Letters to the editor

Letters to the editor
Ziprasidone-Induced Angioedema: A Case Report
direct potential y life-threatening immunologic response to zipra- sidone. A limitation of our report is the absence of an intradermal Sir: Ziprasidone is an antipsychotic agent that is general y well
skin test that could have conclusively implicated ziprasidone as the tolerated. Al ergic responses to ziprasidone have been reported, etiologic allergen. Risperidone6 and clozapine7 are other antipsy- including immunoglobulin E (IgE)–related pedal edema,1 life- chotic agents reported in the literature to elicit angioedema. threatening hypersensitivity syndrome,2 and angioedema.3 We This is the second case report about angioedema occurring present a report of a patient who developed angioedema upon after ziprasidone intake. Clinicians in their psychoeducation with starting ziprasidone treatment.
patients should discuss the possibility of severe allergic reactions when commencing ziprasidone treatment, which may ensure Case report. Mr A is a 30-year-old man who presented with
early recognition and intervention of potential y life-threatening psychotic symptoms characterized by persecutory delusions over a 6-week period. His diagnosis according to DSM-IV-TR was bipolar I disorder, most recent episode depressed, severe with psychotic features. He had had 2 previous episodes of mania with psycho- sis that were managed with short-term antipsychotic medication (olanzapine for the first episode and aripiprazole for the second) 1. Ku HL, Su TP, Chow YH. Ziprasidone-associated pedal edema in the and maintenance mood stabilizers (lithium and sodium valproate treatment of schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. for the second episode) without any adverse effects. 2006;30(5):963–964. Mr A's treating psychiatrist started him on ziprasidone thera- 2. Tsai CF, Tsai SJ, Hwang JP. Ziprasidone-induced hypersensitivity syn- py without any other concurrent medication. Prior to treatment drome in an aged schizophrenia patient [letter]. Int J Geriatr Psychiatry. with ziprasidone, Mr A had been free of al other prescription 2005;20(8):797–799. 3. Akkaya C, Sarandol A, Aydogan K, et al. Urticaria and angio-oedema and nonprescription medication in the preceding 3 months. He due to ziprasidone. J Psychopharmacol. 2007;21(5):550–552. commenced ziprasidone 20 mg twice daily on the first day and 4. Naranjo CA, Busto U, Sellers EM. A method for estimating the probabil- had a 40-mg tablet the next morning. Within 6 hours of taking ity of adverse drug reactions. Clin Pharmacol Ther. 1981;30:239–245.
the 40-mg dose, his tongue began to swell and he could not speak 5. Austen KF. Allergies, anaphylaxis and systemic mastocytosis. In: Fauci clearly. He experienced shortness of breath and was immediately AS, Braunwald E, Kasper DL, et al, eds. Harrison's Principles of Internal transferred to the hospital by ambulance. Mr A had no past history Medicine, vol. 2. 17th ed. New York, NY: McGraw Hill; 2008:2061–2070.
of asthma, al ergic rhinitis, urticaria, food al ergies, eczematous 6. Cooney C, Nagy A. Angio-oedema associated with risperidone [letter]. dermatitis, or drug-related allergies.
On examination, his tongue and lips were swollen, extending 7. Mishra B, Sahoo S, Sarkar S. Clozapine-induced angioneurotic edema. Gen Hosp Psychiatry. 2007;29:78–80.
up to the jaw line. There was partial obstruction to the airway, and the patient found it difficult to breathe through the mouth. There was no swelling noted of the genitalia, palms, soles, or eyelids. He Titus Mohan, MD
had tachycardia, mildly elevated blood pressure, and an oxygen Tarun Bastiampillai, FRANZCP
saturation of 97%. There was no lymphadenopathy or urticarial le- Rohan Dhillon, FRANZCP
sions, and the findings from systemic examination were normal.
The diagnostic impression was that Mr A's presentation pos- Author affiliations: The Queen Elizabeth Hospital, South Australia, Australia.
Financial disclosure: None reported. Funding/support: None reported.
sibly represented an anaphylactic reaction to ziprasidone. He was immediately treated with nebulized and intramuscular epi- Copyright 2009 Physicians Postgraduate Press, Inc. nephrine, intravenous hydrocortisone, and promethazine. He responded to these interventions, and within 10 minutes, he was able to talk and breathe without distress. Within 4 hours, the swel - ing subsided completely, and he could tolerate oral fluids. Apart Effects of Bupropion Augmentation in
from a marginal increase in white cell count, the results of blood Escitalopram-Resistant Patients With
investigations were otherwise normal. Mr A was discharged from Major Depressive Disorder: An Open-Label,
the medical unit after 48 hours and transferred to the psychiatric ward. The medical team advised the patient to continue oral pred- nisolone for 5 days. Sir: There is a pressing need for improvement of treatment re-
The adverse reaction scored 6 on Naranjo and colleagues' Ad- sponse to antidepressants in depression. Increasing evidence shows verse Drug Reaction (ADR) scale,4 thus implicating ziprasidone that bupropion, a norepinephrine and dopamine reuptake inhibi- as a probable cause for the event. While in the psychiatric unit, tor, is one of the most widely chosen and effective augmenting Mr A was commenced on amisulpride treatment after a 5-day agents for depressive patients with insufficient response to sero- medication-free period. There was no recurrence of angioedema tonin reuptake inhibitors.1–3 In this study, we evaluated the efficacy with amisulpride. His psychotic symptoms improved within a and tolerability of bupropion augmentation in nonresponders to week, and there were no further al ergic reactions in the subse- escitalopram monotherapy in order to better understand this po- quent 3 months.
