[email protected]

Letters to the Editors
Reply to the diagnoses were as follows: schizo- REFERENCES

phrenia, 10 patients; bipolar disorder + 1. Duggal HS. Risperidone-induced obsessive-
‘‘Risperidone-Induced tardive dyskinesia, 1 patient; psychotic compulsive symptoms: serotonin-dopamine im-
balance? J Clin Psychopharmacol. 2003;23:
Obsessive-Compulsive disorder not otherwise specified (NOS)
+ obsessive compulsive disorder (OCD),
681–682.
2. Alevizos B, Lykouras L, Zervas I, et al. Risp-
Symptoms: 1 patient; depression with psychotic eridone-induced obsessive-compulsive symp-
toms: a series of six cases. J Clin Psychophar-
Serotonin-Dopamine features, 1 patient; OCD, 1 patient;
schizoaffective disorder bipolar type, 1
macol. 2002;2:461–467.
3. Sinha BNP, Duggal HS, Nizamie SH. Risper-
Imbalance?’’ patient; and bipolar II disorder, 1 idone-induced obsessive-compulsive symptoms:
a reappraisal. Can J Psychiatry. 2000;45:
patient.5 The last 2 patients3,4 men- 397–398.
To the Editors: tioned by Duggal1 did not develop OC 4. Ramasubbu R, Ravindran A, Lapierre Y. Sero-
We appreciate Dr Duggal’s1 com- symptoms on reinstitution of risperi- tonin and dopamine antagonism in obsessive-
compulsive disorder: effect of atypical anti-
ments about our recent article.2 He men- done at a higher dose. Both patients had psychotic drugs. Pharmacopsychiatry. 2000;33:
tions that we focus on an association a diagnosis other than schizophrenia 236–238.
between higher doses of risperidone and and differed from their remaining coun- 5. Lykouras L, Alevizos B, Michalopoulou P,
et al. Obsessive-compulsive symptoms induced
emergence of obsessive compulsive (OC) terparts in that they were on lithium by atypical antipsychotics. A review of the re-
symptoms, found in all 6 patients with therapy. ported cases. Progr Neuro-Psychopharm Biol
schizophrenic disorder we presented. The neurobiologic substrate of the Psychiatry. 2003;27:333–346.
He also elaborates further on our postu- primary disorder should be considered
lation regarding a serotonin-dopamine as a potent contributing factor in the
production of OC symptoms. Typical
imbalance as a possible mechanism of
OC symptom production raising impor- antipsychotics and other psychotropic
Fluvoxamine and
tant issues. He reports on a case in which drugs, for example, serotonergics and Graded Psychotherapy
lithium, may modify it. Having in mind
OC symptoms emerged at a dose of 4
mg/d, which is apparently not a low the above, differences in terms of neu-
in the Treatment of
dose, but they did not reemerge at a robiologic substrate and the use of lith- Bulimia Nervosa
dose of 6 mg/d.3 The same was the case ium that characterized the 2 patients
for another patient (doses: 1 and 3 mg/d, should be taken into account. A Randomized,
respectively4). Due to the complexity of sero- Double-Blind,
A MEDLINE search of the litera- tonergic neurotransmitter system, the
ture from 1990 to 2002 disclosed 10 ad- limited knowledge of the dopamine Placebo-Controlled,
ditional reports. These reports included abnormalities in OCD, and involvement Multicenter Study
10 cases in which a de novo emergence of the non-5-HT2 and D2 receptors and of Short-term and
or exacerbation of OC symptoms during other neurotransmitter systems, identi-
treatment with risperidone emerged. In fication of pathogenetic mechanisms Long-term
all but 1 case, the dose was 3 mg/d or involved in the induction of OC symp- Pharmacotherapy
higher: 6 mg/d, 4 patients; 5 mg/d, one toms is apparently difficult. However, Combined With
patient; 4 mg/d, 3 patients; and 1 mg/day, investigations of the dose-response be-
1 patient. It is worth noting that con- tween OC symptoms and atypical anti- a Stepped Care Approach
trary to risperidone, clozapine induced psychotics are recommended.4 to Psychotherapy
OC symptoms (30 cases) at a broad dos-
age spectrum. Another observation was Basil Alevizos, MD
that, in most cases in risperidone, OC Lefteris Lykouras, MD To the Editors:
symptoms emerged shortly after initia- Iannis M. Zervas, MD Fluvoxamine is a selective seroto-
tion of treatment and rapid escalation of George N. Christodoulou, nin reuptake inhibitor which has shown
the dose. As Dr. Duggal pointed out, the MD, FICPM, FRCPsych promise in the treatment of bulimia
5-HT2A/D2 antagonism of risperidone Athens University, Department of nervosa (BN) in an open pilot study1
differs concerning low and high doses. Psychiatry, Eginition Hospital, and was found to reduce relapse after in-
It is worth noting that in 16 cases Athens, Greece patient treatment of BN.2,3 Fluvoxamine
reported in the literature, including ours, [email protected] also reduced bingeing in obese people
Journal of Clinical Psychopharmacology Volume 24, Number 5, October 2004 549
Copyr ight © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Letters to the Editors Journal of Clinical Psychopharmacology Volume 24, Number 5, October 2004
with binge-eating disorder in open4 term fluvoxamine (50%) (see Fig. 1 for B = bulimic behavior; I = intake of food;
and placebo-controlled evaluations,5 al- CONSORT diagram). Exclusion criteria N = nervosa characteristics; G = grade of
though 1 study only found this effect if were pregnancy, breast-feeding, or no effect on quality of life; E = extracted
fluvoxamine was used in combination adequate contraception; psychosis or ac- bulimic severity index), Clinical Global
with cognitive-behavioral therapy6. The tive suicidality; any clinically important Impression Scale,8 Hamilton Depression
aims of the present study were (1) to medical illness; multiple drug allergies Rating Scale,9 Bulimic Investigatory
assess the efficacy of fluvoxamine in the or substance dependence; any serious Test Edinburgh,10 and Eating Disorders
treatment of BN, both in the short-term laboratory abnormality; treatment with Inventory.11 During part I, patients re-
and over 12 months; (2) to assess the risk psychoactive medication or appetite sup- corded their bulimic symptoms in a di-
of relapse after discontinuation of flu- pressants within 2 weeks of allocation to ary. The BINGE scale was rated at each
voxamine; and (3) to assess the need for double-blind drug; failure to take med- visit, all other outcomes were assessed
the addition of psychologic treatment ication as instructed during the washout at regular intervals. Safety measures in-
to fluvoxamine. period; or less than 2 binges per week cluded adverse experiences, clinical lab-
The study was a 1-year, prospec- at baseline. oratory findings, physical examination,
tively randomized, double-blind, place- During part I of the study, patients and vital signs.
bo-controlled 3-way parallel group study were seen weekly, whereas in part II, A primary outcome variable dur-
conducted in 5 centers in the United assessments occurred monthly until week ing both parts I and II was the Bulimic
Kingdom. The 3 groups were (a) a short- 24 and then at weeks 32, 40, and 52. Severity Index on the BINGE scale.
term fluvoxamine group, who received Outcomes were assessed on the follow- (This was rated in relation to Diagnostic
fluvoxamine for the first 8 weeks of the ing scales: the BINGE scale (an inves- and Statistical Manual of Mental Dis-
double-blind period then placebo for the tigator assessment of bulimic symptoms, orders, Revised Third Edition diagnostic
following 44 weeks (Flu!Pla); (b) a
long-term fluvoxamine group, who re-
ceived fluvoxamine throughout the dou-
ble-blind period (Flu!Flu); and (c) a
placebo control group, who received
placebo throughout (Pla!Pla). The
study was divided into 2 parts. Part I
consisted of 8 weeks of double-blind
medication treatment, with limited sup-
port (level I psychotherapy). Patients’
dose of medication was increased from
1 tablet a day (50 mg) to a maximum
of 6 tablets a day (300 mg). Part II con-
sisted of a 44-week period of double-
blind treatment. In part II of the study,
each center could offer 2 further pre-
specified levels of psychotherapy (lev-
els II and III) depending on patients’
response to treatment.
Sample size was determined by an
a priori power calculation. Two hundred
and sixty-seven female outpatients with
Diagnostic and Statistical Manual of
Mental Disorders, Revised Third Edi-
tion bulimia nervosa, who were between
18 and 50 years old and weighed be-
tween 85% and 115% of ideal body
weight7 gave informed consent for par-
ticipation in the study and following a
2-week single-blind washout phase, were
randomized to either placebo (25%),
short-term fluvoxamine (25%), or long- FIGURE 1. Flow of patients through the trial.
550 n 2004 Lippincott Williams & Wilkins
Journal of Clinical Psychopharmacology Volume 24, Number 5, October 2004 Letters to the Editors
criteria: 1 indicates in full remission; 2, of relapse and time to relapse in part II of out additional psychotherapy. This con-
in partial remission (mild); 3, in partial the study. Logistic regression was used trasted with 5 (11%) patients after short-
remission (moderate); 4, actively bulim- for the analysis of binary variables. term fluvoxamine and 10 patients (12%)
ic according to diagnostic criteria; and 5, Continuous data were analyzed by para- after long-term fluvoxamine. Overall,
extremely severe disorder). During part metric analysis of variance unless the the figures for the ‘‘performance index’’
I, the second primary outcome variable assumptions underlying this procedure levels of 1, 2, 3, or 4 at week 52 for the
was the percent reduction of binges were violated, in which case corre- 3 groups were Flu!Flu group: 10, 9, 6,
‘‘over the last week’’ (taken from the sponding nonparametric methods were and 48 patients, respectively; Flu!Pla
patient diary) and computed as a per- used. All tests were 2-sided. group: 5, 9, 1, and 27 patients; and for the
centage of the mean number of binges During part I, there were 19 se- Pla!Pla group: 1, 10, 4, and 31 patients.
during the last 2 weeks of the baseline rious adverse events according to Food Our study shows that in the treat-
period. and Drug Administration criteria12 17 of ment of BN, short-term fluvoxamine
During part II, further primary which were in the fluvoxamine group. was no more effective than placebo,
outcome variables were: These included 3 patients with grand mal and long-term fluvoxamine was not su-
1. A ‘‘performance score’’ defined as fits. In general, fluvoxamine was better perior to short-term fluvoxamine or to
follows: 1, the patient maintains re- tolerated during part II of the study. Of placebo. However, long-term fluvox-
mission (see below) while receiving the 14 dropouts due to adverse experi- amine appeared to confer some bene-
level I psychotherapy; 2, the patient ences in this part of the study, 5 were due fit as a greater proportion of patients
maintains remission while receiving to liver function test abnormalities, and taking the drug achieved remission
level II psychotherapy; 3, the patient all of these patients had been treated with without additional psychotherapy. How-
maintains remission while receiving fluvoxamine. ever, these findings are tempered by
level III psychotherapy; and 4, the During part I, there were no dif- the fact that fluvoxamine gave rise to a
patient fails to maintain remission. ferences between the fluvoxamine and rather high frequency of unwanted ef-
A patient was defined as maintaining placebo group on either of the 2 primary fects (especially seizures and impaired
remission if she had a bulimic se- outcome variables. During part II, there liver function).
verity index of 1 or 2 at the stated visit was no difference between the 3 treat- The lack of apparent efficacy of
and at all visits during the previous ment groups in terms of the bulimic fluvoxamine in this trial is unexpected
8 weeks (12 weeks in the case of severity index, ‘‘performance score’’ or as many antidepressant drugs have been
week 52). A patient failed to maintain proportions of patients with good or found to have short-term benefits in bu-
remission if she provided an extracted poor outcome. The remission rates at limia nervosa. In particular, fluoxetine,
bulimic severity index at all qualify- week 52 (defined as maintaining a bu- another selective serotonin reuptake
ing visits but did not satisfy the def- limic severity index of 1 or 2 over at inhibitor, has been evaluated and used
inition of maintaining remission. least 8 previous weeks) were 34% for the widely for the treatment of bulimia
2. The proportion of patients assessed Flu!Flu group, 36% for the Flu!Pla nervosa. One possibility is that phar-
as having a good outcome on an group, and 33% for the Pla!Pla group. macologic differences between these
outcome score with ‘‘good’’ defined At some time points (between weeks 12 2 drugs may account for the differences
as categories 1, 2, and 3 on the per- and 20), the CGI scores favored short- in efficacy.13 Alternatively, the question
formance score and ‘‘poor’’ if the term fluvoxamine over placebo. The arises whether there was anything about
patient failed to maintain remis- relevance of this is unclear as the short- the present study in terms of the design,
sion (category 4 of the performance term fluvoxamine patients (now on pla- sample characteristics, medication com-
score). cebo) also appeared to do better than pliance, or placebo response that might
3. The Clinical Global Impression ‘‘se- those patients who remained on flu- account for our negative findings. How-
verity of illness’’ score8 defined as 1, voxamine. The picture on secondary ever, this does not seem to be the case.
normal, not ill at all; 2, borderline outcome variables was equally disap- For example, compared to the Fluox-
mentally ill; 3, mildly ill; 4, moder- pointing. One supplementary analysis etine Multicenter Trial14 part I of the
ately ill; 5, markedly ill; 6, severely was of interest. While analysis of present study had a very similar design,
ill; and 7, among the most extremely the ‘‘performance index’’ score itself used the same diagnostic criteria, and
ill patients. showed no treatment-related effects, had a similar primary outcome measure,
In both parts of the study observed analysis of those patients who did similar baseline severities, and very com-
cases analyses were performed at each achieve remission showed consistent parable placebo responses. Drug dosage
visit. To account for dropouts, last fluvoxamine benefits. Thus, at week 52, might be relevant, since in the fluox-
observation carried forward analyses only one placebo patient (2% of the part etine study, only higher doses were asso-
were performed in part I and analyses II group) achieved this remission with- ciated with benefit. Thus, it is possible
n 2004 Lippincott Williams & Wilkins 551
that, with higher doses of fluvoxamine, Jenny Munro, DPhilx Department of Health, Education and Wel-
fare; 1976:227–340.
the drug might have proved superior Richard Newton, MDx 9. Hamilton M. Development of a rating scale
to placebo. However, the frequency of Jane Tiller, MD* for primary depressive illness. Br J Soc
side effects might well have precluded Mark L. Tattersall, MD{ Clin Psychol. 1967;6:278–296.
10. Henderson M, Freeman CPL. The BITE: a
patients tolerating this. Christine Vize, MDz self-rating scale for bulimia. Br J Psychiatry.
Our sole positive finding of an Jenny Webster, PhDk 1987;150:18–24.
association between having taken flu- *Institute of Psychiatry, London, UK; 11. Garner DM, Olmsted MP, Polivy JP. Devel-
ySolvay Pharmaceuticals, B.V., opment and validation of a multidimensional
voxamine and achieving remission with- eating disorder inventory for anorexia ner-
out additional therapy during part II is Weesp, The Netherlands; vosa and bulimia. Int J Eat Disord. 1983;2:
in line with the findings by Fichter et al3 zDepartment of Psychiatry, Addenbrooke’s 15–34.
Hospital, Cambridge, UK; 12. Food and Drug Administration. COSTART—
who showed that fluvoxamine was su- Coding Symbols for a Thesaurus of Adverse
xRoyal Edinburgh Hospital, Edinburgh, UK;
perior to placebo in reducing the return Reaction Terms. National Adverse Drug
kDepartment of Psychiatry, Leicester Reaction Directory. Rockville, MD: De-
of bulimic behavior. General Hospital Leicester, UK and partment of Health Education and Welfare,
Compared to other patient popu- {Gordon Hospital, London, UK Public Health Service, US Government Print-
lations,15 there was a high frequency [email protected] ing Office; 1985.
of treatment emergent signs and symp- 13. Stahl SM. Essential Psychopharmacology
of Depression and Bipolar Disorder. Cam-
toms, withdrawals for adverse experi- bridge, UK: Cambridge University Press;
ences, and potentially serious adverse ACKNOWLEDGMENTS 2000;100–103.
experiences associated with fluvoxamine. 14. Fluoxetine Bulimia Nervosa Collaborative
The study was funded by a grant
Study Group. Fluoxetine in the treatment
Of most concern were the 3 patients from Solvay Duphar B.V. awarded to of bulimia nervosa. A multi-centre, placebo-
who had grand mal seizures. In all P.J. Cooper, C.P.L. Freeman, R.L. controlled, double-blind trial. Arch Gen
3 cases, this occurred within the first Palmer, G. Russell, and E. Shur. We Psychiatry. 1992;49:139–147.
15. In: Cobb J, ed. Fluvoxamine: New Perspec-
6 weeks of fluvoxamine treatment. Sei- thank Mr. Geoff Ashford, Solvay Phar- tives in Clinical Practice. Int Clin Psycho-
zure is a recognized but infrequent maceuticals for his helpful comments pharmacol 6:suppl 3.Oxford, UK: Clinical
complication of BN.16 However, in a on the manuscript. Neuroscience Publications; 1991.
16. Pope HG, McElcroy SL, Keck PE, et al.
study17 of 55 patients taking buprop- Electrophysiologic abnormalities in bulimia
rion, 4 had seizures (7.2%). In the pres- and their implications for pharmacother-
ent study with a 3:1 randomization, the REFERENCES apy: a reassessment. Int J Eat Disord. 1989;
8:191–201.
occurrence of 3 fits in those treated with 1. Ayuso-Gutierrez JL, Palazon M, Ayuso-Mateos 17. Horne RL, Ferguson JM, Pope HG Jr, et al.
fluvoxamine could be a chance finding, JL. Open trial of fluvoxamine in the treatment Treatment of bulimia with bupropion: a
of bulimia nervosa. Int J Eat Disord. 1994;15: multicenter controlled trial. J Clin Psychiatry.
but it cannot be excluded that fluvox- 245–249. 1988;49:262–266.
amine exacerbated the propensity of 2. Fichter MM, Leibl C, Kruger R, et al. Effects of
these patients to have fits. fluvoxamine on depression, anxiety, and other
areas of general psychopathology in bulimia
Overall, we cannot recommend
the use of fluvoxamine in the treatment
nervosa. Pharmacopsychiatry. 1997;30:85–92.
3. Fichter MM, Kruger R, Rief W, et al. Fluvox-
A Prospective
of patients with BN in view of the lim- amine in prevention of relapse in bulimia
nervosa: effects on eating-specific psychopa-
Multicentric Trial for
ited evidence of benefit, problems of tol-
eration, and doubts about the safety of
thology. J Clin Psychopharmacol. 1996;16:9–18.
4. Gardiner HM, Freeman CP, Jesinger DK, et al.
Effectiveness and
the drug in this population. Fluvoxamine: an open pilot study in moderately
obese female patients suffering from atypical
Tolerance of a N2O/O2
eating disorders and episodes of bingeing. Int
J Obes Relat Metab Dis. 1993;17:301–305.
Premix Used as a
Ulrike Schmidt, MD* 5. Hudson JI, McElroy SL, Raymond NC, et al.
Fluvoxamine in the treatment of binge-eating
Sedative Drug
Peter J. Cooper, PhDz disorder: a multicenter placebo-controlled,
Hans Essers, MScy double-blind trial. Am J Psychiatry. 1998;
Christopher P.L. Freeman, MDx 155:1756–1762. To the Editors:
6. Ricca V, Mannucci E, Mezzani B, et al.
Robert L. Holland, MD, PhDy Fluoxetine and fluvoxamine combined with Many expanded research reports
Robert L. Palmer, MDk individual cognitive-behaviour therapy in binge have been published in the field of
Eric Shur, MD{ eating disorder. A one-year follow-up study. nitrous oxide (N2O) medical uses, but
Psychother Psychosom. 2001;70:298–306.
Gerald F.M. Russell, MD* 7. Metropolitan Life Insurance Company. Metro- few studies give evidence-based results.
Clare Bowler, MDk politan height and weight tables. Statistical The different indications for N2O have
Sian Coker, DPhilz Bulletin of the Metropolitan Life Foundation. influenced the protocols for its adminis-
1983;64:3–9.
John R. Geddes, MDx 8. Guy W. ECDEU Assessment Manual for tration independently from the pharma-
Fiona Mackenzie, MDk Psychopharmacology. Rockville, MD: US cologic effects of the gas. Protocols vary
in the following ways: (1) N2O titration: focused on the sedative effects of this in a different order) for scoring by each
N2O may be administered using a med- drug and does not evaluate analgesic investigator at 1-week intervals. Neither
ical device with 2 bottles, which allows properties. the center (P = 0.109) nor the investiga-
the percentage of N2O to be varied The protocol was approved by the tor (P = 0.353) was correlated to the
between 0% and 70%, or using a premix local ethical committee (project N8 AU Venham score (General Linear Models
of 50% N2O and oxygen (O2), which is 402). Data management was conducted procedure). Finally, the safety of the
considered as a drug and delivered in a in accordance with Good Clinical Prac- method was assessed by the percentage
single cylinder. The 2-bottle system im- tice, a standard for clinical trials that of sessions during which adverse events
plies a titrated induction procedure,1–3 provides assurance that the reported occurred.
while no progressive titration takes place results are accurate and that the rights The included patients could be
when using the prefixed mixture.4–7 (2) of human subjects are protected.15 divided into 3 groups: (i) 333 patients
N2O/O2 ratio during treatment: some Patients for whom conventional with intellectual disability (22.7 ± 13.3
authors report the use of a set 50% N2O dental treatment had failed due to in- years), (ii) 193 precooperative children
concentration,4–7 while others titrate the sufficient cooperation were referred to (3.6 ± 1.1 years, and (iii) 135 patients
ratio for each patient according to patient 7 French dental centers over a 1-year with dental phobia (10.9 ± 9.1 years).
cooperation, the suitable ratio of N2O to period. Those who accept spontaneously The treatment was successfully per-
O2 ranging between 30% and 50%.1,2,8,9 to be treated by the investigator without formed in 93% of the 1205 sedation
(3) Drug associations: for dental indica- sedation were not included. A premix of sessions administered. Neither the group
tions, N2O/O2 is usually administered as 50% N2O/50% O2 (Kalinox1 170 bar, (P = 0.118, Fisher exact test) nor the
a single agent in Northern Europe, while Air Liquide Santé, Paris, France) was patient age (Wilcoxon score = 0.29)
in the USA, it is also used in combina- administered, either via a full facial or a affected the success rate. Forty-five per-
tion with other sedatives.10,11 Moreover, nasal mask depending on the age and the cent of the sessions corresponded to a
there is currently insufficient evidence to morphology and type of spontaneous repeat experience of sedation (range: 2
be able to compare the effectiveness of respiration of the patient (nose or mouth to 12 times) over the year period of
these associations as the N2O/O2 ratio breather). The gas was distributed via a the study.
varies greatly between studies. (4) Recov- modified Mappleson-D system (Inter- The sedative effect was sufficient
