Journal of Clinical Psychopharmacology
Letters to the Editors
REFERENCES 1. Alexopoulos GS, Streim JE, Carpenter D. Expert consensus guidelines for using antipsychotic agents in older patients. J Clin Psychiatry. 2004;65:100Y102. 2. Washington NB, Brahm NC, Kissack J. Which psychotropics carry the greatest risk of QTc prolongation? Curr Psychiatry. 2012;11:36Y39. 3. Taylor DM. Antipsychotics and QT prolongation. Acta Psychiatr Scand. 2003;107:85Y95. 4. Meltzer HY, Cucchiaro J, Silva R, et al. Lurasidone in the treatment of schizophrenia: a randomized, double-blind, placebo- and olanzapine-controlled study. Am J Psychiatry. 2011;168:957Y967. 5. FDA. Clinical evaluation of QT/QTc interval prolongation and proarrhythmic potential for non-antiarrhythmic drugs. October 2005. Available at: http://www.fda.gov/downloads/ RegulatoryInformation/Guidances/ ucm129357.pdf. Accessed February 16, 2014. 6. Haddad PM, Anderson IM. Antipsychotic-related QTc prolongation torsade de pointes and sudden death. Drugs. 2002;62:1649Y1671. 7. Viskin S. Long QT syndromes and torsade de pointes. Lancet. 1999;354:1625Y1633. 8. Goodnick PJ, Jerry J, Parra F. Psychotropic drugs and the ECG: focus on the QTc interval. Expert Opin Pharmacother. 2002;3:479Y498. 9. Nelson S. Aripiprazole-induced QTc interval prolongation and torsades de pointes: a case report. Crit Care Med. 2011;39:257. 10. Robbins J, Nelson JC, Rautaharju PM, et al. The association between the length of the QT interval and mortality in the Cardiovascular Health Study. Am J Med. 2003;115:689Y694. 11. Haugaa KH, Bos J, Borkenhagen E, et al. Concomitant QT prolongation predicts all-cause mortality in patients with voltage-criteria for left ventricular hypertrophy on a 12-lead ECG. J Am Coll Cardiol. 2013;61. doi:10.1016/S0735-1097(13)61337-6. 12. Mallikaarjun S, Shoaf SE, Boulton DW, et al. Effects of hepatic or renal impairment on the pharmacokinetics of aripiprazole. Clin Pharmacokinet. 2008;47:533Y542. 13. Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981;30:239Y245. 14. Baumgartner RN, Koehler KM, Romero L, et al. Serum albumin is associated with skeletal muscle in elderly men and women. Am J Clin Nutr. 1996;64:552Y558. 15. Kitada M. Genetic polymorphism of cytochrome P450 enzymes in Asian populations: focus on CYP2D6. Int J Clin Pharmacol Res. 2003;23:31Y35. 16. Kim JR, Seo HB, Cho JY, et al. Population pharmacokinetic modelling of aripiprazole and its active metabolite, dehydroaripiprazole, in psychiatric patients. Br J Clin Pharmacol. 2008;66:802Y810.