tential approach to improving treatment outcome in depression.
Angioedema is a well-demarcated localized edema involving Method. The study sample consisted of 135 subjects with ma-
the deeper layers of the skin, including the subcutaneous tissue. It jor depressive disorder (mean ± SD age = 31.1 ± 11.6 years, 66.1% may occur as an IgE-dependent allergic reaction to a specific an- female) recruited from outpatients admitted to the Psychiatry tigen such as drugs, although other immunologic mechanisms are Clinic of the Tartu University Hospital in Tartu, Estonia, be- postulated. Angioedema of the upper respiratory tract may be life- tween December 2006 and March 2008. Diagnosis according to threatening due to laryngeal obstruction.5 The clinical picture of DSM-IV criteria was determined using the Mini-International Mr A and temporal association with ziprasidone intake suggest a Neuropsychiatric Interview (MINI, version 5.0.0)4 and substantiated J Clin Psychiatry 70:7, July 2009

Letters to the editor
by psychiatric history and medical records. A depression severity Figure 1. Mean Change in Montgomery-Asberg Depression
of at least "moderate" was required for inclusion as indicated by Rating Scale (MADRS) Scores for Responders and
a Montgomery-Asberg Depression Rating Scale (MADRS)5 total Nonresponders to Escitalopram Monotherapy and
score of 22 or higher. Only secondary current comorbid anxiety disorders, including generalized anxiety disorder and social pho- bia, but not other psychiatric or somatic diseases were al owed. Escitalopram responder (n = 82) Bupropion responder (n = 25) None of the patients had psychotic features during their depressive Escitalopram nonresponder (n = 44) Bupropion nonresponder (n = 13) episodes or met criteria for psychotic depression. Patients were treated with escitalopram 10–20 mg/day for 12 weeks in an open- label naturalistic design. No other medications, except zolpidem or zopiclone for insomnia, were al owed during the study. After 12 weeks, the nonresponders to 20 mg of escitalopram monotherapy were given a combination of 20 mg of escitalopram and 150–300 mg/day of bupropion for an additional 6 weeks. Clinical severity and treatment response were assessed biweekly using the MADRS and Clinical Global Impressions (CGI) scale.6 The 17-item Hamil- ton Rating Scale for Depression (HAM-D-17)7 and the Beck De- MADRS Mean Change pression Inventory (BDI)8 were also used as secondary assessments of depressive symptoms, and adverse effects were reported on the Toronto Side Effect Scale (TSES)9 at each visit. There were high correlations between assessments on the clinical scales MADRS or HAM-D-17 and the BDI self-evaluations.
At week 4 of the initial 12-week study, the dose of escitalopram aAt baseline, the severity of depression on the MADRS scale was was increased and kept at 20 mg/day until the end of the study in significantly lower in responders to escitalopram monotherapy as patients who demonstrated less than a 50% decrease in MADRS compared with nonresponders (t = 19.79, df = 55,80; p < .0001). The total score. Patients showing at least 50% decline in the MADRS responders to bupropion augmentation had significantly lower severity total score at week 4 continued on the 10-mg dose. However, later of depression on the MADRS scale before starting of augmentation (week 12) than nonresponders (t = 2.60; df = 21,0; p = .01).
the dose was increased and kept at 20 mg in 2 patients who showed exacerbation of depressive symptoms in fol ow-up visits, one at week 5 and one at 6.