ery: some authors maintain that 100% surgical1). After an induction period of to improve cooperation throughout the
O2 should be administered for 2 to 5 at least 3 minutes, local anesthesia was session for the 3 groups of patients
minutes upon completion of treatment. administered for each potentially painful (Table 1). Intragroup comparison of the
This procedure was originally proposed procedure. Touch and verbal contacts Venham scores at T0, T1, and T3 showed
to avoid the risk of diffusion hypoxia1,2 were maintained at all times, and behav- that behavior improved significantly
and is applied systematically in dentistry ior management techniques appropriate during the induction period, while it
in certain countries where the 2-bottle to the patient’s cognitive capacities were worsened slightly during the act for each
system is in use, regardless of the N2O used continuously. group. However, the behavior was better
ratio administered and the duration of The success of the procedure was during the act than before starting the
the session. Reoxygenation is not under- evaluated by the percentage of sessions sedation in each group. The sedative
taken when a prefixed 50% N2O/50% where planned dental treatment could be effect appeared to be more marked in
O2 mixture is used.4,12 (5) Contraindica- completed under sedation. Cases were patients with dental fear. Intergroup
tions: the use of N2O sedation for considered to have failed when N2O comparison showed that values at T0
children under 4 years, the intellectually could not be administered, when the and T3 did not differ between patients
disabled, or patients with autism or psy- dental treatment was not performed, or with intellectual disability and preco-
chiatric illness remains contentious.8,13,14 when neither inhalation nor dental care operative children (P = 0.98 for T0 and
(6) Desired end point: the mixture of was accomplished. P = 0.26 for T3). These values were
O2 and N2O has both sedative and The modified Venham scale16 was lower in the group of patients with dental
analgesic properties. Studies need to be used by the practitioner to score patient phobia (P < 0.0001 for T0 and for T3
specifically designed to evaluate either behavior at 5 steps throughout each comparing the group with dental phobia
the sedative or the analgesic effect. session. Interinvestigator variability for with each of the other 2 groups).
This prospective multicenter trial the Venham scale was controlled be- No serious adverse events were
is the first to evaluate the effectiveness fore the study. For measuring interrater recorded. Nausea and vomiting occurred
and tolerance of nitrous oxide in accord- agreement, 13 sequences of different in 61 sessions (5%), while other minor
ance with the protocols generally ob- dental care sessions were video-recorded events occurred exceptionally (6 cases
served for drug testing, that is, as a single and proposed 3 times (the first and of sweating, pallor, or vertigo; 6 cases of
agent and at a fixed concentration. It is second times in 1 order, the third time euphoria and agitation; and 2 cases of
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2001;3:1514–1515.
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care, patient either in the waiting room or in the surgery; T0, on application of the mask to the face; T1, 5. Masood J, Shah N, Lane T, et al. Nitrous
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France; zFondation Sonnenhof, Bischwiller,
that indicates: ‘‘More knowledge is 11. Lahoud GY, Averley PA. Comparison of
France; xUnité de soins spécifiques, sevoflurane and nitrous oxide mixture with
required to understand what treatment,
Service d’Odontologie, Centre Hospitalier nitrous oxide alone for inhalation conscious
either singly or in combination, works Universitaire de Clermont Ferrand, France; sedation in children having dental treatment:
best and for whom.’’17 Kalinox1, a kFaculté de Chirurgie Dentaire, Centre a randomised controlled trial. Anaesthesia.
prefixed 50% N2O/50% O2 mixture, 2002;57:446–450.
Hospitalier Universitaire de Reims, France; 12. Quarnstrom FC, Mar RS. A premix of 50%
was shown to safely improve the ability {Faculté d’Odontologie, Service nitrous oxide–50% oxygen for sedation dur-
to cope with invasive treatment for 3 d’Odontologie, Hôpital de La Timone, ing dental procedures. Anesth Prog. 1983:
Marseille, France; #Faculté de Chirurgie 197–198.
groups of patients. These groups can thus
Dentaire, Centre Hospitalier 13. Holroyd I, Roberts GJ. Inhalation sedation
be defined as having special needs that with nitrous oxide: a review. Dent Update.
Universitaire de Nancy, France;
may indicate N2O sedation, at least for 2000;27:141–146.
**Faculté de Chirurgie Dentaire, 14. Stach DJ. Nitrous oxide sedation: understand-
dental care. The percentage of minor
Paris V, Centre Hospitalier ing the benefits and the risks. Am J Dent.
adverse effects was low and that of major Universitaire d’Ivry, France; 1995;8:47–50.
adverse effects was nil, despite adminis- yyInstitut Gustave Roussy, Paris, 15. International Clinical Harmonisation. Guid-
ance for Industry. E6 Good Clinical Practice:
tration as a single agent and at a fixed France and zzAir Liquide Santé Consolidated Guidance, 1996. Available at:
concentration, lack of titration of the International, Paris, France http://www.fda.gov/cder/guidance/index.htm.
N2O during the induction period, and the [email protected] 16. Veerkamp SJ, Gruythuysen JM, vanAmerongen
WE, et al. Dental treatment of fearful chil-
absence of intentional reoxygenation dren using nitrous oxide. Part 3: Anxiety
during recovery. In particular, this study during sequential visits. J Dent Child. 1993;
questions certain procedures that are ACKNOWLEDGMENT 60:175–181.
17. World Health Organization. Mental health:
applied dogmatically for the administra- This study was supported finan- new understanding, new hope. Geneva, 2001.
tion of N2O in dentistry. cially by Air Liquide Santé International. Available at: http//www.who.int/whr2001.
Effectiveness of Orlistat profile of orlistat, the authors proposed change was 0.35 for orlistat and
and completed a pilot case control study +0.37 for controls. Between subjects
Versus Diet and that sought to compare the effectiveness design statistical analysis showed no
Exercise for Weight of orlistat versus a diet and exercise
educational support group.
statistical significance between groups
(Table 1). However, it should be noted
Gain Associated With Eleven subjects who had gained at that there was an average of 50% more
Antidepressant Use least 10 lb after being started on an
antidepressant were allowed to enter this
weight loss and 25% lessening of body
mass index and body fat percentage
A Pilot Study prospective, case control study after in orlistat-treated subjects. Orlistat was
informed consent. All subjects attended relatively well tolerated with gastroin-
1-hour, didactic diet and exercise work- testinal complaints only. These generally
To the Editors: shops every other week for 3 months for lessened with time. Two orlistat subjects
Weight gain is an unfortunate, yet 6 sessions. Six subjects were randomly exited the study in the first few days due
common, side effect of many psychotro- assigned to take orlistat 120 mg 3 times to diarrhea; they were not included in
pic medications. The amount and mech- daily with meals while attending work- data analysis. Four diet-and-exercise-
anism by which weight is induced have shops. All orlistat subjects took a only subjects were excluded as they
been largely addressed for mood stabil- multivitamin due to potential vitamin failed to attend most of the classes.
izers and antipsychotics; however, there malabsorption. Subjects took their usual Weight gain, as a side effect, of
is very little literature that addresses psychiatric and medical medications 1 to psychotropics is a formidable problem.
weight gain seen with the newer anti- 2 hours apart from orlistat doses as well. There are no papers in regards to re-
depressants.1–4 This lack of current data The remaining 5 subjects acted as un- ducing antidepressant-induced weight
in regards to antidepressant use seems blinded controls and only attended di- gain by way of an augmentation strategy.
odd, in that (A) there is a clear track dactic groups. Subjects were excluded if Many psychiatric patients are unable to
record of weight-producing agents5 and other medications or medical conditions improve diet or exercise due to their
(B) antidepressant use far exceeds the could explain their weight gain. All sub- psychiatric symptoms (fatigue, amotiva-
combined use of mood stabilizers and jects confirmed that there was an abrupt tion, anhedonia, etc) which may warrant
antipsychotics in the United States. The increase in weight gain, chronologically, a pharmacologic intervention. Our re-
most commonly prescribed selective after start of an approved antidepressant. sults clearly show a 2 to 1 dropout rate
serotonin reuptake inhibitors are shown Every 2 weeks, the subject’s weight in disfavoring a diet and exercise program.
to produce a net weight gain of several pounds, body mass index, and body fat Depressed and anxious patients are more
pounds over long-term use.6 percentage were measured. The diet and likely to be able to comply with a phar-
There have been few studies that exercise didactic workshops were de- macologic diet intervention than starting
look to lower weight gain in patients signed by a registered dietician and a new diet and exercise program.
taking antidepressants. Sibutramine is exercise consultant. Initial sessions fo- What is surprising is the negative
FDA-approved to treat obesity but may cused on establishing subjects’ current statistical outcome for orlistat in this
not be used in selective serotonin re- eating habits and educated them about
uptake inhibitor patients due to risk weight-losing strategies. Lectures with
TABLE 1. Median Change From Study
of serotonin syndrome.7 Off-label ap- handouts and subsequent homework Entry to Week 7
proaches have shown amantadine,8 top- were utilized. Low level, generic exer-
iramate,9 and metformin7 to be reasonably cise plans were also suggested to sub- Diet/Exercise Orlistat P
effective in small trials. Orlistat is the jects for implementation. Change n=5 n=6 –
newest FDA-approved antiobesity agent Six subjects received orlistat plus (median)
which lowers weight by lowering fat group therapy, and 5 controls were Weight 0.5 2.5 0.225
absorption via lipase inhibition in the established and were evenly matched at (lb)
intestinal tract.10 A 2-patient case series study entry. Controls weighed 164 lb Body fat 0.1 0.4 0.662
showed that orlistat may lower weight and cases 179 lb on average before (%)
gain produced by lithium, amitryptiline, taking psychotropics. At baseline, con- Body mass 0.1 0.4 0.247
index
risperidone, and clozapine.11 An extend- trols weighed 198.3 lb and cases 210.3 lb.
ed case series revealed that 13 patients The mean weight loss for orlistat was The Exact Wilcoxon rank sum test was used to
compare the treatment groups. The change is
taking antidepressants lost a third of the 2.83 lb (controls gained 1.4 lb) over defined as follow-up minus baseline. Thus, num-
weight gain acquired from psychotropic 3 months. The mean change in body bers greater than zero represent a gain in weight,
use.12 Given the novel mechanism of mass index was 0.4 for orlistat and body fat, or body mass index, whereas negative
numbers signify a decrease (ie, improvement).
action and relatively benign side effect +0.4 for controls. Body fat percent
study. A previous extended case series12 sibutramine, orlistat and metformin in leptics in this population, as a number of
the treatment of obesity. Diabetes Obes
showed promising results for orlistat in Metab. 2002;4:49–55.
studies have described beneficial, al-
this population, but it appears that low 8. Gracious BJ, Krysiak TE, Youngstrom EA. though modest, effects of olanzapine,
level diet and exercise programs are as Amantadine treatment of psychotropic-induc- risperidone, and quetiapine7–9 on spe-
ed weight gain in children and adolescents:
beneficial as drug treatment in our pilot case series. J Child Adolesc Psychopharmacol.
cific PTSD symptoms. The relative short
data. It should be noted that the statis- 2002;12:249–257. duration of these studies may account for
tical power of this study is quite low 9. Lessig MC, Shapira NA, Murphy TK. Top- their relatively modest findings.
iramate for reversing atypical antipsychotic
given the small sample size of each weight gain. J Am Acad Child Adolesc Psych.
Risperidone is an atypical neuro-
group. When one looks at statistical 2001;40:1364. leptic with effects on dopaminergic,
trends, the orlistat group had more 10. Sjostrom L, Rissanen A, Andersen T, et al. serotonergic, and noradrenergic neuro-
Randomized placebo-controlled trial of orli-
weight loss and reduction of body mass stat for weight loss and prevention of weight
transmitter systems,10 which have been
index and body fat percentage, which regain in obese patients. Lancet. 1998;352: implicated in the pathogenesis of chronic
is of indeterminant clinical relevance. 167–173. PTSD, and could have potentially ben-
11. Anghelescu I, Klawe C, Benkert O. Orlistat
Given this, the authors suggest that diet in the treatment of psychopharmacologically
eficial effects on PTSD target symptoms.
and exercise education continue to be induced weight gain. J Clin Psychopharma- The objectives of the current
frontline treatment for antidepressant col. 2000;20:716–717. study were (1) to determine whether
12. Schwartz TL, Beale M. Psychotropic induced
induced obesity but that pharmacologic weight gain alleviated with orlistat: a case se-
prominent symptoms of chronic PTSD
approaches be considered if behavioral ries. Psychopharmacol Bull. 2003;37(1):5–8. will show improvement during a 12-
approaches fail. Future study is warrant- week adjunctive risperidone trial, in a
ed given the conflicting nature of our group of veterans with only partial
data with that previously reported.
Adjunctive response to current pharmacologic treat-
Risperidone Treatment ment; (2) to determine whether PTSD-
Thomas L. Schwartz, MD associated psychotic symptoms respond
Shefali Jindal, MD
in Combat Veterans to risperidone treatment; and (3) to
Mihai Simionescu, MD With Chronic PTSD assess the safety and tolerability of
Nikhil Nihalani, MD risperidone in this population.
Nouman Azhar, MD Twenty male Vietnam combat vet-
Syed Tirmazi, MD To the Editors: erans were recruited through the PTSD
Juhi Hussein, MD Posttraumatic stress disorder program at the Miami Veterans Affairs
Department of Psychiatry, SUNY Upstate (PTSD) develops following exposure Medical Center and signed the Veterans
Medical University, Syracuse, NY to a life-threatening event, is prevalent Affairs Medical Center institutional
[email protected] in the general population, and frequently review board–approved informed con-
becomes chronic and disabling.1 Com- sent. Subjects were included if they (1)
bat-related PTSD is frequently associat- met Diagnostic and Statistical Manual
REFERENCES ed with complex comorbidity, as well as of Mental Disorders, Fourth Edition
1. Atmaca M, Kuloglu M, Tezcan E, et al. Weight functional impairment in social, inter- criteria for PTSD as their primary diag-
gain and serum leptin levels in patients on
lithium treatment. Neuropsychobiology. 2002; personal, and occupational roles.2 Sev- nosis; (2) had been only partially re-
46:67–69. eral studies in the last 2 decades have sponsive to their present pharmacologic
2. Monteleone P, Fabrazzo M, Tortorella A, et al. also documented the occurrence of psy- treatment, as evidenced by persistent
Pronounced, early increase in circulating
leptin predicts a lower weight gain during chotic symptoms in combat veterans symptoms and functional impairment;
clozapine treatment. J Clin Psychopharmacol. with chronic PTSD,3–5 and it has been (3) were alcohol-free and drug-free for at
2002;22: 424–426. postulated that comorbid psychosis may least 2 months; (4) were medically sta-
3. Reynolds GP, Zhang ZJ, Zhang X. Association
of antipsychotic drug-induced weight gain affect severity, prognosis, and treatment ble; (5) were on stable doses of other
with a 5-HT2C receptor gene polymorphism. intervention. psychotropic medications (antidepres-
Lancet. 2002;359:2086–2087. The efficacy of serotonin reuptake sant, anxiolytic, or mood stabilizers) for
4. Ellingrod VL, Miller D, Schultz SK, et al.
CYP2D6 polymorphisms and atypical anti- inhibitors, which are the only category of the past 4 weeks; (6) did not meet current
psychotic weight gain. Psychiatr Genet. 2002; medications approved by the Food and or lifetime diagnostic criteria for a schiz-
12:55–58. Drug Administration for PTSD,6 has not ophrenia-spectrum disorder or mania;
5. Fava M. Weight gain and antidepressants.
J Clin Psychiatry. 2000;61:37–41. been established in combat veterans, and and (7) were not currently taking other
6. Masand PS, Gupta S. Selective serotonin- frequently, a combination of agents from antipsychotic medications.
reuptake inhibitors: an update. Harv Rev several psychotropic categories is used. Of the twenty subjects who signed
Psychiatr. 1999;7:69–84.
7. Gokcel A, Gumurdulu Y, Karakose H, et al. In recent years, there has been increased the informed consent, 2 were excluded
Evaluation of the safety and efficacy of interest in the use of atypical neuro- due to abnormal baseline laboratory tests
and 1 was lost to follow-up after the first a baseline medical history, vital signs, showed significant improvement at end
visit. A total of 17 patients were started and physical examination, electrocardio- point (see Table 1).
on study medication and completed at gram, and routine laboratory tests. Tests Of the secondary outcome mea-
least 6 weeks. Two discontinued after were repeated at 6 and 12 weeks. Cli- sures, there was significant improvement
6 weeks (1 due to increased sedation nicians inquired about adverse events in the Clinician-Rated Global Severity
and 1 due to lack of efficacy), and 2 were during each biweekly follow-up, and and Improvement Scale, with 8 of 17
lost to follow-up after 8 weeks. These vital signs were obtained at each visit. patients (47%) being rated as ‘‘much
last 4 subjects were included in the Side effects and adverse reactions improved’’ by the end of the study
data analysis, with the last observation were assessed with the Extrapyramidal (see Table 1).
carried forward. Thirteen subjects com- Symptoms Rating Scale, the Abnormal No major adverse events were
pleted all 12 weeks of the study, and Involuntary Movements Scale, and the observed. Abnormal Involuntary Move-
of these, 12 elected to continue risper- Treatment Emergent Symptom Scale. ments Scale score remained at 0. One
idone at study end. All subjects were The primary outcome measures subject developed mild extrapyramidal
enrolled in either the outpatient or were the Clinician-Administered PTSD side effects which responded to dose
the residential PTSD program at the time Scale and the Positive and Negative decrease, and the Extrapyramidal Symp-
of recruitment and continued to attend Syndrome Scale total and subscale toms Rating Scale showed a nonsignif-
the therapeutic activities they were scores. Secondary outcome measures icant increase compared to baseline.
attending before the beginning of the were the Clinician-Rated Global Sever- Two subjects developed transient epi-
study. ity and Improvement Scale, Hamilton sodes of sinus tachycardia, had 24-hour
Subjects’ service in Vietnam was Anxiety Scale, Hamilton Depression Holter monitor tests that were read as
verified through review of discharge Scale, and the Buss-Durkee Hostility normal, and responded to low-dose
military records (DD214). Lifetime and Inventory. Baseline ratings of the above treatment with metoprolol. One subject
current psychiatric comorbidity was instruments were compared with the 6- had a significant weight gain of 25 lb;
determined by the Mini-International week and/or 12-week ratings, by paired however, he refused to discontinue the
Neuropsychiatric Interview.11 Severity t tests, with the last observation carried risperidone due to its beneficial effects
of chronic PTSD was evaluated with forward. and was referred for diet and exercise
the Clinician-Administered PTSD Scale The 17 subjects who completed counseling. The Treatment Emergent
for Diagnostic and Statistical Manual at least 6 weeks of the study had a Symptom Scale showed significant in-
of Mental Disorders, Fourth Edition,12 mean age of 53.7 ± 3.8 years; mean crease (28.4 ± 2.1 vs. 34.3 ± 5.2, t = 4.8,
and psychotic symptom severity was education level was 13.0 ± 1.66 years df = 16, P < 0.001), and common side
assessed with the Positive and Negative (range 11 to 17); 35.3% were White, effects included dry mouth (15 of 17,
Syndrome Scale.13 Depressive and anx- 41.2% were Black, and 23.5% were 88%), mild decrease in motor activity
iety symptoms were evaluated with Hispanic. Fourteen subjects (82.4%) (9 of 17, 53%), sedation (5 of 17, 29%),
the Hamilton Depression and Hamilton had a comorbid major depressive dis- headache (3 of 17, 18%), nasal conges-
Anxiety Scales, respectively. The Cli- order, 14 (82.4%) had current or life- tion (3 of 17, 18%), tremor (3 of 17,
nician-Rated Global Severity and Im- time psychotic features, 9 (52.9%) had 18%), and constipation (3 of 17, 18%).
provement Scale was used to assess dysthymia, 7 (41.2%) had a comorbid No significant changes occurred in
severity of illness and degree of im- anxiety disorder, 12 (70.6%) had a blood count, metabolic panels, liver and
provement. Patients also completed a history of alcohol abuse, and 7 (41.2%) thyroid function tests, and lipid levels.
self-report hostility measure, the Buss- had a history of substance abuse. All Fasting glucose levels showed a trend-
Durkee Hostility Inventory.14 Struc- subjects (100%) were taking stable level increase from baseline to end
tured interviews and self-report forms doses of antidepressants at the time of of study (105.7 ± 26.8 vs. 112.1 ± 28.4,
were also obtained at 6 and 12 weeks. study enrollment; 35% were taking a t = 1.5, df = 14, P = 0.1). Prolactin levels
Risperidone was started at 1 mg at mood stabilizer, and 41% were taking were significantly elevated (8.5 ± 4.8 vs.
bedtime, and the dose was increased an anxiolytic agent. 20.4 ± 11.6, t = 3.6, df = 14, P = 0.003);
gradually until subjects reported im- Of the primary outcome mea- however, no clinical symptoms were
provement in target symptoms and/or sures, the total Clinician-Administered associated with this finding.
developed mild and tolerable side ef- PTSD Scale score and the reexperienc- In this open-label, 12-week study
fects. The mean maximum dose of ris- ing and heightened arousal subscales of adjunctive risperidone in a popula-
peridone was 2.3 ± 0.6 mg (range 1 to showed significant improvement. The tion of combat veterans with chronic
3 mg) per day. total Positive and Negative Syndrome PTSD, who exhibited only partial re-
Safety and tolerability were mon- Scale score and the Positive and Neg- sponse to their current treatment, the
itored every 2 weeks. All subjects had ative Syndrome Scale subscales all addition of risperidone resulted in
TABLE 1. Outcome Variables

