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finding that would explain amenorrhea was not detected by the obstetrician. The patient’s prolactin level was determined as 45.6 ng/mL (reference range, 5.18Y 26.53 ng/mL), and it was thought to be related to the use of duloxetine. The dosage was reduced to 30 mg/d, and the prolactin level was measured after 1 week and found as 23 ng/mL; 10 days later, menstruation was detected. The patient’s treatment with a dosage of 30 mg/d duloxetine continued for 5 months; amenorrhea complaints did not reiterate, and prolactin levels remained normal. Recently reviewed Beck Depression Inventory score was found as 12, and Beck Anxiety Inventory score was 8.
CASE 2 A 47-year-old woman presented with demoralization, reluctance, fatigue, headache, and complaints of excessive sleepiness. There were complaints for many years. She had used various antidepressant drugs over the years, and for the last 5 years, she has been using escitalopram 20 mg/d and quetiapine 50 mg/d. Her history shows no alcohol and drug use, continuous drug use, or organic disorders. She was not sexually active. She had a regular menstrual period, and follow-up was being done by gynecologists. Beck Depression Inventory score was found as 38, and Beck Anxiety Scale score was found to be 22. The patient was treated with a dosage of 30 mg/d due to the diagnosis of major depressive disorder according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition; the patient’s depressive symptoms at the end of the first month fell, but delayed menstruation was seen. The physical examination result and laboratory values for thyroid stimulating hormone, urea, creatinine, glucose, urea, creatinine, aspartate transaminase, alanine transaminase, and electrolyte were normal. She did not use oral contraceptives and was not pregnant. The patient’s prolactin level was determined as 57.6 ng/mL (reference range, 5.18Y26.53 ng/mL). The patient was referred by neurology and gynecology. The result of cranial MRI was normal. The pathologic finding that would explain amenorrhea was not detected by the obstetrician, and the patient was started on dopamine receptor agonist cabergoline 0.5 mg/d twice a week. The prolactin level was measured 1 month later and found as 26.8 ng/mL; menstrual period was detected 15 days later. With normalization of the patient, prolactin cabergoline treatment was discontinued by the obstetrician. Duloxetine therapy was stopped, and the treatment with venlafaxine 37.5 mg was started; the patient was then treated with venlafaxine * 2014 Lippincott Williams & Wilkins
75 mg/d; amenorrhea complaints were not reiterated, and prolactin levels remained normal. The last Beck Depression Inventory score was 14, and Beck Anxiety Inventory score was 9. In our cases, we think that hyperprolactinemia and amenorrhea are related to duloxetine due to the emergence of hyperprolactinemia and amenorrhea after the treatment with duloxetine, other drug use, the patient did not use other drugs, cranial MRI being normal, and the fact that the woman in the first case by birth ruled out organic causes of amenorrhea, and in the second case after the treatment was stopped and cabergoline treatment was applied, it was seen that amenorrhea and hyperprolactinemia were treated. More studies are needed in this regard. AUTHOR DISCLOSURE INFORMATION The authors declare no conflicts of interest. Birmay C ¸ am, MD Department of Psychiatry Manisa Mental Health Manisa, Turkey [email protected]
Tunay Karlıdere, MD Department of Psychiatry Faculty of Medicine Balikesir University BalNkesir, Turkey
REFERENCES 1. Girayalp BO. Galactorrhea due to fluoxetine in a patient with depression and a pituitary adenoma: a case report. Bull Clin Psychopharmacol. 2009;19:159Y163. 2. Korkmaz S, Kulo?lu M, IzNk U, et al. Galactorrhea during duloxetine treatment: a case report. Tu¨rk Psikiyatri Derg. 2011;22(3):200Y201. 3. Bronzo MR, Stahl SM. Galactorrhea induced by sertraline (letter). Am J Psychiatry. 1993;150:1269Y1270. 4. Feuchtl A, Bagli M, Stephan R, et al. Pharmacokinetics of m-chlorophenylpiperazine after intravenous and oral administration in healthy male volunteers: implication for the pharmacodynamic profile. Pharmacopsychiatry. 2004;37:180Y188. 5. Gu¨lsu¨n M, Evrensel Al, Verim S. Galactorrhea during escitalopram treatment: a case report. Bull Clin Psychopharmacol. 2006;16:39Y41. 6. Meltzer H,Bastani B, Jayathilake K, et al. Fluoxetine, but not tricyclic antidepressants, potentiates the 5-HydroxytryptophanYmediated increase in plasma cortisol and prolactin secretion in subjects with major depression
Letters to the Editors
or with obsessive compulsive disorder. Neuropsychopharmacology. 1997;17:1Y11. 7. Anand VS. Clomipramine-induced galactorrhoea and amenorrhoea. Br J Psychiatry. 1985;147:87Y88. 8. Fowlie S, Burton J. Hyperprolactinaemia and nonpuerperal lactation associated with clomipramine. Scott Med J. 1987;32(2):52. 9. Peterson MC. Reversible galactorrhea and prolactin elevation related to fluoxetin use. Mayo Clin Proc. 2001;76(2):215Y216. 10. Spigset O, Mjorndal T. The effect of fluvoxamine on serum prolactin and serum sodium concentrations: relation to platelet 5- HT2A receptor status. J Clin Psychopharmacol. 1997;17:292Y297. 11. Morrison J, Remick RA, Leung M, et al. Galactorrhea induced by paroxetine. Can J Psychiatry. 2001;46(1):88Y89. 12. Sternbach H. Venlafaxine-induced galactorrhea. J Clin Psychopharmacol. 2003;23(1):109Y110. 13. Ashton AK, Longdon MC. Hyperprolactinemia and galactorrhea induced by serotonin and norepinephrine reuptake inhibiting antidepressants. Am J Psychiatry. 2007;164:1121Y1122. 14. Ha¨rmark L, van Puijenbroek E, van Grootheest K. Intensive monitoring of duloxetine: results of a Web-based intensive monitoring study. Eur J Clin Pharmacol. 2013;69(2):209Y215.