Bupropion was started at 150 mg/day in the morning and of bupropion did not significantly differ between the 2 groups was allowed to increase up to 300 mg/day, given as 150 mg twice (265 ± 66 mg vs. 234 ± 76 mg, respectively, p = .30), demonstrating daily, after week 2 or later if patients still demonstrated insuf- also that frequency or severity of adverse effects was not related to ficient response according to clinical assessments. The patients administered dose of medication. None of the following character- were defined as responders if the decrease in both MADRS and istics differed significantly between responders and nonresponders HAM-D-17 total scores was at least 50% and the score on the to bupropion augmentation: age, sex, onset of disease, melancholic CGI-Improvement scale was 2 or less. The remitters were defined features, number of previous depressive episodes, and duration of as those whose scores were less than 12 on the MADRS and less current depressive episode.
than 8 on the HAM-D-17. The Human Studies Ethics Committee of the University of Tartu approved the study protocol, and all In agreement with previous studies,10–12 we found that bupro- patients provided written informed consent.
pion augmentation successful y facilitated treatment response in Results. At the end of week 12 of treatment with escitalopram,
nonresponders to monotherapy with an SSRI. However, our re- 82 patients (60.7%) were defined as responders (Figure 1) and 79 mission rate with bupropion augmentation was higher than those of them (58.5%) achieved remission. Forty-four patients (32.6%) demonstrated by the Sequenced Treatment Alternatives to Relieve showed insufficient or partial response to treatment, and 9 pa- Depression (STAR*D) trial,11 probably due to lower dropout and tients (6.7%) discontinued escitalopram treatment due to lack discontinuation rates and to methodological differences. We found of efficacy or adverse effects. The daily dose of escitalopram was that the melancholic features of depression were associated with increased and kept at 20 mg in 85 patients, 41 of whom were re- insufficient or partial response to escitalopram and that these could sponders. The nonresponders to escitalopram monotherapy had effectively be resolved by bupropion augmentation. Our results may significantly higher prevalence of melancholic type of depres- give additional support to the importance of focusing treatment sion than did responders (86.4% vs. 63.4% respectively, p = .007) on the predominant or driving symptomatology of depression in and experienced more adverse events, including weakness and order to maximize the chances of response and remission among fatigue, during the escitalopram stage of the trial according to patients and suggest that the use of bupropion is an appropriate TSES assessments (p < .05).
treatment for patients with melancholic type of depression.13–15 In total, 41 patients showing nonresponse to 8 weeks of mono- Importantly, there were similarly low proportions of patients who therapy with 20 mg of escitalopram received bupropion augmen- discontinued either monotherapy with escitalopram or combined tation, whereas 3 patients declined to continue participation in treatment with bupropion due to adverse events, indicating that the study due to personal reasons. At week 6 of augmentation, both medications were general y well tolerated. Although our re- 25 (61.0%) were defined as responders and 22 of them (53.7%) sponse and remission rates with escitalopram monotherapy were achieved remission, whereas 13 patients (31.7%) showed insuffi- comparable to those reported by previous randomized and con- cient or partial response and 3 patients (7.3%) discontinued due to trolled clinical trials with escitalopram,16 we showed that almost adverse effects or lack of efficacy. Bupropion dose was increased to all responders fulfilled the criteria for remission. We suggest that 300 mg in 24 patients, of whom 14 were responders. Only muscle a longer treatment period and relatively earlier increasing of dose twitching was reported more often or more severely on the TSES up to 20 mg/day (from week 4) might significantly reduce the dif- in the nonresponders to bupropion augmentation as compared ference between the response and remission rates, due to cumula- with responders (p < .01). Moreover, the mean ± SD daily dose tive treatment efficacy in some patients. In addition, a consistent J Clin Psychiatry 70:7, July 2009

Letters to the editor
increase in response rates was also demonstrated in another study and anxiety disorders. Expert Rev Neurother 2008;8(4):537–552 using long-term treatment with escitalopram,17 suggesting that 17. Wade A, Despiegel N, Heldbo Reines E. Escitalopram in the long- responders are more likely to achieve remission during longer term treatment of major depressive disorder. Ann Clin Psychiatry treatment periods. Although severity of depressive symptoms and treatment response were careful y rated at each visit and were Eduard Maron, M.D., Ph.D.
supported by patients' self-evaluation, placebo responses cannot Research Department of Mental Health be excluded in our study due to the naturalistic, open-label design. North Estonia Medical Centre Foundation Further randomized clinical trials with longer follow-up periods Psychiatry Clinic and larger sample sizes would be necessary to evaluate the efficacy of bupropion augmentation in resistant depression and particu- Department of Psychiatry larly with melancholic features.
University of Tartu This investigation was supported by Estonian Science Foundation grant Triin Eller, M.D.
7034 (Dr. Maron) and target grant SF0180125s08 (Dr. Vasar) from the Veiko Vasar, M.D.
Ministry of Education of Estonia. Department of Psychiatry Drs. Maron and Nutt have served as consultants for and have received grants and honoraria from Lundbeck and GlaxoSmithKline. Drs. El er and University of Tartu Vasar report no additional financial or other relationships relevant to the subject of this letter. David J. Nutt, D.M., F.R.C.Psych.