Variable Baseline End of Study Significance
PANSS total 85.5 ± 18.2 73.2 ± 20.0 t = 3.8, P =
0.002, df = 16
PANSS positive 18.2 ± 5.6 14.4 ± 5.9 t = 3.7, P =
0.002, df = 16
PANSS negative 22.2 ± 6.7 18.8 ± 6.2 t = 2.8, P =
0.01, df = 16
PANSS general 45.1 ± 9.5 39.9 ± 10.3 t = 2.7, P =
0.01, df = 16
CAPS total 91.4 ± 11.8 79.7 ± 23.6 t = 2.4, P =
0.03, df = 16
CAPS reexperiencing 25.2 ± 6.2 19.4 ± 8.5 t = 3.2, P =
0.006, df = 16
CAPS avoidance 37.4 ± 8.7 35.8 ± 13.8 NS
CAPS hyperarousal 28.8 ± 3.6 25.1 ± 7.3 t = 2.5, P = 0.03, df = 16
CGI 5.6 ± 0.6 4.4 ± 1.0 t = 4.7, P = 0.001, df = 16
HAM-A 24.1 ± 11.7 22.6 ± 11.1 NS
HAM-D 20 ± 5.1 19.3 ± 7.6 NS
Buss-Durkee Hostility Inventory 59.2 ± 9.4 59.7 ± 9.4 NS
CAPS indicates Clinician-Administered PTSD Scale; CGI, Clinician-Rated Global Severity and Improvement Scale; HAM-A, Hamilton Anxiety Scale;
HAM-D, Hamilton Depression Scale; and PANSS, Positive and Negative Syndrome Scale.
improvement in specific PTSD symp- placebo-controlled trial of Hamner Comorbidity Survey. Arch Gen Psychiatry.
toms and in trauma-related psychotic et al,8 which lasted only 5 weeks. 1995;52:1048–1060.
2. Kulka RA, Schlenger WE, Fairbank JA, et al.
symptoms. These results must be con- Larger, multicenter, double-blind, Trauma and the Vietnam War Generation.
sidered preliminary. Absent a control placebo-controlled trials are needed to New York: Brunner/Mazel; 1990.
evaluate whether the use of risperi- 3. Butler RW, Mueser KT, Sprock J, et al.
condition and with ongoing psycho- Positive symptoms of psychosis in posttrau-
social interventions, it is not certain done as adjunctive treatment in chron- matic stress disorder. Biol Psychiatry. 1996;
that the observed improvements are ic PTSD, and especially in difficult 39:839–844.
to treat populations and partially re- 4. David D, Kutcher GS, Jackson EI, et al.
attributable to risperidone. The subjects, Psychotic symptoms in combat-related post-
however, had not demonstrated much sponsive cases, is indeed beneficial and traumatic stress disorder. J Clin Psychiatry.
improvement during their previous indicated. 1999;60:29–32.
5. Hamner MB, Frueh BC, Ulmer HG, et al.
treatment, which was held stable, and Psychotic features and illness severity in com-
they represent a group that is often con- Daniella David, MD*y bat veterans with chronic posttraumatic stress
sidered to be minimally responsive to Ludmila De Faria, MD*y disorder. Biol Psychiatry. 1999;45:846–852.
Olga Lapeyra, MD*y 6. Davidson JRT, Rothbaum BO, van der Kolk
therapeutic interventions. BA, et al. Multicenter, double-blind compar-
Risperidone was relatively well Thomas A. Mellman, MDz ison of sertraline and placebo in the treatment
tolerated, and only minor side effects *Department of Psychiatry and of posttraumatic stress disorder. Arch Gen
Behavioral Sciences, Psychiatry. 2001;58:485–492.
were reported. This benign side effect 7. Hamner MB, Deitsch SE, Brodrick PS, et al.
University of Miami, Miami, FL;
profile may be related to the low dose of yDepartment of Veterans Affairs
Quetiapine treatment in patients with post-
traumatic stress disorder: an open trial of
adjunctive risperidone that appears to be Medical Center, Miami, FL adjunctive therapy. J Clin Psychopharmacol.
effective in PTSD patients, as the mean and zDartmouth University 2003;23:15–20.
dose in this study was similar to the one School of Medicine, 8. Hamner MB, Faldowski RA, Ulmer HG,
et al. Adjunctive risperidone treatment in
reported by Hamner et al.8 Department of Psychiatry, Hanover, NH
post-traumatic stress disorder: a preliminary
The findings of this study are also [email protected] controlled trial of effects on comorbid psy-
limited by the small number of subjects chotic symptoms. Int Clin Psychopharmacol.
2003;18:1–8.
enrolled. However, the psychiatric and ACKNOWLEDGMENT 9. Stein MB, Kline NA, Matloff JL. Adjunctive
side effect assessments used have been This study was supported by an in- olanzapine for SSRI-resistant combat-related
well validated. The study duration of vestigator initiated research grant from PTSD: a double-blind, placebo-controlled study.
Am J Psychiatry. 2002;159:1777–1779.
12 weeks is also more consistent with Jaussen Pharmaceutica, LP. 10. Marder SR, Meibach RC. Risperidone in the
observing a new medication’s longitu- treatment of schizophrenia. Am J Psychiatry.
dinal effects and may be the reason why 1994;151:825–835.
REFERENCES 11. Sheehan DV, Lecrubier Y, Sheehan KH,
no difference in Clinician-Administered 1. Kessler RC, Sonnega A, Bromet E, et al. et al. The Mini-International Neuropsychiatric
PTSD Scale scores were found in the Posttraumatic stress disorder in the National Interview (M.I.N.I.): the development and
validation of a structured diagnostic psychi- years.2 From 1978, for all subjects in Trends in AP drug prescriptions at
atric interview for DSM-IV and ICD-10.
J Clin Psychiatry. 1998;59(suppl 20):22–33. contact with the psychiatric service, the discharge are presented in Table 1. Two
Quiz 34–57. South Verona Psychiatric Case Regis- or more AP agents were prescribed at
12. Blake DD, Weather FW, Nagy LM, et al. A ter routinely records sociodemographic hospital discharge for nearly 20% of
clinician rating scale for assessing current
and lifetime PTSD: the CAPS-1. Behav Ther. characteristics, International Classifi- subjects in 2001/2002, as compared
1990;13:187–188. cation of Diseases, Tenth Revision diag- with around 10% of subjects in previous
13. Kay SR, Fiszbein A, Opler LA. The posi- noses, past psychiatric and medical years (Table 1). Of the 37 patients re-
tive and negative syndrome scale (PANSS)
for schizophrenia. Schizophr Bull. 1987;13: history, clinical data, admissions, and ceiving 2 or more AP agents in 2001/
261–276. outpatient contacts.3 2002, 25 (67.5%) received simultaneous
14. Morrison SD, Chaffin S, Chase TV. Aggres- From the Psychiatric Case Regis- treatment with first- and second-genera-
sion in adolescents: use of the Buss-Durkee
Inventory. South Med J. 1975;68:431–436. ter, the total number of admissions to the tion agents.
inpatient unit and the total numbers of A similar proportion of subjects
consecutive patients admitted during the receiving above standard doses was ob-
The Changing Pattern years 1981/1982, 1991/1992, and 2001/
2002 were extracted. Using the Psychi-
served in 1981/1982 and in 1991/1992;
this proportion, however, increased to
of Inpatient atric Case Register patient code (a code more than 44% in 2001/2002 (Table 1).
Antipsychotic Drug that uniquely identifies individuals) and
the date of admission, we identified the
Haloperidol (mean dose 4.6 mg, SD 3.2)
was the most prescribed agents in the
Use in Italy corresponding clinical records. Clinical 3 periods, while the use of chlorproma-
records were manually reviewed by 2 zine (mean dose 146.9 mg, SD 137.2)
members of the research team to gather declined (Table 1). Quetiapine (mean
To the Editors: detailed information on psychotropic dose 416.4, SD 243.8) was the most
Emerging trends toward higher agents prescribed at discharge. AP daily prescribed second-generation agent, fol-
total antipsychotic (AP) doses and poly- doses in milligrams were converted into lowed by olanzapine (mean dose 13.7,
pharmacotherapy have been observed multiples of the defined daily dose for SD 6.2), clozapine (mean dose 394.1, SD
in the United States. Centorrino et al1 each drug by dividing the prescribed 192.5), and risperidone (mean dose 3.9,
showed that, over the past decade, sec- daily dose by the defined daily dose SD 2.3). Of the total number of patients
ond-generation AP agents have emerged [prescribed daily dose/defined daily who received AP agents at hospital
as the dominant choice among AP dose].4 A ratio of one indicates that the discharge in 2001/2002, 114 (59.3%) of
agents. Two or more AP agents were dose prescribed is equal to the defined 192 were prescribed second-generation
prescribed at discharge for more than daily dose of that drug; a ratio greater agents, and 103 (53.6%) of 192 were
15% of an inpatient population, and the than one indicates a dosage higher than prescribed first-generation agents.
total discharge dose in 1998 was 30% the standard dose, while a ratio lower At patient discharge, cotreatment
higher than the total discharge dose in than one means a low dose. Prescriptions with antidepressants and benzodiaze-
1993. In patients receiving AP agents, of first-and second-generation AP drugs pines was increasingly common, account-
cotreatment with anticonvulsants, but were characterized as off-label when ing for the majority of patients in 2001/
not cotreatment with benzodiazepines, dispensed outside the licensed indica- 2002 (Table 1). Similarly, cotreatment
was increasingly common.1 tions granted by regulatory agencies and with anticonvulsants increased, account-
To understand whether similar stated in the Italian National Formulary. ing for more than 20% of subjects in
trends are emerging outside the United During the 6 years surveyed, there 2001/2002. The proportion of patients
States, we reviewed AP prescriptions were 1142 admissions. AP agents were receiving off-label conventional AP
currently, and in 1981/1982 and 1991/ prescribed at discharge for 395 patients; agents progressively fell, being less than
1992 in South Verona, an area contain- 180 (45.5%) of whom were males and 20% in 2001/2002. In contrast, the pro-
ing approximately 100,000 inhabitants, 215 (54.5%) were females. The patients’ portion of patients receiving off-label
which includes part of the city of Ve- mean age was 45.8 [standard deviation second-generation AP was more than
rona and 3 neighboring small towns. In (SD) 15.6, range 15 to 93], and they were 50% in 2001/2002.
this catchment area, a comprehensive hospitalized for a mean of 23.5 days To investigate factors associated
service providing inpatient, outpatient, (SD 49.1). Their International Clas- with high total discharge dose, multivar-
and community care was set up in 1978. sification of Diseases diagnoses were iate analysis was applied. Four factors
The group stresses psychosocial ap- primarily psychosis (49.5%), bipolar were associated with high total dose:
proach, with strong emphasis on rational disorder (13.8%), personality disorder diagnosis of psychosis (odds ratio 2.36,
drug use.2 No major changes have oc- (12.3%), major depression (10.8%), and 95% confidence interval 1.46, 3.82), use
curred in its organization in the last 25 miscellaneous disorders (13.6%). of 2 or more AP agents (odds ratio 7.82,
TABLE 1. Trends in Antipsychotic Drug Use in 1981/1982, 1991/1992, and 2001/2002