A Case of Late-Onset Angioedema Associated With Clozapine and Redevelopment of Angioedema With Olanzapine To the Editors: ngioedema is a rare but potentially lifethreatening adverse effect of antipsychotics such as risperidone,1Y4 olanzapine,5 clozapine,6 ziprasidone,7,8 droperidol,9,10 and chlorpromazine.11,12 Nonsteroid antiinflammatory drugs, angiotensin-converting enzyme inhibitors (ACEIs), penicillin, and neuromuscular blockers are the most common medications held responsible for angioedema.13 Angioedema is the swelling of deep dermal and subcutaneous tissues that occurs on the face, tongue, extremities, genitals, and rarely larynx.7 The late-onset angioedema is a rare clinical condition that occurs months or years, after which is more likely reported with ACEIs.14Y16 Here we report a female patient who developed late-onset angioedema after treatment with clozapine after 5 years and redevelopment of angioedema with
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introduction of olanzapine, which resolved on discontinuation of both drugs.
CASE REPORT A 27-year-old woman with a condition diagnosed with psychotic disorder and intellectual disability 5 years ago by another psychiatric outpatient clinic with symptoms of self-talking, suspiciousness, inability to sleep, and an idea of persecution was referred to our outpatient clinic a year ago, and the same diagnoses were made by her psychiatric evaluation and her past history of psychiatric and medical illness. At the time of diagnosis, the IQ test result was 61. Her clinical condition was going well with clozapine 150 mg/d, which she had been using for 5 years. At 1 of her follow-up visits, the physical examination revealed swelling over the face and eruption on the perioral region. Results of laboratory examinations including liver and renal function tests, serum electrolytes, blood cell count, and sedimentation rate were within the reference range. The medical and family history of the patient was unremarkable, and she did not report allergic reactions to any drug or food. The patient was consulted with dermatology, and a diagnosis of acute angioedema was established. After discontinuation of clozapine, skin symptoms were resolved within 1 week, and olanzapine 10 mg/d was started. A few days after introduction of olanzapine, the same skin symptoms emerged over the face, and repeated laboratory tests were unremarkable. Skin scratch test revealed hypersensitivity with the medications of clozapine, olanzapine, and sulpiride. Olanzapine was discontinued, and quetiapine 300 mg/d was started because of a negative skin scratch test result. Quetiapine dose was increased up to 900 mg/d in that psychotic symptoms exacerbated over time. She remained well under this dose without any recurrence of psychiatric symptoms or angioedema.
DISCUSSION Angioedema is a transient edema resulting from increased vascular permeability, which is associated with inflammatory mediators.17 The onset usually occurs within the first weeks of drug therapy but can develop months or years, after which was more likely reported with ACEIs.14Y16 Although angioedema associated with clozapine was reported before,6 to our knowledge, this is the first reported case of late-onset angioedema associated with clozapine monotherapy. Mild skin reactions are expected, whereas angioedema is rarely seen with olanzapine. Angioedema associated with olanzapine was reported in
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only 2 patients in a postmarketing surveillance study carried out in England on 8858 patients.5 Hereditary, acquired, allergic, and drug-related mechanisms are underlying causes of angioedema. The allergic form of angioedema mediated by immunoglobulin E (IgE) can be caused by a drug acting as an allergen.18 It is suggested that the drug triggers IgE-mediated degranulation of mast cells and causes release of inflammatory mediators such as histamine, serotonin, and bradykinins. These mediators increase vascular permeability and cause angioedema.19 The same adverse effects seen in both olanzapine and clozapine can be explained by the structural similarity between these drugs.20 The occurrence of angioedema with the administration of a stable dose of clozapine and with the introduction of olanzapine, disappearance of symptoms with discontinuation of both drugs, and results of skin scratch test suggest an allergic form of angioedema associated with clozapine and olanzapine. Although quetiapine is very closely related structurally to clozapine