Trial Registration: www.anzctr.org.au Identifier Department of Community Based Medicine Psychopharmacology Unit University of Bristol Bristol, United Kingdom 1. Mischoulon D, Nierenberg AA, Kizilbash L, et al. Strategies for man- Copyright 2009 Physicians Postgraduate Press, Inc. aging depression refractory to selective serotonin reuptake inhibitor treatment: a survey of clinicians. Can J Psychiatry 2000;45(5):476–481 2. Zisook S, Rush AJ, Haight BR, et al. Use of bupropion in combination Pseudohallucinations Versus True Hallucinations in
with serotonin reuptake inhibitors. Biol Psychiatry 2006;59(3):203–210 3. Stahl SM, Pradko JF, Haight BR, et al. A review of the neuropharma- Prodromal Psychosis: Does It Really Matter?
cology of bupropion, a dual norepinephrine and dopamine reuptake inhibitor. Prim Care Companion J Clin Psychiatry 2004;6(4):159–166 Sir: According to the traditional accounts of European psy-
4. Sheehan DV, Lecrubier Y, Sheehan KH, et al. Mini-International chiatry, true hal ucinations are apparent perceptions of an exter- Neuropsychiatric Interview (M.I.N.I.): the development and validation nal object in the absence of adequate sensory stimuli. Conversely, of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry 1998;59(suppl 20):22–33 Sims1 states that Kandinsky and Jaspers described pseudohal uci- 5. Montgomery SA, Asberg MC. A new depression rating scale designed to nations as a separate form of perception from true hal ucination. be sensitive to change. Br J Psychiatry 1979;134:382–389 Pseudohal ucination is a perceptual experience that is figurative, 6. Guy W. EDCEU Assessment Manual for Psychopharmacology. US Dept not concrete or "real," is located in inner subjective space, and is Health, Education, and Welfare publication (ADM) 76-338. Rockville, perceived with the "inner" ear (or eye) (Table 1). In other charac- MD: National Institute of Mental Health; 1976;218–222 teristics, pseudohal ucinations are more like true hal ucinations 7. Hamilton M. A rating scale for depression. J Neurol Neurosurg than fantasy. Thus, pseudohal ucination may have definite out- line and vivid detail, it may be retained for some time, and it is 8. Beck AT, Ward CH, Mendelson M, et al. An inventory for measuring not deliberately evoked.3 Jaspers2 stressed that there is a gradation depression. Arch Gen Psychiatry 1961;4:561–571 9. Vanderkooy JD, Kennedy SH, Bagby RM. Antidepressant side effects in from the more ful y formed pseudohal ucination to vivid imagery depression patients treated in a naturalistic setting: a study of bupropion, but that there is an absolute distinction between hal ucination and moclobemide, paroxetine, sertraline, and venlafaxine. Can J Psychiatry pseudohal ucination because of the inner location of the latter. As a consequence of these original speculations, it is a common 10. Papakostas GI, Worthington JJ 3rd, Iosifescu DV, et al. The combination belief that pseudohal ucinations do not have the same psychiat- of duloxetine and bupropion for treatment-resistant major depressive ric significance as true hal ucinations, and thus clinicians expend disorder. Depress Anxiety 2006;23(3):178–181 some clinical effort to distinguish the two. True hal ucinations are 11. Trivedi MH, Fava M, Wisniewski SR, et al. Medication augmen- thought to be always indicative of a morbid mental state such as tation after the failure of SSRIs for depression. N Engl J Med psychosis, while pseudohal ucinations are thought to be of less 12. Lam RW, Hossie H, Solomons K, et al. Citalopram and bupropion-SR: diagnostic significance and not necessarily psychopathological. combining versus switching in patients with treatment-resistant depres- However, pseudohal ucinations may be an attenuated and subtle sion. J Clin Psychiatry 2004;65(3):337–340 expression of an evolving psychosis. There have been no previous 13. Jefferson JW, Rush AJ, Nelson JC, et al. Extended-release bupropion studies of the degree to which pseudohal ucinations are predictive for patients with major depressive disorder presenting with symptoms of the subsequent development of psychosis.
