antidepres- Unfortunately, the rigor of prescribing tricyclic antidepres- sants, such as amitriptyline. Unfortunately, findings from sants in research studies usually does not carry over to prac- studies primarily based on tertiary amine tricyclic antide- tice in the community. There is abundant evidence that in pri- pressants are often generalized to include secondary amine mary care settings, where most antidepressants are used, tricyclic antidepressants, which may not be appropriate. The tricyclic antidepressants are seldom prescribed at doses that evidence for inadequate tricyclic antidepressant prescribing, are effective for the treatment of major depression (2, 3).
to which Drs. Flint and Silveira refer, is based primarily on ter- Moreover, the most frequently prescribed tricyclic antide- tiary amine tricyclic antidepressants. These conclusions may pressants are tertiary amine drugs (3, 4), which are probably not be generalizable, since prescribing practices may be least likely to be tolerated by elderly patients (5). In contrast, much more favorable for secondary amine tricyclic antide- the vast majority of patients treated with SSRIs receive an ef- pressants (1). Furthermore, numerous studies have demon- fective dose (2, 3). Also, in clinical practice settings, discontin- strated that treatment with nortriptyline is not associated uation rates appear to be lower for SSRIs than for tricyclic an- with a higher dropout rate than with SSRI treatment (2).
tidepressants (4, 6). Thus, there is good reason to believe thata prescription for an SSRI is more likely to result in adequate Although we concur that SSRIs possess more favorable dos- treatment of depression in elderly patients than is a prescrip- ing characteristics and may be more suitable for select groups tion for a tricyclic antidepressant.
of patients, such as those with ischemic heart disease (3), Although the overall frequencies of side effects may be sim- much more information is needed to determine the appropri- ilar for tricyclic antidepressants and SSRIs, there are impor- ate role of SSRIs and justify such dramatic shifts in prescrib- tant differences between these drugs in types of side effects.
ing practices. For example, recent evidence suggests that nor- In particular, SSRIs do not have significant anticholinergic, triptyline may be significantly more effective than fluoxetine hypotensive, or cardiac effects, and so, compared with tricy- in the treatment of poststroke depression (4). The Danish clic antidepressants, there are fewer limitations to their use in University Antidepressant Group found better remission the elderly (5). Thus, a broader spectrum of elderly depressed rates with tricyclic antidepressants than with SSRIs, raising patients can now be treated. Furthermore, persons aged 80 further questions about the true efficacy of SSRIs versus tricy- years or older, who are most likely to have medical or neuro- clic antidepressants (5, 6). Similarly, emerging literature on logical conditions that limit the use of tricyclic antidepres- the superiority of newer agents, such as venlafaxine, to SSRIs sants (5), are proportionally the fastest growing segment of has invoked the “dual-mechanisms” explanation that is appli- the population (7). This suggests that a diminishing percent- cable to many of the tricyclic agents as well (7). With respect age of elderly patients will be candidates for tricyclic antide- to adverse events, SSRI use may be associated with a substan- tially greater risk of major gastrointestinal bleeding, particu-larly in those taking nonsteroidal anti-inflammatory drugs References
(8). Although the frequency of adverse events associated with 1. Mamdani MM, Parikh SV, Austin PC, Upshur RE: Use of antide- secondary amine tricyclic antidepressants and SSRIs is well pressants among elderly subjects: trends and contributing fac- documented, the burden of side effects and their longer- tors. Am J Psychiatry 2000; 157:360–367 term, clinically relevant implications for patient well-being is 2. Donoghue J: Sub-optimal use of tricyclic antidepressants in pri- poorly understood. Such issues, which may be even more rel- mary care. Acta Psychiatr Scand 1998; 98:429–431 evant to an elderly population, warrant further consideration 3. Donoghue J, Katona C, Tylee A: The treatment of depression: and more stringent analyses of the risks, benefits, and costs antidepressant prescribing for elderly patients in primary care.
associated with treatment alternatives, rather than specula- tive conclusions and strong opinions.
4. Martin RM, Hilton SR, Kerry SM, Richards NM: General practitio- Although clinicians have traditionally ignored the cost of ners’ perceptions of the tolerability of antidepressant drugs: acomparison of selective serotonin reuptake inhibitors and tri- medical treatment, a growing understanding that costs are in- cyclic antidepressants. Br Med J 1997; 314:646–651 deed an important consideration in routine medical decision 5. Flint AJ: Choosing appropriate antidepressant therapy in the making is emerging. The allocation of a fixed budget, which elderly: a risk-benefit assessment of available agents. Drugs Ag- must constantly weigh the benefits of newer and often more expensive treatments against the cost of denying other bene- 6. Simon GE, Von Korff M, Heiligenstein JH, Revicki DA, Grothaus ficial therapies, makes a strong case for judicious prescribing.
L, Katon W, Wagner EH: Initial antidepressant choice in primarycare: effectiveness and cost of fluoxetine vs tricyclic antidepres- References
1. Jerling M: Dosing of antidepressants: the unknown art. J Clin 7. Desjardins B, Dumas J: Population Ageing and the Elderly. Ot- 2. Roose SP, Suthers KM: Antidepressant response in late-life de- ALASTAIR J. FLINT, M.B., CH.B., F.R.C.P.(C.), F.R.A.N.Z.C.P.
pression. J Clin Psychiatry 1998; 59(suppl 10):4–8 3. Roose SP, Laghrissi-Thode F, Kennedy JS, Nelson JC, Bigger JT Jr, Pollock BG, Gaffney A, Narayan M, Finkel MS, McCafferty J, Ger- Am J Psychiatry 158:2, February 2001 LETTERS TO THE EDITOR
gel I:. Comparison of paroxetine and nortriptyline in depressed 6. Danish University Antidepressant Group: Citalopram: clinical patients with ischemic heart disease. JAMA 1998; 279:287–291 effect profile in comparison with clomipramine: a controlled 4. Robinson RG, Shultz SK, Castillo C, Kopel T, Kosier JT, Newman multicenter study. Psychopharmacology 1986; 90:131–138 RM, Curdue K, Petracca G, Starkstein S: Nortriptyline versus flu- 7. Ferrier IN: Treatment of major depression: is improvement oxetine in the treatment of depression and in short-term re- enough? J Clin Psychiatry 1999; 60(suppl 6):10–14 covery after stroke: a placebo-controlled, double-blind study.
8. de Abajo FJ, Rodriguez LA, Montero D: Association between se- lective serotonin reuptake inhibitors and upper gastrointesti- 5. Danish University Antidepressant Group: Paroxetine: a selec- nal bleeding: population based case-control study. Br Med J tive serotonin reuptake inhibitor showing better tolerance, but weaker antidepressant effect than clomipramine in a con- MUHAMMAD M. MAMDANI, PHARM.D., M.A., M.P.H.
trolled multicenter study. J Affect Disorder 1990; 18:289–299 Reprints are not available; however, Letters to the Editor can be downloaded by Journal subscribers at Am J Psychiatry 158:2, February 2001


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