and olanzapine, angioedema did not emerge with this drug. A possible explanation for this might be an unidentified new vulnerability factor that was going on at the time of the development of angioedema and evidently was persisting during the introduction of olanzapine, which may have subsided by the time quetiapine was started. A coincided ingestion of an unknown allergen or drug might have influenced generation of IgE-mediated type 1 hypersensitivity against clozapine and olanzapine. Angioedema can occur even after many years of uneventful drug use. The mechanism behind the late-onset angioedema is not evident, but it is known that any kind of allergy, especially type 1 hypersensitivities, can begin any time in life. Early-onset angioedema associated with antipsychotics may easily be recognizable, but the correlation with late-onset angioedema can be overlooked. This case report indicates the need for clinicians to be aware of lateonset adverse events in patients treated with antipsychotics. AUTHOR DISCLOSURE INFORMATION The authors declare no conflicts of interest. Presented as a poster at the 22nd European Congress of Psychiatry, Munich, Germany, March 1Y4, 2014. Zeynep Baran Tatar, MD Department of Psychiatry Bakirkoy Training and Research Hospital for Psychiatry
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Neurology, and Neurosurgery Istanbul, Turkey [email protected]
Serap Oflaz, MD Department of Psychiatry Istanbul Medical Faculty Istanbul University Istanbul, Turkey
Bulent Baran, MD Department of Internal Medicine Van Training and Research Hospital Van, Turkey
REFERENCES 1. Cooney C, Nagy A. Angio-oedema associated with risperidone. BMJ. 1995;311:1204. 2. Kores Plesnicar B, Vitorovic S, Zalar B, et al. Three challenges and a rechallenge episode of angio-oedema occurring in treatment with risperidone. Eur Psychiatry. 2001;16: 506Y507. ¨ , Okay IT, et al. A case of 3. Erken DD, KNlN0o O angioedema due to risperidone. Bulletin of Clinical Psychopharmacology. 2007;17: 198Y202. 4. Soumya NR, Grover S, Dutt A, et al. Angioneurotic edema with risperidone: a case report and review of literature. Gen Hosp Psychiatry. 2010;32: 646.e1Y646.e3. 5. Biswas PN, Wilton LV, Pearcel GL, et al. The pharmacovigilance of olanzapine: results of a post-marketing surveillance study on 8858 patients in England. J Psychopharmacol. 2001;15:265Y271. 6. Mishra B, Sahoo S, Sarkar S, et al. Clozapine-induced angioneurotic edema. Gen Hosp Psychiatry. 2007;29:78Y80. 7. Akkaya C, Sarandol A, Aydogan K, et al. Urticaria and angiooedema due to ziprasidone. J Psychopharmacol. 2007;21:550Y552. 8. Mohan T, Bastiampillai T, Dhillon R. Ziprasidone-induced angioedema: a case report. J Clin Psychiatry. 2009; 70:1054. 9. Corke PJ, Murray G. Angio-oedema with droperidol. Anaesth Intensive Care. 1993;21:375. 10. Palombaro JF, Klingelberger CE. Angioedema associated with droperidol administration. Ann Emerg Med. 1996;27:379Y381. 11. Hine FR. Severe angioneurotic edema during chlorpromazine therapy. Am J Psychiatry. 1958;114:942. 12. Lutz EG, Rotov MD. Angioneurotic edema of the tongue with phenothiazine administration: report of two cases. Dis Nerv Syst. 1964;25:419Y422. 13. Agostoni A, Cicardi M. Drug-induced angioedema without urticaria. Drug Saf. 2001;24:599Y606.
* 2014 Lippincott Williams & Wilkins
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14. Schiller PI, Messmer SL, Haefeli WE, et al. Angiotensin-converting enzyme inhibitor-induced angioedema: late onset, irregular course, and potential role of triggers. Allergy. 1997;52:432Y435. 15. Weng PK, Wang HW, Lin JK, et al. Late-onset life-threatening angioedema and upper airway obstruction caused by angiotensin-converting enzyme inhibitor: report of a case. Ear Nose Throat J. 1997;76:404Y407. 16. Vleeming W, van Amsterdam JG, Stricker BH, et al. ACE inhibitor-induced angioedema. Incidence, prevention and management. Drug Saf. 1998;18:171Y188. 17. Hallak B, Konu P, Lang F, et al. Acquired form of angioedema of the head and neck related to a deficiency in c1-inhibitor: a case report with a review of the literature. Case Rep Otolaryngol. 2012;2012:1Y3. 18. Li HH. Angioedema [Medscape Web site]. Available at: http://emedicine.medscape.com/ article/135208-overview#aw2aab6b2b4. Accessed July 1, 2013. 19. Krishnaswamy G, Youngberg G. Acute and chronic urticaria. Postgrad Med. 2001;109:107Y108, 111Y114, 119Y223. 20. Erdo?an S. Hematological side effects of atypical antipsychotic drugs. Current Approaches in Psychiatry. 2009;1: 255Y279.