of reduced energy, pleasure, and interest: findings from a random- Here we report 5 cases of young (age range, 18–26 years), drug- ized, double-blind, placebo-controlled study. J Clin Psychiatry naive subjects presenting at a clinical service for prodromal signs of psychosis4 because they were hearing internal voices (pseudo- 14. Papakostas GI, Nutt DJ, Hallett LA, et al. Resolution of sleepiness hal ucinations). At the time of the first assessment (2005 through and fatigue in major depressive disorder: a comparison of bupro- pion and the selective serotonin reuptake inhibitors. Biol Psychiatry 2008), these symptoms did not meet DSM-IV threshold for a psy- chotic episode but met the inclusion clinical criteria for an "at-risk 15. Nutt DJ, Demyttenaere K, Janka Z, et al. The other face of depression, mental state" (ARMS), which is associated with an elevated clinical reduced positive affect: the role of catecholamines in causation and cure. risk of psychosis.5 The diagnosis was based on assessment by 2 J Psychopharmacol 2007;21(5):461–471 experienced clinicians using the Comprehensive Assessment for 16. Höschl C, Svestka J. Escitalopram for the treatment of major depression the ARMS (CAARMS).4,5 J Clin Psychiatry 70:7, July 2009

Letters to the editor
Table 1. Psychopathological Features of Hallucination, Pseudohallucination, and Imagery
Domain
Pseudohal ucination Concrete, tangible, objective, real Pictorial subjective Pictorial subjective Outer objective space Inner subjective space Inner subjective space Definite outlines, complete sound Definite outlines, complete sound Indefinite, incomplete, only individual details Ful , fresh, bright Ful , fresh, bright Most elements are dim or neutral Cannot be dismissed, recalled, or Cannot be dismissed, recalled, or Requires voluntary creation Partly derived from information in Jaspers.2 Case 1. Mr. A was an 18-year-old man who experienced audi-
tory perception abnormalities in that he heard internal voices in the third person commenting on his actions. They typical y hap- 1. Sims A. Symptoms in the Mind: An Introduction to Descriptive pened a few times per week and each episode lasted only 5–10 Psychopathology. 3rd ed. London: WB Saunders Co; 2003:108–111.
minutes. He recognized that the voices were similar to those of 2. Jaspers K. General Psychopathology. Vol. 1. Hoenig J, Hamilton MW, friends, teachers, or his dad and could be neutral or critical in their trans. Baltimore, Md: Johns Hopkins University Press; 1997 content, although occasional y they offered helpful advice.
3. Taylor FK. On pseudohal ucinations. Psychol Med 1981;11(2):265–271 Case 2. Mr. B was a 26-year-old man who reported a voice
4. Broome MR, Woolley JB, Johns LC, et al. Outreach and support he heard inside his head on a weekly basis, which was triggered in south London (OASIS): implementation of a clinical service for by stressful events such as attending col ege. He was unable to prodromal psychosis and the at-risk mental state. Eur Psychiatry discriminate it from his own thoughts, although it sounded like 5. Yung AR, Phillips LJ, Yuen HP, et al. Psychosis prediction: 12-month a young man's voice talking to him in the second person, com- follow-up of a high-risk ("prodromal") group. Schizophr Res menting on his actions and suggesting that he confront people Case 3. Mr. C was a 20-year-old man who could hear his
Paolo Fusar-Poli, M.D., Ph.D.
thoughts aloud in his mind, although he had no awareness of Oliver D. Howes, M.R.C.Psych., D.M.
speaking himself. He felt that the voice was in his head, and it Philip McGuire, M.D., Ph.D., F.R.C.Psych.
sounded the way he would sound normal y, but he did not have Department of Psychological Medicine any control over it and was unable to distract himself. He added Institute of Psychiatry London and the OASIS team that these thoughts in his head became amplified and sometimes National Health Service Lambeth Trust drowned out everything else happening around him.
Case 4. Mr. D was a 20-year-old man who reported hearing a
voice inside his head that was distinct from his normal thoughts Copyright 2009 Physicians Postgraduate Press, Inc. in that its content was repetitive. The voice would repeat a few statements for more than 1 hour at times. He did not recognize the voice and did not have any theories about the cause of the experi- A 5-Year Follow-Up of Diabetes Knowledge in Persons
ence but reported that it "sounded" like a male voice.
With Serious Mental Illness and Type 2 Diabetes
Case 5. Ms. E was a 21-year-old woman suffering from
an alien (male) voice. Although she could hear it inside her Sir: Despite the high prevalence of type 2 diabetes in persons
head (as opposed to being an external sound), it was vivid and with serious mental illness, there has been only limited study of clear. The voice, which occurred almost daily and correlated with diabetes knowledge in this group. In a previous report, we found her levels of stress, expressed thoughts that she recognized as her that among 201 persons with serious mental illness and type 2 dia- own, and it was difficult for her to distinguish them from her betes, the mean score on a diabetes knowledge test was only 54%.1 thoughts. She found the voice distressing but was perfectly capable We reassessed the diabetes knowledge of persons in our sample of not doing what the voice requested by keeping very busy and 5 years later, in a period of heightened focus on diabetes among listening to music.
persons with serious mental illness.