1981/1982 1991/1992 2001/2002
n/N % (CI) n/N % (CI) n/N % (CI) Trend

Two or more AP 12/93 12.9 (6.8, 21.4) 12/110 10.9 (5.7, 18.2) 37/192 19.2 (13.9, 25.5) z = 1.69, P = 0.09
agents at hospital
discharge
PDD/DDD greater 29/91 31.8 (22.4, 42.4) 36/109 33.0 (24.3, 42.6) 85/192 44.2 (37.1, 51.5) z = 2.19, P = 0.03
than one
Haloperidol 24/93 25.8 (17.2, 35.9) 36/110 32.7 (24.0, 42.3) 63/192 32.8 (26.2, 39.9) z = 1.09, P = 0.27
Chlorpromazine 19/93 20.4 (12.7, 30.0) 22/110 20.0 (12.9, 28.6) 19/192 9.8 (6.0, 15.0) z = 2.59, P = 0.01
Clozapine — — — — 17/192 8.8 (5.2, 13.7) —
Olanzapine — — — — 38/192 19.7 (14.4, 26.1) —
Risperidone — — — — 16/192 8.3 (4.8, 13.1) —
Quetiapine — — — — 44/194 22.9 (17.1, 29.5) —
Antidepressants with 11/93 11.8 (6.0, 20.1) 16/110 14.5 (8.5, 22.5) 69/192 35.9 (29.1, 43.1) z = 4.90, P < 0.001
AP agents at
hospital discharge
Benzodiazepines with 29/93 31.1 (21.9, 41.6) 69/110 62.7 (52.9, 71.7) 120/192 62.5 (55.2, 69.3) z = 4.53, P < 0.001
AP agents at hospital
discharge
Anticonvulsants with 7/93 7.5 (3.0, 14.8) 8/110 7.2 (3.1, 13.8) 41/192 21.3 (15.7, 27.8) z = 3.54, P < 0.001
discharge
Off-label conventional 29/93 31.1 (21.9, 41.6) 18/110 16.3 (9.9, 24.6) 13/78 16.6 (9.1, 26.8) z = 2.39, P = 0.02
discharge
Off-label second-generation 49/89 55.0 (44.1, 65.6)
AP agents at
hospital discharge
CI indicates confidence interval; DDD, defined daily dose; PDD, prescribed daily dose.
95% confidence interval 4.13, 14.8), length nation of first- and second-generation vulsants only. In addition, we recorded a
of illness of 20 years or more (odds ratio agents was the most frequent therapeutic growing proportion of subjects receiving
2.68, 95% confidence interval 1.62, option. Polypharmacy is a growing in- AP agents together with antidepressants
4.44), and admission in 2001/2002 (odds ternational phenomenon with potential- and benzodiazepines. These data high-
ratio 1.85, 95% confidence interval 1.11, ly important consequences in terms of light a potentially serious emerging prob-
3.07). Age, sex, and number of days in economic costs, side effects, and risks lem of polypharmacy involving agents
hospital were not associated with high of drug interactions. By multivariate belonging to different pharmacologic
dose. analysis, total discharge dose was sig- classes, with possible negative conse-
The use of AP agents in South nificantly higher for patients prescribed quences for patients whose adherence
Verona was surprisingly similar to that 2 or more agents, suggesting an emerg- to treatment is usually very low.6
described in selected areas of the United ing trend toward the prescription of Finally, a regulatory issue is emerg-
States. Second-generation AP agents moderate doses of multiple agents ing in Italy and in all other European
accounted for 72% of AP prescribed at simultaneously. countries belonging to the European
the McLean Hospital, Massachusetts, Baldessarini et al,5 who analyzed Union.7 While the proportion of subjects
in 1998, with nearly 16% of patients recent (1989) and then current (1993) use receiving off-label prescriptions of con-
receiving 2 or more AP agents at hospital of AP agents by psychiatric inpatients, ventional agents has progressively fall-
discharge.1 In our sample, 60% of sub- showed that cotreatment with anticon- en, the proportion of off-label use of
jects received second-generation agents, vulsants, but not cotreatment with ben- second-generation agents accounted for
and the proportion of polypharmacy at zodiazepines, was increasingly common. nearly 50% of patients. Approved labels
hospital discharge was 20%. A combi- We replicated this finding for anticon- for second-generation AP agents explain
these findings, since they cover a much

narrower range of indications than any
The Reliability of the role of observer. Two weeks after the
initial rating, a third interviewer made
of the old agents; these indications, more- Mini-International an independent assessment, blind to the
over, are difficult to reconcile with the
clinical trials data.8 Likely, the Euro-
Neuropsychiatric result of the first interview (test-retest
reliability test). The 3 raters were as-
pean Agency for the Evaluation of Interview—Italian signed to the roles of interviewer, ob-
Medicinal Products will address this
issue by implementing more homoge-
Version server, and reinterviewer, according to
a fully balanced, randomized design.
nous and evidence-based regulatory pol- For both the interrater and the
icies throughout the European Union. test-retest comparison, we used the
To the Editors: Cohen kappa (j) coefficient. There are
The Mini-International Neuropsy- several version of kappa; Cohen j is
Corrado Barbui, MD* chiatric Interview (MINI) is a short di- used for categorical data where 2 raters
Arcangelo Ciuna, MD* agnostic structured interview developed only have rated each subject. Cohen j
Michela Nosé, MD* in the United States and Europe, de- statistic5 is an index of the diagnostic
Deborah Levi, MD* signed to generate positive diagnosis agreement commonly used in psychiat-
Scott B. Patten, MDy for the main Diagnostic and Statistical ric research, and it is the statistic of
Francesco Amaddeo, MD* Manual, Revised Third Edition/Fourth choice for categorical data as it adjusts
Michele Tansella, MD* Edition disorders. The instrument was the observed agreement rate for agree-
*Section of Psychiatry, Department of validated by a cross-national study in- ment due to chance. This characteristic
Medicine and Public Health, University of volving more than 600 subjects.1 The has made it increasingly popular in
Verona, Verona, Italy and concordance and psychometric values studies of observer variability, but it
yDepartments of Community Health
of the MINI were found to be satisfac- has a significant disadvantage: when the
Sciences and Psychiatry, University of
tory for most diagnoses, including psy- prevalence of 1 of the 2 categories of
Calgary, Calgary, Alberta, Canada
[email protected] chotic disorders. However, as far as we the response is very high, 2 observers
know, the reliability of the interview can get low values for j, despite high
has only been proven for the English agreement. Cicchetti and Feinstein6
and French versions.2,3 The question of have suggested a simple way to solve
the reliability of the instrument in its the problem: the j index should always
REFERENCES Italian version still remains, and it may be accompanied by the observed pro-
1. Centorrino F, Eakin M, Bahk W-M, et al. be particularly relevant in conducting portion of positive (Ppos) and negative
Inpatient antipsychotic drug use in 1998, 1993, multicenter clinical trials, where pa- (Pneg) agreement.
and 1989. Am J Psychiatry. 2002;159: tients have to be interviewed in Italian, Four of the fifty patients involved
1932–1935.
2. Tansella M, Burti L. Integrating evaluative using a short psychiatric interview, ei- in this study missed the retest appoint-
research and community-based mental health ther in Italy (patients taking part in ment and were therefore not included in
care in Verona, Italy. Br J Psychiatry. 2003; international multicenter drugs trials) the test-retest analysis. As this study
183:167–169.
3. Amaddeo F, Beecham J, Bonizzato P, et al. The or abroad (Italian immigrants who live was conducted in a case register area, it
use of a case register to evaluate the costs of in another country). was possible to obtain directly from the
psychiatric care. Acta Psychiatr Scand. 1997; The aim of this study is to assess South Verona Psychiatric Case Register
95:159–198.
4. WHO Collaborating Centre for Drug Statistic the interrater and test-retest reliability patients’ sociodemographic and clinical
Methodology. Guidelines for ATC Classifica- of the Italian version of the MINI. The characteristics.4 The mean age for the
tion and DDD Assignment. Oslo: WHO; 1996. subjects were drawn from those who 50 subjects included in the analysis
5. Baldessarini RJ, Kando JC, Centorrino F.
Hospital use of antipsychotic agents in 1989 contacted the outpatient department of was 46 years (SD = 12). Twenty-three
and 1993: stable dosing with decreased length the South Verona Community Psychiat- of the subjects (46%) were female, 28
of stay. Am J Psychiatry. 1995;152:1038–1044. ric Service.4 Fifty consecutive patients (56%) were married, 42 (84%) lived
6. Nosé M, Barbui C, Tansella M. How often pa-
tients with psychosis fail to adhere with treat- were included in the study; all subjects with a partner or their family, and 18
ment programs? A systematic review. Psychol were 18 years old or older. Subjects with (36%) had a high level of education
Med. 2003;33:1149–1158. dementia, mental retardation, and lan- (ie, high school diploma or university
7. Barbui C, Guaiana G, Garattini S. Regulatory
issues in Europe. J Clin Psychopharmacol. guage problems were excluded. Each degree). Only 8 patients (16%) were
2001;21:545–548. patient was first assessed independently employed, and the sample was quite
8. Barbui C, Tansella M, Garattini S. Varying by 2 interviewers (interrater reliability equally distributed among diagnostic
and ‘‘atypical’’ indications for atypical anti-
psychotics. Psychopharmacology. 2003;169: test); one of whom conducted the in- groups, with a slight prevalence of
205–206. terview, while the other played the affective disorders (38%).
The median length of time be- both the interrater and the test-retest cating a high positive and negative
tween the first (interrater) and the sec- reliability. agreement).
ond (retest) interview was 15 days. The According to the standard bench- In spite of the results of the
mean duration of the interview was marks proposed by Landis and Koch,7 interrater, in the test-retest reliability,
27 minutes (SD = 10) in the interrater the interrater reliability was very high. only 3 of the 28 j values were above 80
(range: 15 to 60) and 21 minutes All the j values were above 0.73 (in- (indicating excellent agreement). For 7
(SD = 7) in the retest (range: 10 to 36). dicating ‘‘good agreement’’) and the diagnoses, the j values indicated ‘‘good
Table 1 shows the values of Ppos majority (23 of 28) were 0.80 or high- agreement,’’ and for 8 diagnoses,
and Pneg and the j values (with the 95% er (indicating ‘‘excellent agreement’’). ‘‘moderate agreement’’; for the other
confidence interval, except for the Both Ppos and Pneg values were very 11 diagnoses, the j values range from
categories where the respondents vari- high in all the diagnostic categories: 0.03 to 0.36 (that is from ‘‘no
ability was too low and therefore it 24 of 28 Ppos values and 27/28 Pneg agreement’’ to ‘‘fair agreement’’). On
was not possible to calculate them) for values were 0.80 or superior (indi- the other hand, the negative cases were
TABLE 1. Interrater and Test-Retest Reliability of the MINI Italian Version
Interrater Reliability Test-Retest Reliability
Diagnoses Ppos Pneg Interrater 95% CI Ppos Pneg Test-Retest 95% CI