Serotonin-Norepinephrine Reuptake InhibitorYAssociated Mixed Episode in an Adolescent With Schizoaffective Disorder To the Editors: ntidepressants have been recognized to have the potential to induce mania since the 1950s.1 Although there is significant variation between studies, the risk of antidepressant-induced mania has been estimated at 20% to 40% in adult bipolar populations and less than 10% in unipolar depression,2 where tricyclic antidepressants produce higher rates than selective serotonin reuptake inhibitors (SSRIs). The rate of manic switch for unipolar depression patients is G1%, whereas for patients with bipolar depression, the rate is 3.7% to 11.2%, depending on the type of antidepressants used.3 Duloxetine, a newer dual-acting serotonin-norepinephrine reuptake inhibitor (SNRI), was associated with low incidence of treatment emergent hypomania or mania in major depressive disorder patients in adult population.4 To our knowledge, there had only been 1
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* 2014 Lippincott Williams & Wilkins
report on ultrarapid cycling associated with duloxetine in an adolescent with bipolar disorder.5 Here we report a mixed episode switch associated with duloxetine in an adolescent with schizoaffective disorder.
CASE REPORT Miss A, a 17-year-old female adolescent with juvenile rheumatoid arthritis and schizoaffective disorder (depressive type) was hospitalized for depressed mood, visual/ auditory hallucination, delusion of persecution and of being controlled for 4 months, and suicide attempt for 1 month. She had reported long-term dysthymia with spontaneous shortterm remission of 2 to 3 days of low mood since late childhood and mood incongruent visual/tactile hallucinations (people figures looking, pulling, and talking to her), but she did not seek medical help until this hospitalization. She was treated with SSRI (fluoxetine) 30 mg/d and risperidone 6 mg/d for her depressive and psychotic symptoms (Hamilton Rating Scale for Depression 17 items [HAMD], 33; Brief Psychiatric Rating Scale [BPRS], 39) and prednisolone 6 mg/d for her juvenile rheumatoid arthritisYassociated joint pains. However, she had persistent low mood, insomnia, hopelessness, suicide ideation and plan, impaired attention, and worthlessness despite some improvement in her joint pain and psychotic symptoms after 2 months of treatment, and hence her antidepressant was switched to duloxetine, and the dosage was titrated up to 60 mg/d. After 2 months of combined treatment with duloxetine and risperidone, she became irritable and talkative, had increased goal-directed activities, multiple planning, decreased sleep need, and aggression along with subjective low mood, suicide ideation, and worthlessness (HAMD, 18; BPRS, 28; Young Mania Rating Scale, 35). Duloxetine was discontinued immediately, and clonazepam 8 mg/d and lamotrigine 100 mg/d were added to risperidone 6 mg/d for her mixed episode, and the mixed episode was resolved after 4 weeks with residual symptoms of visual/auditory hallucinations (HAMD, 10; BPRS, 20; Young Mania Rating Scale, 5).
DISCUSSION This is the first report of duloxetineassociated mixed episode in an adolescent with schizoaffective disorder. There had only been 1 report of ultrarapid cycling in adolescents with bipolar disorder,5 whose age was the same as our patient and was treated with antipsychotic (olanzapine 10 mg/d) as prophylaxis for her bipolar disorder, whereas our patient was treated with risperidone 6 mg/d
Letters to the Editors
for her psychotic symptoms. The reported case was treated with 40 mg/d of duloxetine,5 whereas our patient received 60 mg/d of duloxetine. The reported case had alternating manic with depressive symptoms every 4 days after 2 days of duloxetine treatment, whereas our patient had onset of mixed manic-depressive symptoms after 2 months of duloxetine treatment. A brief review in adult population had suggested that mood switching with SNRI treatment seemed to be dose-related but not time-related because development of hypomanic/manic symptoms can range from days to weeks after introduction or dose titration of SNRI.6 In this reported case, duloxetine was initially prescribed at 30 mg/d for the first 4 weeks and titrated to 60 mg/d because of persistent low mood and suicide ideation, and mixed episode symptoms emerged 8 weeks after duloxetine was first introduced. Moreover, adult patients with suggestive bipolar features, such as chronicity, extreme severe mood episodes, cyclothymic temperament, nonaffective psychotic symptoms, and a family history of psychiatric disorders may be more vulnerable to antidepressant-induced mania/hypomanic symptoms. Our patient had several features suggesting bipolarity such as a chronic course of depressive mood along with nonaffective psychotic symptoms, which may suggest her vulnerability to antidepressant-induced hypomanic/ manic symptoms. Duloxetine is believed to be the most potent and most balanced dual-acting reuptake inhibitors.7 Bipolarity is common later in life of adolescent patients with early-onset unipolar depression.8 Although previous studies9 supported the low incidence of duloxetineassociated mania or hypomania symptoms with satellite case reports10 in adult population, we found that the use of duloxetine, when compared with an SSRI, may possibly increase the risk for mood switch in an adolescent with initial manifestation of psychotic symptoms with unipolar depression. This finding is consistent with the report of Pacchiarotti et al11 where SNRIs have been thought to possibly be more likely associated with mood switch compared with SSRIs. Our case illustrates that careful measures should be taken when duloxetine is prescribed in patients with risk for mood switch. It has been suggested from adult case reports that treatment initiation with lower doses and upward titration when needed may be preferable to minimize the risk of SNRI-associated mood switch.6 Moreover, polytherapy in mood disorders with an SNRI such as duloxetine at low dosage may also help to minimize the risk for mood switching in clinical practice. Hence, further prospective studies should be designed to answer the concerns of duloxetineassociated mood switch in adolescent patients. www.psychopharmacology.com
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
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finding that would explain amenorrhea was not detected by the obstetrician. The patient’s prolactin level was determined as 45.6 ng/mL (reference range, 5.18Y 26.53 ng/mL), and it was thought to be related to the use of duloxetine. The dosage was reduced to 30 mg/d, and the prolactin level was measured after 1 week and found as 23 ng/mL; 10 days later, menstruation was detected. The patient’s treatment with a dosage of 30 mg/d duloxetine continued for 5 months; amenorrhea complaints did not reiterate, and prolactin levels remained normal. Recently reviewed Beck Depression Inventory score was found as 12, and Beck Anxiety Inventory score was 8.