These subjects were followed up by the prodromal team, and, over the following months, they all developed a psychotic episode Method. We recruited psychiatric outpatients with type 2 dia-
and were referred to the local first episode service. Transition was betes and either schizophrenia or major mood disorder as pre- defined as the onset of frank psychotic symptoms (above the psy- viously described.2 Participants were evaluated initial y between chotic threshold on the CAARMS) that did not resolve within a September 1, 1999, and September 30, 2002, and reevaluated again approximately 5 years later between December 8, 2004, and July 12, 2007. Disease-specific diabetes knowledge was assessed at baseline Albeit no quantitative data are available, the present case series and at follow-up by the general subscale of the Diabetes Knowl- strongly suggests that pseudohal ucinations may clinical y charac- edge Test (DKT),3 which was administered in a 1-to-1 interview terize an impending risk for psychosis. Their presence should not by research personnel. be easily dismissed when assessing young subjects seeking help for The test items are designed to be representative of the larger prodromal symptoms of schizophrenia but should be careful y in- domain of il ness-specific diabetes knowledge appropriate for vestigated through a clinical assessment and accurately monitored individuals with type 2 diabetes. The score is calculated as the during an assertive follow-up.
percentage of correct answers out of 14 multiple choice test items that assess diabetes-related issues including dietary choices, blood The authors report no financial or other relationships relevant to the glucose testing, and medical problems that are associated with dia- subject of this letter. betes. We compared the percentage correct for the total score and J Clin Psychiatry 70:7, July 2009

Letters to the editor
for each item on the DKT at baseline and follow-up using a paired specific knowledge of participants did not improve during this t test and McNemar χ2 tests, respectively. We also compared the time period is concerning. Our data suggest that there is a gap percentage correct on the DKT between our sample and a com- between the current focus on diabetes management of persons munity sample referent group of 811 adults with diabetes, almost with serious mental illness in the medical literature and the level all type 2,3 using an ordinary t test and Pearson χ2 tests.
of information about diabetes that is acquired by patients with Results. A total of 95 of the persons with serious mental illness
co-occurring serious mental illness and diabetes in routine clini- were reevaluated at the 5-year fol ow-up. Sample characteristics cal settings. Increased education and discussion about diabetes were mean (SD) age of 49.37 (9.11) years; n = 50 (53%) male; n = 44 by psychiatric clinicians with their patients who have diabetes are (46%) Caucasian; n = 45 (47%) African American; n = 65 (68%) at least high school education; mean (SD) duration of diabetes 13.2 (7.5) years. The sample was divided between those with a diag- nosis of a major mood disorder (n = 50, 53%) and schizophrenia (n = 45, 47%). At follow-up, they were receiving the following anti- 1. Dickerson FB, Goldberg RW, Brown CH, et al. Diabetes knowledge psychotic medications: olanzapine (n = 15, 16%); clozapine (n = 3, among persons with serious mental illness and type 2 diabetes. 3%); risperidone (n = 22, 23%); quetiapine (n = 17, 18%); zipra- sidone (n = 3, 3%); aripiprazole (n = 11, 12%); and first-generation 2. Dixon LB, Kreyenbuhl JA, Dickerson FB, et al. A comparison of type 2 antipsychotic agents (n = 24, 25%).
diabetes outcomes among persons with and without severe mental ill- The sample of n = 95 represents 47.3% of the original sample nesses. Psychiatr Serv. 2004(8);55:892–900.
3. Fitzgerald JT, Funnell MM, Hess GE, et al. The reliability and validity of N = 201 who were evaluated at baseline. Persons who could not of the brief Diabetes Knowledge Test. Diabetes Care. 1998;21(5): be followed up did not differ significantly from those who were reevaluated in terms of baseline demographic variables of age, race, 4. Sernyak MJ. Implementation of monitoring and management guidelines gender, education, psychiatric diagnosis (schizophrenia vs mood for second-generation antipsychotics. J Clin Psychiatry. 2007;68 disorder), or baseline DKT score (all P > .14).
(suppl 4):14–18.
The mean (SD) score on the DKT at follow-up was 56% (19%). Fifty-six of the 95 persons in the sample answered at least 6 of Faith B. Dickerson, PhD
the 14 items incorrectly. The items that were the most likely to Julie Kreyenbuhl, PharmD, PhD
be answered incorrectly were those concerning the diabetes diet. Richard W. Goldberg, PhD
For example, only 36% (n = 34) of the sample endorsed the cor- LiJuan Fang, MS
rect response to the question, "What is a free food?" from among Deborah Medoff, PhD
the 4 response options; the correct response was "any food that Clayton H. Brown, PhD
has less than 20 calories per serving." Similarly, in response to the Lisa Dixon, MD
question, "Which of the fol owing is highest in fat?" only 24% (n = 23) of the sample endorsed the correct response of "low fat Author affiliations: Sheppard Pratt Health System (Dr Dickerson); the VA Capitol
Healthcare Network Mental Il ness Research, Education, and Clinical Center (Drs milk." General y low correct response rates were also found for the Kreyenbuhl, Goldberg, Brown, and Dixon); and the Departments of Psychiatry (Drs items concerning blood glucose. Only 34% (n = 32) of the sample Kreyenbuhl, Goldberg, Medoff, Brown, and Dixon and Ms Fang) and Epidemiol- correctly endorsed that the time period for which glycosylated ogy (Dr Brown), University of Maryland School of Medicine, Baltimore, Maryland. hemoglobin (hemoglobin A1c) measures average blood glucose is Financial disclosure: None reported. Funding/support: The work described in this
letter was supported in part by an unrestricted grant from Bristol-Meyers Squibb and the past 6–10 weeks rather than much longer or shorter time in- by National Institutes of Health grant RO1MH058717.