Major depressive disorder—current 0.97 0.98 0.96 [0.87 1.00] 0.57 0.87 0.46 [0.18 0.74]
Major depressive disorder—recurrent 0.89 0.71 0.84 [0.69 0.98] 0.43 0.33 0.36 [0.09 0.62]
Dysthymia 0.90 0.95 0.85 [0.72 0.99] 0.40 0.74 0.30 [0.04 0.55]
Hypomanic—current 1.00 1.00 1.00 NC 0.00 0.97 0.03 [0.07 0.12]
Hypomanic—past 1.00 1.00 1.00 NC 0.50 0.98 0.48 [0.12 1.00]
Manic—current 0.67 0.99 0.66 [0.03 1.00] 0.00 0.98 0.00 NC
Manic— past 1.00 1.00 1.00 NC 0.57 0.92 0.50 [0.15 0.84]
Panic disorder—lifetime 0.91 0.97 0.88 [0.73 1.00] 0.60 0.89 0.49 [0.18 0.79]
Limited symptom panic attacks—lifetime 1.00 1.00 1.00 NC 0.33 0.95 0.24 [0.20 0.68]
Panic disorder—current 1.00 1.00 1.00 NC 0.54 0.93 0.53 [0.20 0.86]
Agoraphobia—current 0.96 0.99 0.94 [0.83 1.00] 0.60 0.89 0.49 [0.19 0.79]
Panic disorder without agoraphobia—current 1.00 1.00 1.00 NC 0.00 0.97 0.03 [0.07 0.01]
Panic disorder with agoraphobia—current 1.00 1.00 1.00 NC 0.75 0.98 0.73 [0.37 1.00]
Agoraphobia—current without panic disorders 0.80 0.98 0.78 [0.48 1.00] 0.28 0.94 0.23 [0.23 0.69]
Social phobia—current 1.00 1.00 1.00 NC 0.72 0.96 0.69 [0.36 1.00]
Obsessive-compulsive disorders—current 0.75 0.98 0.73 [0.37 1.00] 0.75 0.98 0.73 [0.37 1.00]
Posttraumatic stress disorder—current 0.86 0.99 0.85 [0.55 1.00] 0.33 0.95 0.29 [0.21 0.79]
Alcohol dependence—current 1.00 1.00 1.00 NC 0.88 0.99 0.88 [0.64 1.00]
Alcohol abuse—current 1.00 1.00 1.00 NC 0.66 0.98 0.64 [0.19 1.00]
Substance dependence—current 1.00 1.00 1.00 NC 1.00 1.00 1.00 NC
Substance abuse—current 1.00 1.00 1.00 NC 0.00 0.99 0.00 NC
Psychotic disorders—current 1.00 1.00 1.00 NC 0.57 0.96 0.54 [0.08 1.00]
Psychotic disorders—lifetime 0.92 0.99 0.91 [0.74 1.00] 0.75 0.95 0.70 [0.43 0.97]
Mood disorder with psychotic features—current 0.67 0.80 0.80 [0.56 1.00] 0.86 0.00 0.49 [0.17 0.81]
Anorexia nervosa—current NC 1.00 NC NC NC 1.00 NC NC
Bulimia nervosa 0.80 0.99 0.79 [0.39 1.00] 0.00 0.98 0.00 NC
Anorexia nervosa (binge eating/purging type) NC 1.00 NC NC NC 1.00 NC NC
Generalized anxiety disorder—current 0.44 0.94 0.39 [0.04 1.00] 0.22 0.91 0.14 [0.25 0.53]
Antisocial personality disorder—lifetime 1.00 1.00 1.00 NC 0.67 0.98 0.65 [0.20 1.00]
Suicide risk—current 0.95 0.96 0.92 [0.81 1.00] 0.87 0.93 0.81 [0.63 0.99]
Major depressive disorder—current 0.97 0.98 0.96 [0.87 1.00] 0.57 0.87 0.46 [0.18 0.74]
CI indicates confidence interval; n, kappa; NC, not calculable.
strongly prevalent in every single diag- REFERENCES calcium level, high-dose antipsychotic
nostic category, and the corresponding 1. Sheehan D, Lecrubier Y, Sheehan K, et al. The therapy,3 and acute medical illness.1
Pneg values were all very high: 25 of 28 Mini-International Neuropsychiatric Interview Mechanism is thought to relate to D2
(MINI): the development and validation of a
of them were 0.87 or greater, indicating structured diagnostic psychiatric interview for
receptor blockade; the phenomenon
high negative agreement. DSM-IV and ICD-10. J Clin Psychiatry. 1998; is thought to occur only rarely with
The present study is the first re- 59:22–33. atypical antipsychotics.
2. Lecrubier Y, Sheehan D, Weiller E. The Mini-
liability study conducted on the Italian International Neuropsychiatric Interview (MINI).
Ziprasidone is an atypical anti-
version of the MINI. The average du- A short diagnostic structured interview: reli- psychotic with a high 5-HT2/D2 recep-
ration of the interview, 27 minutes in the ability and validity according to the CIDI. Eur tor affinity ratio and inhibition of
interrater and 21 minutes in the retest, Psychiatry. 1997;12:224 –231.
3. Sheehan D, Lecrubier Y, Sheehan K, et al.
norepinephrine and serotonin reuptake.
was relatively short. Since most of the The validity of the Mini-International Neuro- The compound is an agonist at the 5-
patients have a psychiatric diagnoses, psychiatric Interview (MINI) according to the HT1A receptor, an antagonist at the 5-
the average length of the interview SCID-P and its reliability. Eur Psychiatry.
1997;12:232–241.
HT2C and 5-HT2D receptors, and shows
was longer than that found in general 4. Tansella M, Amaddeo F, Burti L. Community antagonism at a1-adrenergic and H1
practice settings (15 minutes) but still based mental care in Verona, Italy. In: Gold- histamine receptors.
acceptable, to be used in routine prac- berg D, Thornicroft G, eds. Mental Health in
Our Future Cities. Hove: Psychological Press; Premarketing clinical trials of oral
tice, when a shorter interview is needed, 1998:239–262. ziprasidone resulted in torticollis in less
and in studies where it is not possible 5. Cohen J. A coefficient of agreement for than 0.1% of patients and an EPS rate of
to use more complex instruments. nominal scales. Educ Psychol Meas. 1960;20:
37– 46. 5%. A randomized, double-blind com-
Although the results of the analy- 6. Cicchetti D, Feinstein A. High agreement but parison of ziprasidone with haloperidol
ses performed indicated an interrater low kappa: II. Resolving the paradoxes. J Clin found a 1% rate of EPS with zipra-
reliability similar, or even superior, to Epidemiol. 1990;6:551–558.
7. Landis J, Koch G. The measurement of ob- sidone.4 A literature search found no
that reported by previous studies,2 test- server agreement for categorical data. Bio- published reports of torticollis since the
retest reliability showed relatively low metrics. 1977;33:159–174. drug’s release.
j values in this sample. The main reas- Expert consensus has deemed
ons for the discrepancies between test
and retest j values were identified as (i) Acute Dystonic the EPS risk presented by ziprasidone
therapy as equal to that of olanzapine,
the high prevalence of patients who Reaction With less than that of risperidone, and more
did not receive a psychiatric diagnosis
that produced the lowering of j and (ii) Moderate-Dose severe than that seen with clozapine or
quetiapine.5 A prospective study of the
the length of time between test and Ziprasidone prevalence of acute dystonia among
retest. The MINI is probably sensitive
neuroleptic-treated inpatients found a
to changes over time and allows the
rate of 3.1% overall. Ten cases of acute
identification of minor modifications of To the Editors: dystonic reactions occurred among 766
the patients’ clinical conditions.
Acute dystonia is a distressing patients treated with novel antipsy-
However, further research may
and sometimes life-threatening form of chotics; 8 of these were associated with
be useful for further assessing the re-
extrapyramidal syndrome (EPS). Occur- risperidone therapy. No patients in this
liability of the Italian version of this
ring within 3 days of initiation of study were treated with ziprasidone.
instrument, across 2 separate inter-
antipsychotic therapy in 90% of cases,1 Although package information on
views, with a shorter time period be-
acute dystonic reactions may be precip- ziprasidone recommends an initial dose
tween the interviews.
itous, frightening, and lead to a breach of 20 mg BID, recent expert consensus
in therapeutic alliance. A subtype, tor- has advocated initial dosing be in-
Alberto Rossi, PhD*
ticollis, consists of sustained contrac- creased to 40 mg BID.5 The following
Roberta Alberio, MD*
tion of strap muscles causing a lateral report details the case of a cocaine-
Alberto Porta, MD*
twisting of the neck. Here presented abusing, neuroleptic-naive female pa-
Marco Sandri, EconomDy
is a case of acute torticollis following tient started on ziprasidone 40 mg BID
Michele Tansella, MD*
moderate-dose administration of a novel who developed acute torticollis early in
Francesco Amaddeo, MD*
antipsychotic, oral ziprasidone. the course of treatment.
*Section of Psychiatry and Clinical
Psychology, Department of Medicine and
Previously described risk factors LS was a 31-year-old African
Public Health and yInterdepartmental Centre for acute dystonia include young age, American female admitted to a state
of Economic Documentation, University of male gender, history of acute dystonic psychiatric facility after physical alter-
Verona, Verona, Italy reactions, and cocaine use.2 EPS in cation with a peer. Before admission, the
[email protected] general is associated with low serum patient had been at a halfway house for
2 weeks, following inpatient detoxifica- despite the negative UDS, that recent refer to nighttime wetting as noctur-
tion from cocaine and alcohol. Sub- cocaine use directly precipitated the nal enuresis; this distinguishes it from
sequent to her attack on a peer at this dystonia.6 daytime wetting. Despite extensive re-
placement, the patient complained of Rapid medication titration may search, the mechanism of enuresis has
auditory hallucinations commanding be crucial for severely ill patients; it not yet been clarified in detail. Tricyclic
her to attack the woman in her sleep. may also be encouraged by the current antidepressants (TCAs) possess estab-
At admission, LS reported a sev- atmosphere of managed care, which lished antienuretic properties, while
eral years’ history of intermittent au- demands cost-efficient use of inpatient some recent case reports have shown
ditory hallucinations described as one days. However, acute dystonia is in selective serotonin reuptake inhibitors
clear voice issuing violent commands some cases life-threatening and in most (SSRIs) to also have similar antienuretic
and insults. These had occurred during cases extremely uncomfortable. Risk properties and a safer side effect pro-
periods of sustained sobriety as well as factors for this condition, such as age, file.1–7 We herein report a case of de
while actively abusing drugs. She de- gender, history, and drug use, should novo enuresis induced by paroxetine,
nied past neuroleptic trials. be kept in mind when designing a one of the SSRIs, which was observed
The patient denied use of drugs medication titration schedule, even with in an adult with major depressive dis-
or alcohol in the preceding 2 weeks. an atypical antipsychotic. orders. To our knowledge, there have
Previous use had featured periods of been no previous reports of SSRI-
daily crack cocaine use intermittent for Rachel E. Dew, MD induced enuresis in adult cases, while
10 years as well as alcohol several times Doreen Hughes, MD there has only been one recent case
per week. Examination showed no evi- Department of Psychiatry, Wake Forest report of paroxetine-induced enuresis
dence of acute withdrawal. Urine drug University Medical Center, observed in a 14-year-old girl.8
screen (UDS) was negative, and serum Winston-Salem, NC
calcium level was within normal limits. [email protected]
The remainder of the laboratory workup REFERENCES CASE REPORT
was unremarkable. At hospitalization, 1. In: Kaplan HI, Sadock BJ, eds. Comprehensive A 28-year-old woman was diagnosed
the patient was taking sertraline 50 mg Textbook of Psychiatry. 6th ed. Baltimore: to have major depressive disorders at 26
QD and trimethoprim-sulfamethoxazole Williams & Wilkins; 1995:2003–2004. years of age according to Diagnostic and
2. van Harten PN, Hoek HW, Kahn RS. Acute Statistical Manual of Mental Disorders,
for a urinary tract infection. dystonia induced by drug treatment. BMJ.
To treat the patient’s ongoing September 1999;319:623–626. Fourth Edition in our hospital. She showed
3. In: Schatzberg AF, Nemeroff CB, eds. Amer- depressive symptoms such as a depressive
psychotic symptoms, ziprasidone thera-
ican Psychiatric Publishing Textbook of Psy- mood, insomnia, psychomotor inhibition,
py was initiated at a dose of 40 mg BID. chopharmacology. 2nd ed. Baltimore: Williams and suicidal idea. Her personal and family
The first 2 doses were well tolerated. & Wilkins. 1998:350. histories were negative for either affective
Approximately 3 hours following the 4. Hirsch SR, Kissling W, Bauml J, et al. A 28-
week comparison of ziprasidone and haloper- or any other psychiatric disorders. She did
third dose of ziprasidone 40 mg, the idol in outpatients with stable schizophrenia. not have a history of enuresis. The labora-
patient complained of a strange sen- J Clin Psychiatry. 2002;63:516–523. tory data, including the thyroid indices,
sation in her tongue and subjective 5. Weiden PJ, Iqbal N, Mendelowitz AJ, et al. showed no definite abnormality. Paroxetine
Best clinical practice with ziprasidone: update
dyspnea. Over the next hour, she de- after one year of experience. J Psychiatr Pract.
was started at a dose of 10 mg/d, and it
veloped torticollis to the right as well as March 2002;8(2):81–97. was gradually increased up to a dose of
a writhing lingual dystonia. She was 6. Catalano G, Catalano MC, Rodriguez R. 40 mg/d within 3 months. Nocturnal enure-
Dystonia associated with crack cocaine use. sis was first observed within 2 weeks after
given benztropine and diphenhydramine South Med J. October 1997;90(10):1050–1052.
the initiation of 40 mg/d paroxetine. The av-
intramuscularly, which produced full
erage frequency of nocturnal enuresis was
resolution of symptoms within the next
4 times a week. Due to the occurrence of
30 minutes. Ziprasidone was discon- SSRI-Induced Enuresis enuresis after the use of 40 mg/d paroxetine,
tinued and replaced with olanzapine, the dosage was gradually reduced to 20 mg/d
which the patient tolerated without A Case Report within 2 months. Thereafter, the occurrence
further EPS for the remainder of of nocturnal enuresis gradually decreased
hospitalization. To the Editors: and stopped within 1 month.
Acute dystonia is rare with atyp- Enuresis is the habitual involun- The established effective treat-
ical neuroleptics but may still occur. tary discharge of urine after the age of ments of enuresis have been shown to
Risk factors in this patient include her expected continence. This term is often include both behavioral and psycho-
age, history of cocaine abuse, and pos- used alone, imprecisely, to describe pharmacologic interventions. TCAs have
sibly, her recent urinary tract infection. wetting that occurs only at night during been demonstrated to possess an anti-
It also cannot be completely ruled out, sleep. It is more accurate, however, to enuretic effect; however, TCAs are
also known to induce cardiotoxicity and sis may possibly be either precipitated orders, toxic reactions are common with
present a high risk in the event of an or exacerbated by SSRIs. In addition, minor increases in serum concentration
overdose.1,2 The rapid antienuretic ef- placebo-controlled, double-blind studies due to its extremely narrow therapeutic
fect of TCAs, as opposed to their should be performed in future studies range. Recently, a number of new anti-
antidepressant activity, which emerges to confirm the effectiveness of SSRIs convulsant medications have demon-
only after several weeks, suggests that for the treatment of enuresis. strated efficacy in treating various phases
enuresis is not a depressive equivalent, of bipolar disorder and are generally
although the mechanism of action is un- Akira Monji well tolerated. They have, however,
known. In contrast to early reports, the Kazuyuki Yanagimoto not replaced lithium, and treatment-
muscarinic receptor affinities of TCAs Ichiro Yoshida refractory patients often use a combina-
are now known to be unrelated to their Sadayuki Hashioka tion of lithium and an anticonvulsant.
inhibitory activity in the bladder.2 Some Department of Neuropsychiatry, Graduate Unexpected drug interactions resulting
recent case reports have demonstrated School of Medical Sciences, from combining lithium with other
the successful treatment of enuresis in Kyushu University, Fukuoka, Japan mood stabilizers are, therefore, of con-
children taking such SSRIs as fluoxe- [email protected] cern. We present a case demonstrating
tine, sertraline, paroxetine, and fluvox- a toxic interaction following the intro-
amine.3–7 A central serotonergic effect REFERENCES duction of the anticonvulsant topiramate
has been suggested as a possible mech- to a lithium-treated patient.
1. Fornier JP, Garfinkle BD, Bond A, et al.
anism for the antienuretic effect of Pharmacological and behavioral management
SSRIs. On the other hand, psychotropic of enuresis. J Am Acad Child Adolesc Psych. CASE REPORT
drugs such as thioridazine, clozapine, 1987;26:849–853. The patient is a 26-year-old single fe-
2. Toren P, Eldar S, Loar N, et al. Fluvoxamine
and risperidone have been reported to male transferred from a general hospital unit
is ineffective in the treatment of enuresis in
induce enuresis.9,10 Took and Buck10 children and adolescents: an open- label pilot to the Mood Disorders service for stabiliza-
reported 5 cases of de nova appearance study. Human Psychopharmacol. 2001;16: tion. She was diagnosed with type 1 bipolar
327–332. illness 10 years ago and was doing well,
of enuresis after the combined use of 3. Freeney DJ, Klykylo WM. SSRI treatment initially on lithium (900 to 1200 mg/d) alone
risperidone and SSRIs including fluox- of enuresis. J Am Acad Child Adolesc Psych.
1997;36:1326–1327. but later on lithium and valproate (1500 to
etine, sertraline, and paroxetine. In these 2000 mg/d). While attending college 2 years
4. Kano K, Arisaka O. Fluvoxamine and enure-
cases, enuresis was observed after the sis. J Am Acad Child Adolesc Psych. 2000;39: ago, she became so unstable that she had to
addition of risperidone to each SSRI. 1464–1465. quit school and return home to live with her
The first open study on the use of 5. Kano K, Arisaka O. More on fluvoxamine
mother. During this time, she remained in a
and enuresis. J Am Acad Child Adolesc Psych.
SSRIS for enuresis by Toren et al2 2001;40:865. dysphoric mania despite treatment with lith-
demonstrated that fluvoxamine had no 6. Murray ME. Treatment of enuresis with ium and valproate and, at different times,
statistically significant effect on enure- paroxetine. Dev Behav Pediatr. 1997;18: the addition of risperidone and lamotrigine.
435–436. Risperidone and lamotrigine caused derma-
sis, while 4 of 9 children tended to 7. Sprenger D. Sertraline for nocturnal enuresis.
show an increased frequency of enuresis J Am Acad Child Adolesc Psych. 1996;36: tologic side effects. Olanzapine was refused
304–305. for fear of weight gain.
during fluvoxamine treatment in their
8. Toros F, Erdogan K. Paroxetine-induced On admission to the general hospital,
study. Moreover, Toros and Erdogan8 enuresis. Eur Psychiatr. 2003;18:43–44. she was taking lithium (900 mg) with a level
recently reported a case of de novo 9. Cheng LY. Nocturnal enuresis and psycho-
of 0.82 mmol/L, valproate (2 g), and clo-
enuresis induced by paroxetine which tropic drugs. Am J Psychiatry. 1981;138:
538–539. nazepam (prn). Topiramate (75 mg) was
was observed in a 14-year-old girl. In 10. Took KJ, Buck BL. Enuresis with combined started around the time of admission. Seven
the present case, paroxetine seemed to risperidone and SSRI use. J Am Acad Child days later, she was transferred to the Mood
induce de novo enuresis dose-depen- Adolesc Psych. 1996;35:840–841. Disorders service in a mixed state but more
11. Rushton JL, Clark SJ, Freed GL. Pediatrician
dently. Enuresis has now been reported and family prescription of selective seroto- manic; her lithium level had increased to
to be the sixth most frequent reason for nin reuptake inhibitors. Pediatrics. 2000;105 1.24 mmol/L. Over the next 4 days, serum
prescribing an SSRI for children.11 In (6):E82. lithium continued to increase to 1.97 mmol/L
comparison to TCAs, SSRIs induce a despite decreasing the dose of lithium to
750 mg/d. Other medications were held
minimal degree of cardiotoxicity and
also present a relatively low risk in the Topiramate Can Cause constant. During this time, her fluid intake
had remained the same or increased, and
event of an overdose. The administra- Lithium Toxicity serum blood urea nitrogen, creatinine, and
tion of SSRIs for enuresis is thus ex- electrolytes all remained normal. Lithium
pected to substantially increase in the To the Editors: was then discontinued, and within 4 days,
future. Therefore, we clinicians should Although lithium has been the serum lithium levels returned to safe levels
bear in mind the possibility that enure- backbone of treatment for bipolar dis- with a half-life of elimination of about 48
hours. During this time, she demonstrated of renal carbonic anhydrase reduces creased their topiramate dose to lose
evidence of clinical toxicity (worsening con- reabsorption of bicarbonate and Na+. weight. Over 5 weeks, the patient in-
centration, confusion, and lethargy) which This leads to a metabolic acidosis and creased the topiramate dose from 500 to
cleared upon return to therapeutic levels. Na+ depletion. Diuresis results from a 800 mg/d and lost 35 lb. They suggest
Lithium was restarted and produced ther-
corresponding reduction in water reab- that both pharmacokinetics (competi-
apeutic levels (0.67 mmol/L) at half the
sorption. Generally, carbonic anhydrase tion for renal excretion, renal clear-
admission dose. While maintaining the dose
of lithium (450 mg/d), further increases in inhibitor diuretics have little effect on ance accounts for 50% to 80% of
topiramate dose from 75 to 125 mg/day lithium levels. In conditions of Na+ topiramate elimination9) and pharmaco-
over the next 4 weeks resulted in parallel depletion, however, renal mechanisms dynamics (weight loss induced decrease
elevations of lithium levels (from 0.67 to promote lithium retention.5 Gay et al6 in sodium-lithium counter transport
0.92 mmol/L) (see Table 1). report a case of lithium toxicity due activity) as potential mechanisms for the
The patient had been on the same to a 5-fold increase in lithium levels topiramate-induced lithium toxicity.
or higher dose of lithium and valproate following the introduction of the Case reports, by their nature,
for many years without any toxicity. The carbonic anhydrase inhibitor acetazol- often suffer from weak experimental
sudden increase in serum lithium levels amide. At the time of lithium toxicity, design. Our observations do not con-
could not be explained by a change in the subject of Gay et al was hyponatre- form to an appropriate test-retest proto-
fluid intake or metabolic state. The in- mic (128 mmol/L), suggesting that re- col. However, the data do indicate a
crease in lithium levels following the duced lithium clearance may have significant increase in lithium level
introduction of topiramate such that been the result of acetazolamide-in- following introduction of topiramate
therapeutic lithium levels were obtained duced hyponatremia. and suggest further reductions in lith-
with one half the previous dose and the Although the patient in our case ium elimination with increasing top-
subsequent rise in lithium levels with in- was not clinically hyponatremic, topiramate dose. These observations, taken
creasing topiramate dose suggests that iramate may have changed Na+ balance together with the report of Pinninti and
topiramate had a role in reducing lithium sufficiently to increase lithium retention. Zilinski and the description by Gay et al
elimination. A study of rats undergoing chronic (10 of the potential interaction of carbonic
Bioavailability of oral lithium days) ammonium chloride–induced met- anhydrase inhibitors on lithium elimi-
preparations is about 100%, and lithium abolic acidosis suggests that serum Na+ nation, imply that topiramate may alter
excretion is 95% through urine. Ac- levels may be an insensitive indicator of lithium pharmacokinetics in an incon-
cordingly, drug interactions which sig- Na+ balance. In spite of metabolic acid- sistent manner.
nificantly raise lithium levels must do osis-induced increase in fractional prox- Until this issue is resolved, we
so by reducing renal clearance. Top- imal and postproximal Na+ and urinary recommend that all patients treated with
iramate may affect renal excretion of K+ excretion, compensatory mechanisms lithium and topiramate be closely mon-
lithium by several mechanisms. maintained serum Na+ levels identical to itored for lithium levels and hydration
Topiramate has significant activi- that of control and pair-fed animals.7 status. Further studies are required to
ty as a carbonic anhydrase inhibitor1 Pinninti and Zilinski8 describe an determine if topiramate-induced eleva-
and is known to cause kidney stones2,3 increase in lithium levels from 0.5 mEq/L tion of lithium levels is a rare or
and metabolic acidosis.4 Inhibition to 1.4 mEq/L in a patient who had in- common event.
TABLE 1. Patient’s Dosing and Laboratory Data