CASE 2 A 47-year-old woman presented with demoralization, reluctance, fatigue, headache, and complaints of excessive sleepiness. There were complaints for many years. She had used various antidepressant drugs over the years, and for the last 5 years, she has been using escitalopram 20 mg/d and quetiapine 50 mg/d. Her history shows no alcohol and drug use, continuous drug use, or organic disorders. She was not sexually active. She had a regular menstrual period, and follow-up was being done by gynecologists. Beck Depression Inventory score was found as 38, and Beck Anxiety Scale score was found to be 22. The patient was treated with a dosage of 30 mg/d due to the diagnosis of major depressive disorder according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition; the patient’s depressive symptoms at the end of the first month fell, but delayed menstruation was seen. The physical examination result and laboratory values for thyroid stimulating hormone, urea, creatinine, glucose, urea, creatinine, aspartate transaminase, alanine transaminase, and electrolyte were normal. She did not use oral contraceptives and was not pregnant. The patient’s prolactin level was determined as 57.6 ng/mL (reference range, 5.18Y26.53 ng/mL). The patient was referred by neurology and gynecology. The result of cranial MRI was normal. The pathologic finding that would explain amenorrhea was not detected by the obstetrician, and the patient was started on dopamine receptor agonist cabergoline 0.5 mg/d twice a week. The prolactin level was measured 1 month later and found as 26.8 ng/mL; menstrual period was detected 15 days later. With normalization of the patient, prolactin cabergoline treatment was discontinued by the obstetrician. Duloxetine therapy was stopped, and the treatment with venlafaxine 37.5 mg was started; the patient was then treated with venlafaxine * 2014 Lippincott Williams & Wilkins
75 mg/d; amenorrhea complaints were not reiterated, and prolactin levels remained normal. The last Beck Depression Inventory score was 14, and Beck Anxiety Inventory score was 9. In our cases, we think that hyperprolactinemia and amenorrhea are related to duloxetine due to the emergence of hyperprolactinemia and amenorrhea after the treatment with duloxetine, other drug use, the patient did not use other drugs, cranial MRI being normal, and the fact that the woman in the first case by birth ruled out organic causes of amenorrhea, and in the second case after the treatment was stopped and cabergoline treatment was applied, it was seen that amenorrhea and hyperprolactinemia were treated. More studies are needed in this regard. AUTHOR DISCLOSURE INFORMATION The authors declare no conflicts of interest. Birmay C ¸ am, MD Department of Psychiatry Manisa Mental Health Manisa, Turkey [email protected]
Tunay Karlıdere, MD Department of Psychiatry Faculty of Medicine Balikesir University BalNkesir, Turkey
REFERENCES 1. Girayalp BO. Galactorrhea due to fluoxetine in a patient with depression and a pituitary adenoma: a case report. Bull Clin Psychopharmacol. 2009;19:159Y163. 2. Korkmaz S, Kulo?lu M, IzNk U, et al. Galactorrhea during duloxetine treatment: a case report. Tu¨rk Psikiyatri Derg. 2011;22(3):200Y201. 3. Bronzo MR, Stahl SM. Galactorrhea induced by sertraline (letter). Am J Psychiatry. 1993;150:1269Y1270. 4. Feuchtl A, Bagli M, Stephan R, et al. Pharmacokinetics of m-chlorophenylpiperazine after intravenous and oral administration in healthy male volunteers: implication for the pharmacodynamic profile. Pharmacopsychiatry. 2004;37:180Y188. 5. Gu¨lsu¨n M, Evrensel Al, Verim S. Galactorrhea during escitalopram treatment: a case report. Bull Clin Psychopharmacol. 2006;16:39Y41. 6. Meltzer H,Bastani B, Jayathilake K, et al. Fluoxetine, but not tricyclic antidepressants, potentiates the 5-HydroxytryptophanYmediated increase in plasma cortisol and prolactin secretion in subjects with major depression
Letters to the Editors
or with obsessive compulsive disorder. Neuropsychopharmacology. 1997;17:1Y11. 7. Anand VS. Clomipramine-induced galactorrhoea and amenorrhoea. Br J Psychiatry. 1985;147:87Y88. 8. Fowlie S, Burton J. Hyperprolactinaemia and nonpuerperal lactation associated with clomipramine. Scott Med J. 1987;32(2):52. 9. Peterson MC. Reversible galactorrhea and prolactin elevation related to fluoxetin use. Mayo Clin Proc. 2001;76(2):215Y216. 10. Spigset O, Mjorndal T. The effect of fluvoxamine on serum prolactin and serum sodium concentrations: relation to platelet 5- HT2A receptor status. J Clin Psychopharmacol. 1997;17:292Y297. 11. Morrison J, Remick RA, Leung M, et al. Galactorrhea induced by paroxetine. Can J Psychiatry. 2001;46(1):88Y89. 12. Sternbach H. Venlafaxine-induced galactorrhea. J Clin Psychopharmacol. 2003;23(1):109Y110. 13. Ashton AK, Longdon MC. Hyperprolactinemia and galactorrhea induced by serotonin and norepinephrine reuptake inhibiting antidepressants. Am J Psychiatry. 2007;164:1121Y1122. 14. Ha¨rmark L, van Puijenbroek E, van Grootheest K. Intensive monitoring of duloxetine: results of a Web-based intensive monitoring study. Eur J Clin Pharmacol. 2013;69(2):209Y215.