tervals. The percentage of correct responses was higher on items concerning diabetes-related health problems, although for no item Copyright 2009 Physicians Postgraduate Press, Inc. did the overall percentage correct exceed 80%. A full 80% (n = 76) of the sample endorsed correctly that the correct way to take care of their feet is to "look at and wash them everyday." Aripiprazole Treatment of
The average score for persons in the sample on the DKT was not significantly changed from their baseline score. No individual item had a significant increase in mean correct responses (P > .05). No baseline demographic or clinical variables predicted a change Sir: Hyperprolactinemia is a well-recognized complication
in knowledge score. A comparison of scores in our serious men- of some antipsychotic agents that results from the blocking of tal il ness sample with those from a community referent group dopamine-2 (D2) receptors in the anterior pituitary.1 Aripiprazole, showed that the community comparison group had a significantly a potent partial agonist of the D2 receptors,2 inhibits spontaneous higher percentage correct on 8 of 14 items.
prolactin release from isolated anterior pituitary slices.3 Clinical y, switching to aripiprazole monotherapy resolves antipsychotic- Diabetes-specific knowledge in persons with serious mental induced hyperprolactinemia.4,5 A double-blind, placebo-control ed illness and co-occurring type 2 diabetes remains markedly low de- trial and a few single case reports demonstrated that the addition spite the increased attention to diabetes in this population. Persons of aripiprazole reversed haloperidol-induced hyperprolactinemia in our sample showed a particular deficit in knowledge related and associated symptoms.6–8 We conducted an 8-week, prospective, to diabetes dietary issues that has implications for the ability of open-label study to assess whether adjunctive treatment with aripip- persons to manage their diet effectively on a day-to-day basis, a razole would improve risperidone-induced hyperprolactinemia.
central aspect of diabetes self-care. Dietary information may less likely be a focus of interactions with medical care providers than Method. Twenty-one male Chinese outpatients and inpa-
are health-related diabetes problems that are more directly medi- tients meeting DSM-IV criteria for schizophrenia were recruited cal in content.
after they gave informed consent and institutional review board In the approximately 5-year interval between the baseline and approval was obtained. Data were collected from December 2007 fol ow-up assessments of our study, there have been increased to June 2008.
initiatives to better identify, assess, and treat persons with seri- Nineteen subjects completed the trial, receiving a fixed dose ous mental illness and type 2 diabetes.4 The fact that the diabetes- of 10 mg/d of aripiprazole at 7:00 am for 8 weeks. The doses of J Clin Psychiatry 70:7, July 2009

Letters to the editor
risperidone and concomitant medications remained fixed through- anterior pituitary gland. J Pharmacol Exp Ther. 1996;277(1):137–143. out the study. Serum prolactin levels were measured at baseline 4. Mir A, Shivakumar K, Williamson RJ, et al. Change in sexual dysfunc- and 2, 4, and 8 weeks using standard radioimmunoassay. Symptom tion with aripiprazole: a switching or add-on study. J Psychopharmacol. severity was assessed using the Positive and Negative Syndrome 2008;22(3):244–253. Scale (PANSS)9 and the Clinical Global Impressions scale (CGI).10 5. Lee BH, Kim YK, Park SH. Using aripiprazole to resolve antipsy- Tolerability was evaluated with the Barnes Akathisia Scale (BAS)11 chotic-induced symptomatic hyperprolactinemia: a pilot study. Prog Neuropsychopharmacol Biol Psychiatry. 2006;30(4):714–717. and the Simpson Angus Scale (SAS).12 The same investigator rated 6. Shim JC, Shin JG, Kel y DL, et al. Adjunctive treatment with a do- patients with these scales at baseline and at 8 weeks.
pamine partial agonist, aripiprazole, for antipsychotic-induced Results. Mean ± SD prolactin levels at baseline and 2, 4,
hyperprolactinemia: a placebo-controlled trial. Am J Psychiatry. and 8 weeks were 62.4 ± 22.1 ng/mL, 26.1 ± 11.2 ng/mL, 18.9 ± 8.1 ng/mL, and 18.1 ± 7.7 ng/mL, respectively (F = 41.68, df = 5, 7. Chen CH, Lu ML. Aripiprazole resolves symptomatic hyperprolactin- P < .0001). Pairwise comparisons showed that prolactin levels sig- emia in a male schizophrenic patient. Prog Neuropsychopharmacol Biol nificantly decreased between baseline and 2, 4, and 8 weeks, and Psychiatry. 2008;32(3):893–894. between 2 and 4 weeks (P < .0001), with no significant difference 8. Wahl R, Ostroff R. Reversal of symptomatic hyperprolactinemia by between 4 and 8 weeks. At the completion of the study, all patients aripiprazole. Am J Psychiatry. 2005;162(8):1542–1543. 9. Kay SR, Opler LA, Fizbein A. The Positive and Negative Syndrome Scale demonstrated significantly reduced serum prolactin levels, and 6 (PANSS) Manual. North Tonawanda, NY: Multi-Health System; 1986.
of 19 (32%) patients had clinical y normal prolactin levels.