Days Posthospitalization 0 3 7 8 11 12 13 14 15 18 19 20 32 36 39 43
Lithium dose* 900 — — 750 — 0 — — — — 450 — — — — —
Lithium levely 0.84 1.07 1.24 — 1.89 1.97 1.40 0.89 0.74 0.27 — 0.67 — 0.82 — 0.92
Topiramate dose* 75 — — — — — — — — — — — 100 — 125 —
Blood urea nitrogeny 8.5 — — — 7.1 — 6.6 7.7 — 6.7 — — — — — —
Serum creatininez 59 — — — 106 — 81 90 — 97 — — — — — —
Serum Na+ y 140 — — — — — 139 136 — — — — — — — —
Serum K+ y 4.0 — — — — — 4.1 4.0 — — — — — — — —
*All doses in mg/d.
y
Lithium, blood urea nitrogen, serum Na+, and serum K+ concentrations in mmol/L.
z
Serum creatinine concentration in Amol/L.
Gebrehiwot Abraham, MD, FRCP(C) The patient is an 11-year-old erbated if he did not take guanfacine. In
J. Owen, PhD white male previously diagnosed with addition, he became more irritable and
Providence Continuing Care Centre, attention deficit hyperactivity disorder violent at home and at school. He began
Mental Health Services, Departments by Diagnostic and Statistical Manual of talking about knives and guns. He
of Psychiatry and Pharmacology, Mental Disorders, Fourth Edition crite- struck a female peer in the face with
Queen’s University, Kingston, ria and with a family history suggestive a closed fist and was having frequent
Ontario, Canada
for bipolar disorder. The patient had anger outbursts at home and school.
[email protected]
been previously treated with a number During one anger outburst at home, he
of medications. He had experienced threatened to kill his family.
REFERENCES
anger outbursts on psychostimulants and The family was not overly
1. Dodgson SJ, Shank RP, Maryanoff BE. Topira-
mate as an inhibitor of carbonic anhydrase iso- manic responses to antidepressants. For alarmed by this behavior, as they did
enzymes. Epilepsia. 2000;41(suppl 1):S35–S39. example, at age 6 years, he became not report these problems and resched-
2. Natsch S, Hekster YA, Keyser A, et al. Newer manic on sertraline, eating worms and uled their appointment to a later date.
anticonvulsant drugs: role of pharmacology,
drug interactions and adverse reactions in drug small frogs, exposing himself, and climb- However, at week 7, he became angry,
choice. Drug Safety. 1997;17:228–240. ing a water tower. He experienced a stripped off his clothing, covered his
3. Kossoff EH, Pyzik PL, Furth SL, et al. Kidney similar activation on buproprion. Under body with markings using a felt-tipped
stones, carbonic anhydrase inhibitors, and the
ketogenic diet. Epilepsia. 2002;43:1168–1171. my care, he was maintained on clonidine, pen, and began screaming and yelling.
4. Montenegro MA, Guerreiro MM, Scotoni AE, then later on guanfacine, but continued to He obtained a sword that belonged to
et al. Predisposition to metabolic acidosis in- have problems with concentration, atten- his father and began brandishing it in a
duced by topiramate. Arq Neuro-Psiquiatr.
2000;58:1021–1024. tion to detail, academic performance, and threatening manner towards his family.
5. Ward ME, Musa MN, Bailey L. Clinical anger regulation. However, he was not He was hospitalizing at this point. The
pharmacokinetics of lithium. J Clin Pharma- hypersexual or overtly grandiose and atomoxetine was stopped. The patient
col. 1994;34:280–285.
6. Gay C, Plas J, Granger B, et al. Intoxication au did not have decreased need for sleep. continued on his guanfacine and no
lithium—Deux interactions inedites: l’acetazo- He was somewhat arrogant, insolent, other medications were started. Within
lamide et l’acide niflumique. L’Encephale. and provocative during sessions, but his 7 days, the patient had returned to
1985;11:261–262.
7. Menegon LF, Figueiredo JF, Gontijo JAR. mother was convinced that this behav- his baseline behaviors both at home
Effect of metabolic acidosis on renal tubular ior was confined to my office. Reports and at school. He resumed sleeping
sodium handling in rats as determined by lith- from school showed no oppositional normally.
ium clearance. Braz J Med Biol Res. 1998;31:
1269–1273. behavior but continued problems with The literature contains a case re-
8. Pinninti NR, Zelinski G. Does topiramate attention, focus, and academic perform- port of the same molecule (under the
elevate serum lithium levels? J Clin Psycho- ance. Although the patient previously name tomoxetine) treating depressive
pharmacol. 2002;22:340.
9. Sachdeo RC. Topiramate: clinical profile in epi- had demonstrated mania while taking symptoms, but later inducing mania in
lepsy. Clin Pharmacokinet. 1998;34:335–346. antidepressants, the mania cleared after an adult male.3 During the course of
the medications were discontinued, and clinical trials leading to Food and Drug
Mania Induction he had no reported spontaneous epi- Administration approval, 2% to 5% of
sodes of mania or hypomania. subjects experienced ‘‘mood swings,’’
Associated With Atomoxetine was added to his and 1% of subjects discontinued the
Atomoxetine regimen of guanfacine (Tenex) 1 mg trials due to aggression or irritabil-
BID at a dose of 25 mg/d (0.8 mg/kg/d ity.1,2,4 However, a history of mood
at a body weight of 34 kg). After, 3 symptoms was an exclusion criterion
To the Editors: weeks, behavior rating scales from the for these studies,1,2 so the incidence of
Atomoxetine is a selective inhib- school teacher demonstrated a marked these adverse events will likely be higher
itor of norepinephrine reuptake recently increase in activity level in the class- in general clinical practice. The above
approved for the treatment of attention room and little change in attention. case suggests that caution should be used
deficit hyperactivity disorder. In con- After 4 weeks, the patient demonstrated in selecting atomoxetine as a treatment
trolled studies, roughly 70% of child a marked increase in oppositional and for children with symptoms of mood
and adolescent subjects without comor- impulsive behavior at school. The dysregulation or mood disorder or who
bidity responded as measured by reduc- patient threatened to kill a peer, was have a family history of mood disorders.
tion of scores on a variety of measures defiant with teachers, and had a violent Moreover, children who have experi-
for attention deficit hyperactivity dis- anger outburst at school. After 6 weeks, enced irritability or mood dysregulation
order symptomatology.1,2 Here I report the patient began experiencing insom- on antidepressants may be at higher
on a case of mania associated with nia, sleeping only 1 to 3 hours for risk of similar adverse responses with
atomoxetine administration. several nights. The insomnia was exac- atomoxetine.
Theodore A. Henderson, MD, PhD is Q sulfoxide.3 Accordingly, the only all within normal range. Psychotropic med-
Child & Adolescent Psychiatrist clinically relevant drug interaction was ication at the time of analysis of the first Q
Private Practice, Denver CO; found after the combination with keto- serum concentration (trough level) included
Medical Director, Matrix ADHD conazole,3 a potent inhibitor of CYP3A4, 750 mg/d Q (steady state; 6 days continuous
Diagnostic Clinic and dosage), 100 mg/d doxepin, and 4.5 mg
while coadministration of cimetidine4
Associate Medical Director & lorazepam. To alleviate symptoms of a
or fluoxetine5 did not markedly affect
Director of Neurobehavioral presumed reflux esophagitis, 40 mg/d pan-
the pharmacokinetics of Q. In ac- toprazole were prescribed. The Q blood
Research Brain Matters, Inc.
[email protected] cordance to the inhibitory effect of level under comedication of doxepin, lor-
ketoconazole, phenytoin increased the azepam, and pantoprazole was determined
clearance of Q 5-fold.6 This was attri- to be 1860 ng/mL (reanalysis of the same
REFERENCES buted to the CYP3A4 induction by sample 2 weeks later gave 1838 ng/mL)
phenytoin. An increased clearance of (Fig. 1). The doxepin and nordoxepin serum
1. Michelson D, Allen AJ, Busner J, et al. Once-
daily atomoxetine treatment for children and Q was also reported under concurrent concentrations were 21 and 35 ng/mL,
adolescents with attention deficit hyperactivity administration of thioridazine.7 How- respectively. Since only a slight improve-
disorder: a randomized, placebo-controlled ment in schizophrenic symptoms was docu-
study. Am J Psychiatry. 2002;159:1896–1901. ever, very recently, it was reported that
mented, the Q dose was further increased to
2. Spencer T, Heiligenstein JH, Biederman J, Q is a substrate of the efflux transpor-
a maximum of 900 mg/d. Pantoprazole was
et al. Results of 2 proof-of-concept, placebo ter ABCB1 (P-glycoprotein)8 and thus
controlled studies of atomoxetine in children discontinued due to the relief of gastrointes-
with attention-deficit/hyperactivity disorder.
possibly prone to drug interactions tinal symptoms. Furthermore, doxepin was
J Clin Psychiatry. 2002;63:1140–1147. with ABCB1 inhibitors and ABCB1 discontinued, and lorazepam was reduced to
3. Steinberg S, Chouinard G. A case of mania inducers. This study was initiated after 2 mg/d. After discontinuation of doxepin
associated with tomoxetine. Am J Psychiatry.
1985;142:1517–1518. a report of highly elevated Q serum and pantoprazole, the Q serum concentration
4. Eli Lilly and Company, Strattera [package concentrations under combination with had decreased dramatically to 109 ng/mL.
insert]. Indianapolis, IN: Eli Lilly and Com- doxepin, lorazepam, and pantoprazole Gastrointestinal problems reappeared but
pany, 2002. were now treated with ranitidine (300 mg/d).
in a psychotic patient.
Lorazepam was gradually reduced to 0.5
mg/d at the day of the third blood level
Elevated Quetiapine CASE REPORT analysis. Q serum concentration was slightly
further decreased to 68 ng/mL.
Serum Concentrations A 36-year-old male patient suffering
from chronic schizophrenia was admitted to
in a Patient Treated the hospital revealing confusion combined
IN VITRO TESTS ON
with a depressive state. The medication at
Concomitantly With admission included 150 mg/d doxepin, 0.5
CYTOCHROME P450 AND
ABCB1 INHIBITION
Doxepin, Lorazepam, mg lorazepam, and antiinfective eye medi-
Beside human liver microsomes,
cation (of loxazine eyedroppers). He showed
and Pantoprazole no neurologic or internistic abnormalities. recombinant human CYP (Supersomes1,
Results of clinical chemistry analyses were Gentest) were applied to determine the
To the Editors:
Quetiapine (Q) is a recently in-
troduced atypical antipsychotic.1 The
common feature of all atypical anti-
psychotics is their diminished risk to
produce extrapyramidal symptoms. It
was suggested that Q’s low liability to
movement disorders including extrapy-
ramidal symptoms is due to an only
transient blockade of dopaminergic D2
receptors.2 The transient occupancy of
D2 receptors is accompanied by a short
terminal elimination half-life of about 7
hours.3 Q is mainly eliminated through
hepatic metabolism with cytochrome
P450 (CYP) 3A4 playing a predominant FIGURE 1. Quetiapine steady-state trough concentrations after administration of
role. The major metabolite resulting quetiapine in oral daily doses between 25 and 1200 mg. The serum concentration
from the CYP3A4 catalyzed oxidation of the reported case is depicted as filled black circle.
inhibitory potential of lorazepam, doxe- method of Sarkadi et al.9 In brief, mem- Pantoprazole, doxepin, and lora-
pin, and pantoprazole on oxidative Q branes of human multi drug resistance zepam did not affect Q permeability
metabolism that is mainly mediated by protein-1 (MDR-1) expressing Sf9 insect rates in the basolateral to apical; that is,
CYP2D6 and CYP3A4.3 Additionally, cells (SOLVO Biotechnology, Budapest, the direction of ABCB1 mediated efflux
inhibition of CYPs 1A2, 2C19, and 2C9 Hungary) were incubated with the indi- across Caco-2 cells, in concentrations
was assessed by assessing the metabo- cated drugs in concentrations between ranging from 0.1 to 100 lM (see Fig. 2).
lism of fluorescent substrates with or 0.2 and 100 lM and 5 mM MgATP Here, we report an about 17-fold
without coincubation of the respective at 378C for 60 minutes. The liberated increase in the blood level of the
drugs. As marker for the specific cata- inorganic phosphate was measured by a atypical antipsychotic Q during coad-
lytic activity of CYP2D6 we used, colorimetric method described earlier.10 ministration of the proton pump blocker
7-ethoxy-3-cyanocoumarin for CYP1A2 Calcein-AM served as positive control. pantoprazole and the tricyclic anti-
and CYP2C19, dibenzylfluorescein for Inhibition of vanadate-sensitive depressant doxepin. A serum concen-
CYP2C9, 3-[2-(N,N-dimethyl n-methyl- ABCB1 ATPase by doxepin, loraze- tration of 1860 ng/mL was more than
amino)ethyl]-7-methoxy-4-methylcoumarin pam, or pantoprazole was studied by 20-fold higher than the median and
for CYP2D6, and 7-benzyloxy-4-triflu- determining the reduction in ATP hy- more than 10-fold higher than the 75th
oromethyl)-coumarin for CYP3A4 as drolysis after preincubation of 50 lM percentile from our sample of 47 pa-
well as dibenzylfluorescein. Increasing Q with ABCB1 membrane vesicles. tients receiving a median dosage of 600
amounts of doxepin, lorazepam, panto- Cyclosporine A and GF120918 served mg/d. Otherwise, our mean (± standard
prazole, and Q (0.1 to 100 lM) were as positive controls for inhibition of deviation) concentrations were at about
incubated for 30 min in 200 lL of Q-stimulated vanadate-sensitive ABCB1 the same range (99 ± 48 ng/mL) as
0.5 mM potassium phosphate buffer pH ATPase activity. Although Q was found those previously reported at a dosage of
7.4 with 0.5 nmol of the respective re- to stimulate the ABCB1 vanadate-sen- 600 mg/d.5,7 During the increased Q
combinant CYP containing NADPH re- sitive ATPase activity with an EC50 of blood level, the patient seemed restless
generating system (0.87 mM NADP, 0.08 9.2 lM, thereby indicating relatively and agitated, a symptom that could be
IU glucose-6-phosphatase-dehydrogenase, high affinity to the ABCB1 transporter, possibly attributed to the dopamine-
mM MgCl)2. Furafylline, sulfaphenazole, pantoprazole and doxepin in concentra- antagonistic side effects of the antipsy-
tranylcypromine, quinidine, and keto- tions up to 100 lM did not affect the chotic, for example, akathisia. The main
conazole served as positive controls for Q-stimulated ABCB1 ATPase activity adverse events reported in the literature
CYP1A2, CYP2C9, CYP2C19, CYP2D6, (cyclosporine A and GF 120918 inhi- for comparable high concentrations are
and CYP3A4 inhibition, respectively. bited the Q-stimulated ATPase activity related to arrhythmogenic effects (QTc
Neither pantoprazole nor doxepin with IC50 values of 1.6 and 1.1 lM, interval prolongation).12 Unfortunately,
nor lorazepam was able to inhibit the respectively). Transport of Q through no electrocardiogram was conducted
CYPs contributing to oxidative metab- human colon carcinoma cell (Caco-2) during the high Q serum concentration.
olism of Q at therapeutically relevant monolayers was assayed in 2 directions Interference of one of the coadminis-
concentrations (see Table 1). (apical to basolateral and basolateral to tered drugs (doxepin, lorazepam, or
Vanadate-sensitive ABCB1 ATPase apical). Cultivation of Caco-2 cells was pantoprazole) with the chromatograph-
activity was assessed according to the carried out as described earlier.11 ic analysis was tested and could be
TABLE 1. In vitro CYP Profiling and Inhibitory Potencies of Doxepin, Lorazepam, Pantoprazole, and Quetiapine
CYP1A2 CYP2C9 CYP2C19 CYP2D6 CYP3A4 CYP3A4
P450 IC50 [M] IC50 [M] IC50 [M] IC50 [M] IC50 [M] IC50 [M]
Substrate CEC DBF CEC AMMC BFC DBF
Positive control Furafylline Sulfaphenazole Tranylcypromine Quinidine Ketoconazole Ketoconazole
6 12 40 0.06 0.03 0.02
Doxepin >100 >100 >100 35 >100 >100
Lorazepam >100 >100 >100 >100 >100 >100
Pantoprazole >100 >100 >100 >100 >100 >100
Quetiapine >100 >100 >100 >100 10 50
AMMC indicates 3-[2-(N,N-dimethyl n-methylamino)ethyl]-7-methoxy-4-methylcoumarin; BFC, 7-benzyloxy-4-trifluoromethyl-coumarin; CEC,
7-ethoxy-3-cyanocoumarin; DBF, dibenzylfluorescein.
the intestine,17 but nothing is known