A Case of Late-Onset Angioedema Associated With Clozapine and Redevelopment of Angioedema With Olanzapine To the Editors: ngioedema is a rare but potentially lifethreatening adverse effect of antipsychotics such as risperidone,1Y4 olanzapine,5 clozapine,6 ziprasidone,7,8 droperidol,9,10 and chlorpromazine.11,12 Nonsteroid antiinflammatory drugs, angiotensin-converting enzyme inhibitors (ACEIs), penicillin, and neuromuscular blockers are the most common medications held responsible for angioedema.13 Angioedema is the swelling of deep dermal and subcutaneous tissues that occurs on the face, tongue, extremities, genitals, and rarely larynx.7 The late-onset angioedema is a rare clinical condition that occurs months or years, after which is more likely reported with ACEIs.14Y16 Here we report a female patient who developed late-onset angioedema after treatment with clozapine after 5 years and redevelopment of angioedema with
A
www.psychopharmacology.com
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
523
Letters to the Editors
introduction of olanzapine, which resolved on discontinuation of both drugs.
CASE REPORT A 27-year-old woman with a condition diagnosed with psychotic disorder and intellectual disability 5 years ago by another psychiatric outpatient clinic with symptoms of self-talking, suspiciousness, inability to sleep, and an idea of persecution was referred to our outpatient clinic a year ago, and the same diagnoses were made by her psychiatric evaluation and her past history of psychiatric and medical illness. At the time of diagnosis, the IQ test result was 61. Her clinical condition was going well with clozapine 150 mg/d, which she had been using for 5 years. At 1 of her follow-up visits, the physical examination revealed swelling over the face and eruption on the perioral region. Results of laboratory examinations including liver and renal function tests, serum electrolytes, blood cell count, and sedimentation rate were within the reference range. The medical and family history of the patient was unremarkable, and she did not report allergic reactions to any drug or food. The patient was consulted with dermatology, and a diagnosis of acute angioedema was established. After discontinuation of clozapine, skin symptoms were resolved within 1 week, and olanzapine 10 mg/d was started. A few days after introduction of olanzapine, the same skin symptoms emerged over the face, and repeated laboratory tests were unremarkable. Skin scratch test revealed hypersensitivity with the medications of clozapine, olanzapine, and sulpiride. Olanzapine was discontinued, and quetiapine 300 mg/d was started because of a negative skin scratch test result. Quetiapine dose was increased up to 900 mg/d in that psychotic symptoms exacerbated over time. She remained well under this dose without any recurrence of psychiatric symptoms or angioedema.
DISCUSSION Angioedema is a transient edema resulting from increased vascular permeability, which is associated with inflammatory mediators.17 The onset usually occurs within the first weeks of drug therapy but can develop months or years, after which was more likely reported with ACEIs.14Y16 Although angioedema associated with clozapine was reported before,6 to our knowledge, this is the first reported case of late-onset angioedema associated with clozapine monotherapy. Mild skin reactions are expected, whereas angioedema is rarely seen with olanzapine. Angioedema associated with olanzapine was reported in
524
www.psychopharmacology.com
Journal of Clinical Psychopharmacology
only 2 patients in a postmarketing surveillance study carried out in England on 8858 patients.5 Hereditary, acquired, allergic, and drug-related mechanisms are underlying causes of angioedema. The allergic form of angioedema mediated by immunoglobulin E (IgE) can be caused by a drug acting as an allergen.18 It is suggested that the drug triggers IgE-mediated degranulation of mast cells and causes release of inflammatory mediators such as histamine, serotonin, and bradykinins. These mediators increase vascular permeability and cause angioedema.19 The same adverse effects seen in both olanzapine and clozapine can be explained by the structural similarity between these drugs.20 The occurrence of angioedema with the administration of a stable dose of clozapine and with the introduction of olanzapine, disappearance of symptoms with discontinuation of both drugs, and results of skin scratch test suggest an allergic form of angioedema associated with clozapine and olanzapine. Although