10. Guy W. ECDEU Assessment Manual for Psychopharmacology. US Dept The patients showed no significant changes in PANSS or CGI Health, Education, and Welfare publication (ADM) 76-338. Rockville, scores or in SAS or BAS scores between baseline and week 8. Only MD: National Institute of Mental Health; 1976:218–222.
a few side effects were noted, including tachycardia (n = 2) and 11. Barnes TRE. A rating scale for drug-induced akathisia. Br J Psychiatry. anorexia and headache (n = 1; both side effects were in the same 1989;154:672–676. 12. Simpson GM, Angus JWS. A rating scale for extrapyramidal side effects. Acta Psychiatr Scand Suppl. 1970;212:11–19. To our knowledge, this is the first open-label prospective trial 13. El-Sayeh HG, Morganti C, Adams CE. Aripiprazole for schizophrenia: systematic review. Br J Psychiatry. 2006;189:102–108. of aripiprazole to treat risperidone-induced hyperprolactinemia. 14. Grunder G, Carlsson A, Wong DF. Mechanism of new antipsychotic Our study found that 8 weeks of adjunctive aripiprazole treatment medications: occupancy is not just antagonism. Arch Gen Psychiatry. was effective, safe, and wel tolerated in reducing elevated prolactin 2003;60(10):974–977. levels. The mechanism for the resolution of hyperprolactinemia 15. Aihara K, Shimada J, Miwa T, et al. The novel antipsychotic aripiprazole using aripiprazole is likely due to its unique partial agonist activ- is a partial agonist at short and long isoforms of D2 receptors linked to the regulation of adenylyl cyclase activity and prolactin release. Brain 2 receptors and relatively high D2 receptor affinity.13 The partial agonist property means that, in the presence of dopamine Res. 2004;1003(1-2):9–17. (DA) hypoactivity, as induced by risperidone, aripiprazole will function as a DA agonist, restoring tonic inhibition to anterior Jing Xu Chen, MD
pituitary lactotrophs, where tonic DA stimulation controls pro- Yun Ai Su, MD, PhD
lactin secretion.14,15 Shao Li Wang, MD
Limitations of the present study include the relatively small Qing Tao Bian, MD
sample size, the short duration of the trial, and the use of Yan Hong Liu, MD
the fixed dose of aripiprazole. Therefore, larger, double-blind, Ning Wang, MD
placebo-controlled studies of longer duration with different doses Fu De Yang, MD
of aripiprazole (especial y higher doses, such as 20 or even 30 mg) Colin Haile, PhD
might further investigate efficacy, safety, tolerability, and a dose- Thomas R. Kosten, MD
dependent effect of adjunctive aripiprazole.
Xiang Yang Zhang, MD, PhD
Author affiliations: Beijing Hui-Long-Guan Hospital (Drs Chen, S. L. Wang, Bian,
Liu, N. Wang, Yang, and Zhang) and Institute of Mental Health, Peking University 1. Jung DU, Seo YS, Park JH, et al. The prevalence of hyperprolactinemia (Dr Su), Beijing, China; and Department of Psychiatry, Baylor College of Medicine, after long-term haloperidol use in patients with chronic schizophrenia. Houston, Texas (Drs Haile, Kosten, and Zhang). Authorship note: Drs Chen and Su
J Clin Psychopharmacol. 2005;25(6):613–615. contributed equal y to this work. Financial disclosure: None reported. Funding/sup-
2. Kessler RM. Aripiprazole: what is the role of dopamine D2 receptor port: This study was funded by the Stanley Medical Institute Foundation (03T-459,
partial agonism? Am J Psychiatry. 2007;164(9):1310–1312. 05T-726) (Dr Zhang) and the Department of Veterans Affairs, VISN 1, Mental Il ness Research, Education and Clinical Center (MIRECC) and National Institute on Drug 3. Inoue T, Domae M, Yamada K, et al. Effects of the novel antipsychotic Abuse K05-DA0454 and P50-DA18827 (Dr Kosten).
(1H)-quinolinone (OPC-14597) on prolactin release from the rat Copyright 2009 Physicians Postgraduate Press, Inc. J Clin Psychiatry 70:7, July 2009

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