with respect to Q’s affinity to one of
these transporters. In conclusion, Q
trough values were clearly elevated
after coadministration of doxepin and
pantoprazole. Therefore, Q’s pharmaco-
kinetics may have been affected by
doxepin, pantoprazole, or both in com-
bination. However, the only possible
inhibitory potential was found for
doxepin-mediated CYP2D6 inhibition
with an IC50 of 35 lM. It was thus
suggested that the interaction was at-
tributed to a transport process, relevant
FIGURE 2. Permeability of 50 AM quetiapine across Caco-2 cell monolayers in the
efflux direction (basal-apical) in the presence of increasing concentrations (0.1 to
for Q pharmacokinetics. However, al-
100 AM) of doxepin (filled triangles), lorazepam (open triangles), and pantoprazole though Q is a substrate of ABCB1, none
(squares) is given. All data are given as mean ± SD (N = 3). of the coadministered drugs was found
to be an inhibitor of the efflux trans-
excluded. Violation of the blood-sam- tion with an IC50 of 35 lM (Table 1). porter affecting Q transport through
pling procedure (immediately before the Taken, however, into account the low Caco-2 monolayers. The nature of the
first morning dose = trough concen- doxepin blood concentrations (21 ng/mL) observed drug interaction, therefore,
trations) is unlikely due to the strict during the exceptional high Q blood remains unknown. The specific triple
schedule of drug administration and level, it seemed rather unlikely that combination of pantoprazole, doxepin,
blood sampling in a psychiatry hospital. doxepin can cause such a tremendous and Q and/or certain individual pecu-
Even so, the concentration would still increase in Q trough levels as it was larities in this patient might be causal
exceed by far the maximum serum found here. Pantoprazole is a substrate and warrants further investigations.
concentrations ( 1000 ng/mL) reported of CYP2C1915 and might thus alter
for the same dose.6 Q is mainly cleared pharmacokinetics of other CYP2C19 Sebastian Härtter, PhD*
by hepatic metabolism with less than substrates by competitive inhibition. Bernhard Connemann, MDy
1% excreted unchanged.3 An effect on The IC50 of pantoprazole against Carlos Schönfeldt-Lecuona, MDy
drug absorption or metabolism (intes- the CYP2C19 specific metabolism of Julia Sachse, MSc*
tine and/or liver) is thus more likely 7-ethoxy-3-cyanocoumarin was found Christoph Hiemke, PhD*
than any effect on excretion. A phar- to be 165 lM. A competitive inhibition *Department of Psychiatry, University
macokinetic drug interaction between Q of CYP2C19 as a reason for the re- of Mainz, Mainz, Germany and
and at least one of the coadministered ported drug interaction could be ex- yDepartment of Psychiatry, University
of Ulm, Ulm, Germany
drugs was assumed. Since lorazepam is cluded as Cmax values of pantoprazole
[email protected]
mostly devoid of metabolic conversion, even at a single oral dose of 80 mg were
it is most probably devoid of any reported to be in the range of 7.10 to
potential for pharmacokinetic drug in- 14.4 lmol.16 ACKNOWLEDGMENTS
teractions. Moreover, lorazepam was In a recent paper, it was shown The authors thank Drs. von Richter
continuously given and thus was also that Q is a substrate of ABCB1.8 This and Rocker for generously contributing
present during the reduced Q blood was confirmed in this study using the data on cytochrome P450 inhibition, and
levels. CYP3A4, which is the most ATPase assay. However, Q-stimulated ABCB1 ATPase and quetiapine trans-
important CYP in the metabolism of ABCB1 ATPase activity was not in- port across Caco-2 monolayers. This study
Q, was not affected either by pantopra- hibited by pantoprazole, even at high was supported in part by the Deutsche
zole or doxepin. Besides CYP3A4, also concentrations of 100 lM. Doxepin was Forschungsgemeinschaft (Grant Hi 399/
CYP2C19 and CYP2D6 contributed to also found not to inhibit Q-stimulated 5-1/2).
the metabolism of Q. Doxepin was ATPase activity. Besides ABCB1,
recently found to be metabolized by also the human multidrug resistance– REFERENCES
CYP2C19, CYP1A2, CYP2C9, and associated protein, MRP2 (now termed 1. Small JG, Hirsch SR, Arvanitis LA, et al.
CYP2D6.13,14 Accordingly, the only ABCC2), and the breast cancer resis- Quetiapine in patients with schizophrenia. A
high- and low-dose double-blind comparison
possible inhibitory potential was found tance protein BRCP (now termed with placebo. Arch Gen Psychiatry. 1997;54:
for doxepin-mediated CYP2D6 inhibi- ABCG2) act as efflux transporters in 549–557.
2. Kapur S, Zipursky R, Jones C. A positron in the stereospecific metabolism of E- followed for 10 weeks. Their mean age was
emission tomography study of quetiapine in and Z-doxepin. Pharmacogenetics. 2000;10: 24.3 ± 3.7. The mean duration of the illness
schizophrenia. A preliminary finding of an 591– 603.
antipsychotic effect with only transiently high 15. Tanaka M, Ohkubo T, Otani K, et al. was 5.6 ± 4.0 years. All had previously failed
dopamine D2 receptor occupancy. Arch Gen Metabolic disposition of pantoprazole, a at least 1 typical (patient 1: haloperidol;
Psychiatry. 2000;57:553–559. proton pump inhibitor, in the relation to S- patient 3: zuclopentixol) or atypical (patient
3. deVane CL, Nemeroff CB. Clinical Pharma- mephenytoin 40-hydroxylation phenotype and 2: risperidone) neuroleptic trials. None of
cokinetics of quetiapine. An atypical antipsy- genotype. Clin Pharmacol Ther. 1997;62:
chotic. Clin Pharmacokinet. 2001;40:509–522. 619–628. the patients had a history of head injury,
4. Strakowski SM, Keck PE, Wong YW, et al. 16. Huber R, Hartmann M, Bliesath H, et al. convulsion, substance use disorder, obses-
The effect of multiple doses of cimetidine on Pharmacokinetics of pantoprazole in man. Int sive-compulsive disorder, or any organic
the steady-state pharmacokinetics of quetia- J Clin Pharmacol Ther. 1996;34:185–194. brain disorder. After 2 weeks of a discontin-
pine in men with selected psychotic disorders. 17. Ayton A, Morgan P. Role of transport uation period, the patients were started on
J Clin Psychopharmacol. 2002;22:201–205. proteins in drug absorption, distribution and
excretion. Xenobiotica. 2001;31:469–497. olanzapine 5 mg/d and raised to 25 to
5. Potkin SG, Thyrum PT, Alva G, et al. Effect
of fluoxetine and imipramine on the pharma- 35 mg/d over the third week. Mean olanza-
cokinetics and tolerability of the antipsychotic pine doses at end point were 30.0 mg/d. To
quetiapine. J Clin Psychopharmacol. 2002; determine clinical outcome, each of the pa-
22:174–182.
6. Wong YW, Yeh C, Thyrum PT. The effects of
Neurologic Soft Signs tients was rated every 2 weeks on the Positive
and Negative Syndrome Scale7 and Clinical
concomitant phenytoin administration on the
steady-state pharmacokinetics of quetiapine.
and Olanzapine Global Impression Scale8 by a single rater
J Clin Psychopharmacol. 2001;21:89–93. Treatment in Chronic (BT). Baseline and end point NSS scores
7. Potkin SG, Thyrum PT, Alva G, et al. The were evaluated by the Neurological Evalua-
safety and pharmacokinetics of quetiapine Schizophrenia tion Scale (NES).9 The baseline assessment
when coadministered with haloperidol, risper-
idone, or thioridazine. J Clin Psychopharma- of NSS was made after 2 weeks of discon-
col. 2002;22:121–130. To the Editors: tinuation period in 2 patients (patients 1
8. Boulton DW, deVane CL, Liston HL, et al. The issue of whether there might and 3), when significant akathisia or parkin-
In vitro P-glycoprotein affinity for atypical be a relationship between neurologic sonian symptoms totally disapperaed with
and conventional antipsychotics. Life Sci.
2002;71:163–169. soft signs (NSS) and clinical response to appropriate treatment. The NES scores at
9. Sarkadi B, Price EM, Boucher RC, et al. neuroleptic treatment in chronic schizo- admission and after 2 weeks of discontinu-
Expression of the human multidrug resistance phrenics is unclear. Some of the previ- ation period were similar (37 vs. 35) in the
cDNA in insect cells generates a high activity second patient. At admission, before initia-
drug-stimulated membrane ATPase. J Biol ous studies reported that NSS scores are
tion of olanzapine, and every 2 weeks
Chem. 1992;267:4854–4858. a trait characteristic in chronic schizo-
10. Drueckes P, Schinzel R, Palm D. Photometric throughout the treatment, extrapyramidal
phrenics, since no correlation was found symptoms were assessed with the Barnes
microtiter assay of inorganic phosphate in the
presence of acid-labile organic phosphates. between NSS and a good clinical re- Akathisia Scale,10 AIMS,11 and the Simpson-
Anal Biochem. 1995;230:173–177. sponse to conventional or atypical neu- Angus Rating Scale.12
11. Yee S. In vitro permeability across Caco-2 roleptic medications.1–5 However, there The patients did not receive any con-
cells (colonic) can predict in vivo (small
intestinal) absorption in man—Fact or myth. is some evidence that NSS may vary comitant psychotropic medications through-
Pharm Res. 1997;14:763–766. with the course of the illness.6 out the treatment, since they demonstrated
12. Beelen AP, Yeo KT, Lewis LD. Asymptom- We here present 3 cases of chron- no significant drug-induced extrapyramidal
atic QTc prolongation associated with quetia- signs. None of the them discontinued olan-
pine fumarate overdose in a patient being ic schizophrenia who were treated with
treated with risperidone. Hum Exp Toxicol. olanzapine to assess type of changes in zapine because of treatment-emergent side
2001;20:215–219. the severity of NSS. effects. As shown in Table 1, the first 2 pa-
13. Härtter S, Tybring G, Friedberg T, et al. The tients achieved improvements in both total
N-demethylation of the doxepin isomers NES and Positive and Negative Syndrome
is mainly catalyzed by the polymorphic CASE REPORTS
CYP2C19. Pharm Res. 2002;19:1035–1038.
Scale scores at end point. These patients
14. Haritos VS, Ghabrial H, Ahokas JT, et al. Three male chronic schizophrenic pa- were also considered as ‘‘much improve-
Role of cytochrome P450 2D6 (CYP2D6) tients being treated with olanzapine were ment’’ by Clinical Global Impression Scale.
TABLE 1. Characteristics of 3 Patients With Chronic Schizophrenia Treated With Olanzapine