quetiapine is very closely related structurally to clozapine and olanzapine, angioedema did not emerge with this drug. A possible explanation for this might be an unidentified new vulnerability factor that was going on at the time of the development of angioedema and evidently was persisting during the introduction of olanzapine, which may have subsided by the time quetiapine was started. A coincided ingestion of an unknown allergen or drug might have influenced generation of IgE-mediated type 1 hypersensitivity against clozapine and olanzapine. Angioedema can occur even after many years of uneventful drug use. The mechanism behind the late-onset angioedema is not evident, but it is known that any kind of allergy, especially type 1 hypersensitivities, can begin any time in life. Early-onset angioedema associated with antipsychotics may easily be recognizable, but the correlation with late-onset angioedema can be overlooked. This case report indicates the need for clinicians to be aware of lateonset adverse events in patients treated with antipsychotics. AUTHOR DISCLOSURE INFORMATION The authors declare no conflicts of interest. Presented as a poster at the 22nd European Congress of Psychiatry, Munich, Germany, March 1Y4, 2014. Zeynep Baran Tatar, MD Department of Psychiatry Bakirkoy Training and Research Hospital for Psychiatry
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Neurology, and Neurosurgery Istanbul, Turkey [email protected]
Serap Oflaz, MD Department of Psychiatry Istanbul Medical Faculty Istanbul University Istanbul, Turkey
Bulent Baran, MD Department of Internal Medicine Van Training and Research Hospital Van, Turkey
REFERENCES 1. Cooney C, Nagy A. Angio-oedema associated with risperidone. BMJ. 1995;311:1204. 2. Kores Plesnicar B, Vitorovic S, Zalar B, et al. Three challenges and a rechallenge episode of angio-oedema occurring in treatment with risperidone. Eur Psychiatry. 2001;16: 506Y507. ¨ , Okay IT, et al. A case of 3. Erken DD, KNlN0o O angioedema due to risperidone. Bulletin of Clinical Psychopharmacology. 2007;17: 198Y202. 4. Soumya NR, Grover S, Dutt A, et al. Angioneurotic edema with risperidone: a case report and review of literature. Gen Hosp Psychiatry. 2010;32: 646.e1Y646.e3. 5. Biswas PN, Wilton LV, Pearcel GL, et al. The pharmacovigilance of olanzapine: results of a post-marketing surveillance study on 8858 patients in England. J Psychopharmacol. 2001;15:265Y271. 6. Mishra B, Sahoo S, Sarkar S, et al. Clozapine-induced angioneurotic edema. Gen Hosp Psychiatry. 2007;29:78Y80. 7. Akkaya C, Sarandol A, Aydogan K, et al. Urticaria and angiooedema due to ziprasidone. J Psychopharmacol. 2007;21:550Y552. 8. Mohan T, Bastiampillai T, Dhillon R. Ziprasidone-induced angioedema: a case report. J Clin Psychiatry. 2009; 70:1054. 9. Corke PJ, Murray G. Angio-oedema with droperidol. Anaesth Intensive Care. 1993;21:375. 10. Palombaro JF, Klingelberger CE. Angioedema associated with droperidol administration. Ann Emerg Med. 1996;27:379Y381. 11. Hine FR. Severe angioneurotic edema during chlorpromazine therapy. Am J Psychiatry. 1958;114:942. 12. Lutz EG, Rotov MD. Angioneurotic edema of the tongue with phenothiazine administration: report of two cases. Dis Nerv Syst. 1964;25:419Y422. 13. Agostoni A, Cicardi M. Drug-induced angioedema without urticaria. Drug Saf. 2001;24:599Y606.
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14. Schiller PI, Messmer SL, Haefeli WE, et al. Angiotensin-converting enzyme inhibitor-induced angioedema: late onset, irregular course, and potential role of triggers. Allergy. 1997;52:432Y435. 15. Weng PK, Wang HW, Lin JK, et al. Late-onset life-threatening angioedema and upper airway obstruction caused by angiotensin-converting enzyme inhibitor: report of a case. Ear Nose Throat J. 1997;76:404Y407. 16. Vleeming W, van Amsterdam JG, Stricker BH, et al. ACE inhibitor-induced angioedema. Incidence, prevention and management. Drug Saf. 1998;18:171Y188. 17. Hallak B, Konu P, Lang F, et al. Acquired form of angioedema of the head and neck related to a deficiency in c1-inhibitor: a case report with a review of the literature. Case Rep Otolaryngol. 2012;2012:1Y3. 18. Li HH. Angioedema [Medscape Web site]. Available at: http://emedicine.medscape.com/ article/135208-overview#aw2aab6b2b4. Accessed July 1, 2013. 19. Krishnaswamy G, Youngberg G. Acute and chronic urticaria. Postgrad Med. 2001;109:107Y108, 111Y114, 119Y223. 20. Erdo?an S. Hematological side effects of atypical antipsychotic drugs. Current Approaches in Psychiatry. 2009;1: 255Y279.