Duration Final CGI PANSS (Total) NES (Total)
of the Illness Olanzapine
No. Age Sex (years) Dose (mg/d) Baseline End Point Baseline End Point Baseline End Point
1 26 M 10 35.0 6 2 98.0 56.0 24.0 16.0
2 20 M 5 25.0 6 2 94.0 62.0 35.0 22.0
3 25 M 2 35.0 5 4 60.0 53.0 11.0 5.0
CGI indicates Clinical Global Impression Scale; NES, Neurological Evaluation Scale; PANSS, Positive and Negative Syndrome Scale.
The third patient with lower score of base- of the previous findings.1–5 There might 12. Simpson GM, Angus JWS. A rating scale for
line NES presented a decrease in final total extrapyramidal side effects. Acta Psychiatr
be an association between the changes Scand (Suppl). 1970;212:11–19.
NES scores, while no change in Positive in the severity of NSS and psychopa- 13. Cuesta MJ, Peralta V, Zarzuela A, et al.
and Negative Syndrome Scale score was thology scores. It would be worthwhile Neurological soft-signs in psychosis: thresh-
observed. old criteria for discriminating normal controls
to perform larger-scale controlled stud- and for predicting cognitive impairment.
A NES total score of 8 or higher or
ies of atypical neuroleptics with flexible Schizophr Res. 2002;58:263–271.
the presence of 6 or more NSS in this doses, in chronic or drug-naive, first
scale seemed to be valid cut-off points episode schizophrenic patients to exam-
for predicting severe cognitive impair- ine if NSS were a state characteristic,
Olanzapine-Induced
ment in individuals with psychosis.13 All varying with psychopathology scores, Clitoral Priapism
of our cases had baseline NES scores rather than a trait characteristic.
above cut-off points. To the Editors:
Inconsistent with a previous study Levent Sevincok, MD* Priapism, an infrequent side effect
which has reported rapid improvements Beyza Topaloǧlu, MD* of psychotropic medication, occurs pre-
in total NSS score with remission of Nefati Kiyiliogluy dominantly in males1; however, very
the schizophrenic symptoms,6 we have Departments of *Psychiatry and rarely it can occur in females. We re-
found decreases in NSS scores with a yNeurology, Adnan Menderes University port, to our knowledge, the first case
remitting clinical condition in 2 patients Faculty of Medicine, Aydin, Turkey of female priapism associated with
(patients 1 and 2) following with rel- [email protected] olanzapine.
atively higher doses of olanzapine treat-
ment. The issue of whether NSS are REFERENCES CASE REPORT
the sequelae of neuroleptic treatment is 1. Kollakowska T, Williams AO, Jambor K, et al. A 27-year-old female diagnosed with
controversial. The baseline NES scores Schizophrenia with good and poor outcome. bipolar disorder has been maintained on
in these 2 patients might be arisen re- III. Neurological ‘soft’ signs, cognitive im- sodium valproate 500 mg BID for 6 months.
pairment and their clinical significance. Br
lating to the production of neurologic J Psychiatry. 1985;146:348–357. She has developed a manic episode with
symptoms by prior neuroleptic treat- 2. Vaid G, Smith RC, Rosenberger J, et al. psychotic features for which she was pre-
ments. We did not administer NES to Neurological and neuropsychological tests scribed for the first time an antipsychotic
in schizophrenics. Biol Psychiatry. 1993;33 drug—olanzapine 5 mg daily.
2 patients at baseline because of signif- (suppl 6A):92.
Four weeks later, she presented with
icant extrapyramidal symptoms due to 3. Buchanan RW, Koppel E, Brier A. Stability
of neurological signs with clozapine treat- 3-day history of a painful swelling of her
previous neuroleptic treatments. Their clitoris.
ment. Biol Psychiatry. 1994;36:198–200.
first NES assessments were made after 4. Smith RC, Kamedari RP. Neurological soft At the time of her maniac relapse, she
2 weeks of discontinuation period, while signs and response to risperidone in chron- was known to have a variable alcohol intake
ic schizophrenia. Biol Psychiatry. 1996;40:
extrapyramidal side effects totally dis- 1056–1059. of maximum 20 U* a week and she was
appeared. The NES score of the second 5. Smith RC, Hussain MI, Chowdhury SA, et al. using small amounts of cannabis intermit-
patient did not change until olanzapine Stability of neurological soft signs in chron- tently, 2 to 3 times a month for the last 2
ically hospitalized schizophrenic patients. years. During the treatment with olanzapine,
was started. None of the patients had J Neuropsychiatry Clin Neurosci. 1999;11:
extrapyramidal side effects throughout her intake of alcohol and cannabis was
91–96.
the treatment period despite higher doses 6. Schroder J, Niethammer R, Geider F, et al. closed to none. She has never had a clitoral
Neurological soft signs in schizophrenia. priapism or clitoral-related pathology in her
of olanzapine treatment. The last patient Schizophr Res. 1992;6:25–30. medical history. Routine physical and labo-
demonstrated that baseline NES values 7. Kay SR, Fiszbein A, Opler LA. The Posi- ratory investigations were normal.
might improve with olanzapine treat- tive and Negative Syndrome Scale (PANSS)
Olanzapine was discontinued, which
for schizophrenia. Schizophr Bull. 1987;13:
ment. However, longer treatment peri- 261–267. resulted in resolution of clitoral swelling in
ods with larger samples may be required 8. Guy W. ed. ECDEU Assessment Manual 2 days.
in such patients to see if improvement for Psychopharmacology. Washington, DC: The temporal association with the
in neurologic signs is associated with US Department of Health Education and
Welfare; 1976:218–222.
introduction of olanzapine and resolu-
decreases in psychopathology scores. 9. Buchanan RW, Heinrichs DW. The Neuro- tion following its withdrawal suggest
It would also be important to examine logical Evaluation Scale (NES): a structured
if anticholinergic or antidopaminergic instrument for the assessment of neurological *One unit of alcohol is the equivalent of 8 g of
signs in schizophrenia. Psychiatry Res. 1989;
properties might affect the NES scores. alcohol, and it is a measure of alcohol intake widely
27:335–350.
These case results suggest that 10. Barnes TRE. A rating scale for drug-induced used in the United Kingdom. A unit corresponds
akathisia. Br J Psychiatry. 1989;154:672–676. to half a pint of beer, 1 glass of table wine,
NSS may improve in chronically ill 1 conventional glass of sherry or port, and 1 single
11. Guy W. ECDEU Assessment for Psycho-
schizophrenics during an atypical neu- pharmacology. Washington, DC: HEW Public bar measure of spirits. Austoker J. Reducing
roleptic treatment, in contrast to some Health Service; 1976:534–537. alcohol intake. Br Med J. 1994;308:1549–1552.
that it was a case of drug-induced clitoral regimen, she continued to have 2 to 3 par- agent demonstrates moderate affinity
priapism. tial complex seizures daily. The behavioral at the dopamine D4 receptor, serotonin
changes were manifested as increasing para- 5-HT2C and 5-HT7 receptors, a-adre-
Mihaela Bucur, MD noia directed against her neighbors accom- nergic, histamine H1, and the serotonin
panied by delusions of reference, moderately
Tariq Mahmood, FRCPsych reuptake site. Aripiprazole functions as
severe anxiety, and agoraphobia with super-
The Mount Hospital, Leeds, Leeds a partial agonist at the D2 and 5-HT1A
imposed severe daily tension-type head-
Mental Health Trust, United Kingdom receptors, and an antagonist at the
aches. The patient denied auditory or
[email protected] 5-HT2A receptor, which likely explains
visual hallucinations. The patient was begun
on aripiprazole 10 mg daily and increased to its antipsychotic and anxiolytic proper-
REFERENCE a total daily dose of 20 mg over a 4-week ties. Importantly, it appears to have
1. Weiner DM, Lowe FC. Psychotropic drug- period, which the patient tolerated well minimal to no cholinergic muscarinic
induced priapism: incidence, mechanism and without adverse effects or increased seizure
management. CNS Drugs. 1998;9(5):371–379. activity, making it an ideal agent for
frequency. The patient’s paranoia, delusions use in cognitively impaired individuals
of reference, fear, and anxiety improved by requiring neuroleptic agents. The half-
Chronic Interictal approximately 85% on a self-report analog life of the parent compound is approx-
scale, and she was again able to interact with
Psychosis Responsive her neighbors, perform daily errands, and
imately 75 hours with a steady state
achieved in 2 weeks. It is eliminated
to Aripiprazole function around groups of people. In addi-
tion, the patient self-reported that her ten- primarily through the hepatic cyto-
sion-type headaches improved by over 75% chrome P450 2D6 and 3A4 isomers
To the Editors: with respect to both intensity and frequency. and has not been linked to increased
Partial complex epilepsy with The patient, after 2 months, continues to seizure frequency.6
temporal lobe focus has been linked to tolerate aripiprazole well and reports con- However, caution should be main-
a variety of cognitive and behavioral tinued improved social functioning with tained when using anticonvulsants that
abnormalities including the emergence resolution of her paranoia and a marked re- induce the 3A4 isozyme.
of chronic interictal psychotic states duction in the delusions of reference. The To the best of our knowledge,
presumably due to kindling effect and patient has suffered no significant cognitive
this is the first case report of a patient
prolonged neuronal irritability. Treat- adverse effects related to aripiprazole.
with temporal lobe epilepsy–associated
ment of interictal psychosis has histor- Chronic interictal psychosis was
interictal psychosis who has been suc-
ically been achieved with a combina- initially characterized by Slater et al2
cessfully treated with aripiprazole. We
tion of anticonvulsants and neuroleptic who noted a remarkable clinical simi-
offer that mesolimbic dopamine block-
agents, but caution is warranted with larity to schizophrenia, and this pattern
has been confirmed by other studies.3 ade coupled with mesocortical dopa-
antipsychotic use as many have been mine partial agonism can produce
The mainstay of treatment has been the
reported to decrease seizure threshold improvement in psychosis, while mini-
combined use of antipsychotic and
and further impair cognitive ability in mizing adverse cognitive effects in
anticonvulsant medications, but concern
an already susceptible population.1 We this already susceptible population.
exists regarding the potential for anti-
report a case of chronic interictal psy- Further study is needed to replicate
psychotic agents to produce cognitive
chosis associated with temporal lobe these results with larger numbers of
dysfunction and further reduce the
epilepsy responsive to the newest atyp- seizure threshold, especially those in patients. However, given the favorable
ical antipsychotic, aripiprazole. the phenothiazine class.4 A paucity of pharmacologic profile of aripiprazole,
data exist to support the use of newer these authors argue that it should be
CASE REPORT atypical antipsychotics in the treatment considered a first-line agent in the treat-
A 35-year-old Caucasian female with of this behavioral syndrome in spite of ment of patients demonstrating inter-
a greater than 15-year history of refractory, the acknowledgement that the atypical ictal psychosis.
uncontrolled partial complex epilepsy with a agents are better tolerated and have an
temporal lobe focus presented as a referral to improved side-effect profile than older,
the psychiatric clinic because of worsening Harold W. Goforth, MD*
typical agents.5
behavioral abnormalities. The patient had Murali Rao, MDy
Aripiprazole is the newest agent
failed previous trials of multiple medications Roy Sucholeiki, MDz
among the atypical antipsychotics and
for her seizure disorder including dival- *Division of Geriatric Psychiatry, Duke
proex, carbamazepine, oxcarbazine, levetir- has a novel pharmacologic profile un- University Medical Center, Durham, NC and
acetam, and mysoline. The patient’s seizures like other atypical agents. It exhibits a Departments of yPsychiatry and Behavioral
were currently treated with lamotrigine 200 high affinity for the D2 and D3 dopa- Neurosciences and zNeurology, Loyola
mg twice daily and clonazepam 0.5 mg mine receptors and serotonin 5-HT1A University Medical Center, Maywood, IL
thrice daily. However, in spite of this and 5-HT2A receptors. In addition, the [email protected]
REFERENCES with cocaine dependence and schizo- his cravings had decreased considerably and
1. Brewerton TD. The phenomenology of psycho- affective disorder. he was better able to maintain drug absti-
sis associated with complex partial seizure dis- nence. Because some cravings persisted, the
order. Ann Clin Psychiatry. 1997;9:31–51. baclofen dose was increased to 20 mg orally
2. Slater E, Beard AW, Glithero E. The schizo- CASE REPORT 3 times daily and he remained on risperidone
phrenia-like psychoses of epilepsy. V. Discus- The patient is a 58-year-old African and fluoxetine. Several months later, the
sion and conclusions. Br J Psychiatry. 1963; American male who started abusing both patient stopped his baclofen, and within 2
109:95–150.
3. Perez MM, Trimble MR. Epileptic psychosis: cocaine and alcohol at 24 years of age. The weeks, he relapsed to cocaine use. Abrupt
diagnostic comparison with process schizo- patient reported experiencing auditory hallu- cessation of baclofen can produce a with-
phrenia. Br J Psychiatry. 1980;137:245–249. cinations at the age of 25. He also reported drawal syndrome within 12 to 72 hours after
4. Pisani F, Oteri G, Costa C, et al. Effects of autonomous episodes of mania and depres- discontinuation that consists of agitation,
psychotropic drugs on seizure threshold. Drug sion starting in his 20s and 30s. There have
Safety. 2002;25:91–110.
psychosis, confusion, insomnia, hypertonia,
5. Bradford D, Perkins D, Lieberman J. Pharma- been significant periods of abstinence in this fever, and/or seizures.6 No such syndrome
cological management of first-episode schizo- patient’s history in which psychotic and developed in this patient. He was admitted
phrenia and related nonaffective psychoses. affective symptoms were present. The pa- to an inpatient substance abuse treatment
Drugs. 2003;63:2265–2283. tient was diagnosed with schizoaffective facility and restarted on baclofen 20 mg
6. Abilify Product Prescribing Information. Avail-
able at: www.abilify.com. Accessed October disorder–bipolar type (Diagnostic and Sta- orally 3 times daily, risperidone 1 mg orally
15, 2003. tistical Manual of Mental Disorders, Fourth daily, and fluoxetine 40 mg orally daily.
Edition criteria), and his prominent symp- After discharge, urine toxicology screens
toms included command auditory hallucina- and blood alcohol levels were performed
Baclofen as Adjunctive tions, paranoid delusions, depression, mania, randomly on a regular basis and were always
Treatment for a and suicidal ideation that resulted in major
dysfunction. He was also diagnosed with
negative.
For a 1-year period from 2002 to 2003,
Patient With Cocaine cocaine and alcohol dependence and canna- the patient had been stable on baclofen,
bis abuse, but he and his clinicians identified risperidone, and fluoxetine and did not dem-
Dependence and cocaine use as his primary drug problem. onstrate previous symptoms of auditory hal-
Schizoaffective Consequences of his cocaine use included
physical, family, and legal problems. For
lucinations, depression, or suicidality. He
regularly reported that his cocaine cravings
Disorder periods, he used high doses of alcohol on a were substantially reduced, and he main-
daily basis and demonstrated compulsive tained abstinence from all drugs of abuse.
To the Editors: use, tolerance, and withdrawal symptoms. This has been the longest period of stability
Drugs that act as receptor agonists He also used cannabis on a daily basis for in the course of his comorbid psychiatric
at c-aminobutyric acid type B receptors periods of time. Between 1970 and 1998, the illnesses, and he required no hospitalizations.
may be used as adjunctive treatments patient was hospitalized 15 to 20 times for Adjunctive treatment with baclofen was well
for substance abuse disorders. Many his comorbid addictive and schizoaffective tolerated, and there were no side effects
studies using animal models have dem- disorders and was treated with neuroleptics even while taking antipsychotic medication.
onstrated that c-aminobutyric acid type and serotonin reuptake inhibitors. During It appears unlikely that the anticraving ef-
B agonist baclofen reduces the reward- that period, his longest period of abstinence fects cannot be attributed to the antipsychotic
was only 6 months. treatment (risperidone 1 mg every day), be-
ing effects of drugs of abuse, such
Since 2000, he was treated with flu- cause the dose of this medication was reduc-
as opiates, cocaine, nicotine, and etha- ed in dosage throughout the baclofen trial.
oxetine 40 mg orally once daily and risper-
nol.1,2 Recent clinical reports show that idone 2 to 3 mg orally twice daily. Despite Some exciting preliminary work dem-
baclofen treatment blocks drug craving this treatment, he experienced command onstrates the efficacy of baclofen as an ad-
and improves abstinence in drug-abus- auditory hallucinations, heavy and frequent junct in the treatment of both addictive and
ing patients.3,4 Patients with schizophre- cocaine use, depression, persistent suicidal psychotic disorders. In one study, alcoholic
nia are more likely to have a substance ideation, and suicide attempts and was patients were treated with baclofen (10 mg
abuse disorder than persons without admitted to an acute inpatient unit on 3 orally 3 times daily) or placebo for 30 con-
mental illness, and comorbidly ill pa- occasions. After each inpatient discharge, he secutive days.7 Baclofen-treated alcoholics
tients are more vulnerable to psychotic relapsed to cocaine use and stopped his showed a significant improvement in absti-
relapses and poorer medication re- medications soon thereafter. Because of his nence, decreased obsessive and compulsive
chronic and persistent craving for cocaine, he symptoms of craving, and reduced drug intake
sponses.5 Given these problems for pa-
was tried on baclofen at the end of 2001. He compared to the placebo-treated group. In a
tients with both substance dependence was started at a dose of 5 mg, and it was pilot study, open-label baclofen treatment
and schizophrenia, novel treatment ap- increased to 10 mg orally 3 times daily. There (60 mg/d) reduced cocaine craving and use
proaches to address both conditions are was no other psychotherapeutic changes or and produced periods of abstinence in 10 co-
sought. This is the first case report on changes in his psychosocial status. caine abusers in drug counseling.8 In another
the safe and beneficial use of baclofen Within 2 months of the initiation of open-label trial in cocaine abusers short-
as an adjunctive treatment for a patient baclofen treatment, the patient reported that term baclofen treatment was given (10 to
20 mg orally twice daily) produced blunting Departments of *Psychiatry and Human that can be ameliorated by clozapine? Harv
of cue-induced drug craving and a blockade Behavior and yMolecular Pharmacology, Rev Psychiatr. 1999;6:287–296.
of limbic activation.4 Pilot studies in schizo- Physiology, and Biotechnology, 6. Olmedo R, Hoffman RS. Withdrawal syn-
dromes. Emerg Med Clin North Am. 2000;18:
phrenic patients also showed the utility of Brown University Medical School, 273–288.
adjunctive treatment with baclofen in some Providence, RI and zMental Health and 7. Addolorato G, Caputo F, Capristo E, et al.
studies9 but not others.10 Behavioral Sciences Service, Veterans Rapid suppression of alcohol withdrawal
Addiction is a disorder of abnormally Affairs Medical Center, Providence, RI syndrome by baclofen. Am J Med. 2002;112:
increased motivation for drugs which results [email protected] 226–229.
8. Ling W, Shoptaw S, Majewska D. Baclofen
in part from excessive activation of meso- as a cocaine anti-craving medication: a pre-
limbic dopaminergic circuitry; additionally, liminary clinical study. Neuropsychopharma-
psychosis is also associated with increas- cology. 1998;18:403–404.
REFERENCES 9. Gulmann NC, Bahr B, Andersen B, et al. A
ed dopaminergic activity.11 c-Aminobutyric
1. Cousins MS, Roberts DCS, de Wit H. GABAB double-blind trial of baclofen against placebo
acid type B receptor activation by baclofen in the treatment of schizophrenia. Acta Psy-
receptor agonist for the treatment of drug
influences the stimulant and motivational addiction: a review of recent findings. Drug chiatr Scand. 1976;54:287–293.
properties of drugs of abuse by inhibiting Alcohol Depend. 2002;65:209–220. 10. Schopf J, Hucker H. Baclofen in the treat-
mesolimbic dopaminergic function.2,12,13 By 2. Kaplan GB, Leite-Morris KA, Joshi M, et al. ment of schizophrenia: a pilot study. Phar-
reducing the activation of dopaminergic sys- GABAB receptor agonist inhibits opiate-in- makopsychiatr Neuropsychopharmakol. 1977;
duced conditioned place preference and asso- 10:89–91.
tems in neural circuits, baclofen would be ciated induction of Fos in cortical and limbic 11. Grace AA. The tonic/phasic model of dopa-
expected to reduce drug craving in drug- regions. Brain Res. 2003;987:122–125. mine system regulation: its relevance for
addicted patients and to stabilize positive 3. Addolorato G, Caputo F, Capristo E, et al. understanding how stimulant abuse can alter
psychotic symptoms in schizophrenics. Clin- Ability of baclofen in reducing alcohol craving basal ganglia function. Drug Alcohol Depend.
and intake: II. Preliminary clinical evidence. 1995;37:111–129.
ical trials of baclofen are warranted as
Alc Clin Exp Ther. 2002;24:67–71. 12. Xi ZX, Stein E. Baclofen inhibits heroin self-
an adjunct in the treatment of comorbid 4. Brebner K, Childress AR, Roberts DC. A administration behavior and mesolimbic do-
schizophrenia and drug dependence. potential role for GABAB agonists in the pamine release. J Pharmacol Exp Ther. 1999;
treatment of psychostimulant addiction. Alco- 290:1369–1374.
hol Alcoholism. 2002;37:478– 484. 13. Leite-Morris KA, Fukudome EY, Shoeb M,
Gary B. Kaplan, MD*yz 5. Green AI, Zimmet SV, Strous RD, et al. et al. GABAB receptor activation in the ven-
Clozapine for comorbid substance use disorder tral tegmental area blocks opiate-induced
Robert Lowell McRoberts III, MD*z and schizophrenia: do patients with schiz- motor stimulation and sensitization. J Phar-
Herbert J. Smokler, MD*z ophrenia have a reward-deficiency syndrome macol Exp Ther. 2004;308:667–678.

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Letters to the Editors

Reply to the diagnoses were as follows: schizo- REFERENCES

Journal of Clinical Psychopharmacology Volume 24, Number 5, October 2004 549

550 n 2004 Lippincott Williams & Wilkins

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552 n 2004 Lippincott Williams & Wilkins

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554 n 2004 Lippincott Williams & Wilkins

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556 n 2004 Lippincott Williams & Wilkins

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TABLE 1. Outcome Variables

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TABLE 1. Trends in Antipsychotic Drug Use in 1981/1982, 1991/1992, and 2001/2002

n/N % (CI) n/N % (CI) n/N % (CI) Trend

560 n 2004 Lippincott Williams & Wilkins

these findings, since they cover a much

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TABLE 1. Interrater and Test-Retest Reliability of the MINI Italian Version

Interrater Reliability Test-Retest Reliability

Diagnoses Ppos Pneg Interrater 95% CI Ppos Pneg Test-Retest 95% CI

562 n 2004 Lippincott Williams & Wilkins

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TABLE 1. Patient’s Dosing and Laboratory Data

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the intestine,17 but nothing is known

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TABLE 1. Characteristics of 3 Patients With Chronic Schizophrenia Treated With Olanzapine

n 2004 Lippincott Williams & Wilkins 571

572 n 2004 Lippincott Williams & Wilkins

n 2004 Lippincott Williams & Wilkins 573

574 n 2004 Lippincott Williams & Wilkins

n 2004 Lippincott Williams & Wilkins 575

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