Serotonin-Norepinephrine Reuptake InhibitorYAssociated Mixed Episode in an Adolescent With Schizoaffective Disorder To the Editors: ntidepressants have been recognized to have the potential to induce mania since the 1950s.1 Although there is significant variation between studies, the risk of antidepressant-induced mania has been estimated at 20% to 40% in adult bipolar populations and less than 10% in unipolar depression,2 where tricyclic antidepressants produce higher rates than selective serotonin reuptake inhibitors (SSRIs). The rate of manic switch for unipolar depression patients is G1%, whereas for patients with bipolar depression, the rate is 3.7% to 11.2%, depending on the type of antidepressants used.3 Duloxetine, a newer dual-acting serotonin-norepinephrine reuptake inhibitor (SNRI), was associated with low incidence of treatment emergent hypomania or mania in major depressive disorder patients in adult population.4 To our knowledge, there had only been 1
A
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report on ultrarapid cycling associated with duloxetine in an adolescent with bipolar disorder.5 Here we report a mixed episode switch associated with duloxetine in an adolescent with schizoaffective disorder.
CASE REPORT Miss A, a 17-year-old female adolescent with juvenile rheumatoid arthritis and schizoaffective disorder (depressive type) was hospitalized for depressed mood, visual/ auditory hallucination, delusion of persecution and of being controlled for 4 months, and suicide attempt for 1 month. She had reported long-term dysthymia with spontaneous shortterm remission of 2 to 3 days of low mood since late childhood and mood incongruent visual/tactile hallucinations (people figures looking, pulling, and talking to her), but she did not seek medical help until this hospitalization. She was treated with SSRI (fluoxetine) 30 mg/d and risperidone 6 mg/d for her depressive and psychotic symptoms (Hamilton Rating Scale for Depression 17 items [HAMD], 33; Brief Psychiatric Rating Scale [BPRS], 39) and prednisolone 6 mg/d for her juvenile rheumatoid arthritisYassociated joint pains. However, she had persistent low mood, insomnia, hopelessness, suicide ideation and plan, impaired attention, and worthlessness despite some improvement in her joint pain and psychotic symptoms after 2 months of treatment, and hence her antidepressant was switched to duloxetine, and the dosage was titrated up to 60 mg/d. After 2 months of combined treatment with duloxetine and risperidone, she became irritable and talkative, had increased goal-directed activities, multiple planning, decreased sleep need, and aggression along with subjective low mood, suicide ideation, and worthlessness (HAMD, 18; BPRS, 28; Young Mania Rating Scale, 35). Duloxetine was discontinued immediately, and clonazepam 8 mg/d and lamotrigine 100 mg/d were added to risperidone 6 mg/d for her mixed episode, and the mixed episode was resolved after 4 weeks with residual symptoms of visual/auditory hallucinations (HAMD, 10; BPRS, 20; Young Mania Rating Scale, 5).
DISCUSSION This is the first report of duloxetineassociated mixed episode in an adolescent with schizoaffective disorder. There had only been 1 report of ultrarapid cycling in adolescents with bipolar disorder,5 whose age was the same as our patient and was treated with antipsychotic (olanzapine 10 mg/d) as prophylaxis for her bipolar disorder, whereas our patient was treated with risperidone 6 mg/d
Letters to the Editors
for her psychotic symptoms. The reported case was treated with 40 mg/d of duloxetine,5 whereas our patient received 60 mg/d of duloxetine. The reported case had alternating manic with depressive symptoms every 4 days after 2 days of duloxetine treatment, whereas our patient had onset of mixed manic-depressive symptoms after 2 months of duloxetine treatment. A brief review in adult population had suggested that mood switching with SNRI treatment seemed to be dose-related but not time-related because development of hypomanic/manic symptoms can range from days to weeks after introduction or dose titration of SNRI.6 In this reported case, duloxetine was initially prescribed at 30 mg/d for the first 4 weeks and titrated to 60 mg/d because of persistent low mood and suicide ideation, and mixed episode symptoms emerged 8 weeks after duloxetine was first introduced. Moreover, adult patients with suggestive bipolar features, such as chronicity, extreme severe mood episodes, cyclothymic temperament, nonaffective psychotic symptoms, and a family history of psychiatric disorders may be more vulnerable to antidepressant-induced mania/hypomanic symptoms. Our patient had several features suggesting bipolarity such as a chronic course of depressive mood along with nonaffective psychotic symptoms, which may suggest her vulnerability to antidepressant-induced hypomanic/ manic symptoms. Duloxetine is believed to be the most potent and most balanced dual-acting reuptake inhibitors.7 Bipolarity is common later in life of adolescent patients with early-onset unipolar depression.8 Although previous studies9 supported the low incidence of duloxetineassociated mania or hypomania symptoms with satellite case reports10 in adult population, we found that the use of duloxetine, when compared with an SSRI, may possibly increase the risk for mood switch in an adolescent with initial manifestation of psychotic symptoms with unipolar depression. This finding is consistent with the report of Pacchiarotti et al11 where SNRIs have been thought to possibly be more likely associated with mood switch compared with SSRIs. Our case illustrates that careful measures should be taken when duloxetine is prescribed in patients with risk for mood switch. It has been suggested from adult case reports that treatment initiation with lower doses and upward titration when needed may be preferable to minimize the risk of SNRI-associated mood switch.6 Moreover, polytherapy in mood disorders with an SNRI such as duloxetine at low dosage may also help to minimize the risk for mood switching in clinical practice. Hence, further prospective studies should be designed to answer the concerns of duloxetineassociated mood switch in adolescent patients. www.psychopharmacology.com
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