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Acute Lurasidone Overdose To the Editors: urasidone is a benzoisothiazol derivative that was approved for the treatment of schizophrenia by the Food and Drug Administration (FDA) in 2010.1 Since that time, it has also been approved for the treatment of bipolar depression.2 The maximum approved dose in the United States is 160 mg once daily.3 It should be taken with food to increase the absorption of lurasidone.1 A study by Preskorn et al4 found that lurasidone exposure increased between ‘‘2- to 3-fold’’ when taken with meals of at least 1465 kJ. Absorption of lurasidone was not influenced by the fat content of the meal.4 It is absorbed rapidly after oral administration, and it reaches its maximum concentration between 1 and 3 hours after ingestion. The bioavailability of lurasidone ranges from between 9% and 19%, and it is 99.8% protein bound.1,5 A study of patients with schizophrenia found that single doses of lurasidone (between 120 mg and 160 mg) had a mean half-life of between 28.8 and 37.4 hours.5 Elimination is primarily through the liver, and approximately 0.1% of lurasidone is excreted unchanged in the urine.5 Because lurasidone is primarily metabolized via the cytochrome P450 3A4 (CYP3A4) isoenzyme, its concentration would likely be affected when used concurrently with a CYP3A4 inhibitor or inducer.1,6 In fact, a number of interactions between lurasidone and both moderate and strong CYP3A4 inducers and inhibitors have been observed.1,6 Therefore, it has been recommended that lurasidone should not be used with strong CYP3A4 inhibitors or inducers.1,6 It has also been recommended that, when lurasidone is coadministered with a moderate CYP3A4 inhibitor (such as diltiazem), the lurasidone dose should not exceed 40 mg/d.6,7 The United States FDA definitions of moderate and strong inducers/ inhibitors are listed in Table 1.8 Lurasidone is metabolized into 2 active and 2 inactive metabolites.1 It acts as a D2 and 5HT2A receptor antagonist.1,9 It also has antagonistic effects at the >2C and >2A noradrenergic receptors.1,10 It blocks the 5HT7 receptor and acts as a partial agonist of the 5HT1A receptor.1,11 Lurasidone has little, if any, affinity for histamine H1 and acetylcholine M1 receptors.10 The adverse events associated with lurasidone treatment are similar to those seen with the other atypical antipsychotic agents. Commonly seen adverse effects include akathisia, agitation, Parkinsonism, anxiety, somnolence, and dystonia.6 As with other antipsychotic agents, there
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are rare reports of leukopenia or neutropenia. The lurasidone clinical trials found it effective for both positive and negative symptoms of schizophrenia and that the most common adverse events were movement abnormalities, akathisia, nausea, and drowsiness.9 A later study by Citrome et al10 examined more than 400 patients who were treated with lurasidone for 12 months. The lurasidone doses ranged from 40 mg to 120 mg daily. In this study, the most frequent adverse effects were nausea (16.7%), insomnia (15.8%), and sedation (14.6%).10 Studies have found that there is no significant QTc prolongation associated with lurasidone use.5 In fact, 1 study found that high-dose lurasidone (up to 600 mg daily) was associated with minimal QTc interval increases of between 4.4 and 6.4 milliseconds.5 Overall, the authors felt that lurasidone was ‘‘safe and well tolerated’’ with minimal effect on prolactin levels, weight, or metabolic variables.10 Lurasidone has been classified as pregnancy category B by the FDA.1 It has been recommended that mothers do not breast feed while taking lurasidone.1 There are minimal data regarding overdose on lurasidone. In fact, a literature search was unable to find any case reports of overdose in the literature to date. The only mention of lurasidone overdose was the brief description of a single case in the package insert.12 That patient ingested an estimated 560 mg of lurasidone and recovered without sequelae. We now report the case of a 31-year-old man who overdosed on a large amount of lurasidone in an attempt to commit suicide.
CASE REPORT The patient was a 31-year-old man with a history of schizophrenia who was brought to the emergency department 90 minutes after an intentional overdose on seventeen 80-mg lurasidone tablets and five 1-mg clonazepam tablets in an attempt to end his life. The ingestion occurred immediately after lunch and was witnessed by his caregiver. His caregiver was able to confirm the number of pills ingested. His history was negative for tobacco, alcohol, or illicit drug use. His medical history was significant for hypertension and obesity as well as negative for any respiratory or endocrine disorder. Twenty-two days before this overdose, the patient weighed 131.8 kg and had a body mass index of 39.4. The patient’s medication regimen consisted of lurasidone (160 mg nightly), trazodone (150 mg nightly), and clonazepam (1 mg every 8 hours as needed). Upon presentation to the emergency department, the patient was noted to be cooperative, alert, and oriented in all * 2014 Lippincott Williams & Wilkins
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
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TABLE 1. Definitions of Inducers and Inhibitors From the United States FDA Term
Definition
Strong inducer Moderate inducer Strong inhibitor
Moderate inhibitor
A medication that causes an 80% decrease or higher in the AUC of the concurrently used medication A medication that causes a 50% to 80% decrease in the AUC of the concurrently used medication A medication that causes a 5-fold increase or higher in AUC or greater than 80% decrease in CL of the concurrently used medication A medication that causes a 2- or higher but less than 5-fold increase in AUC or 50% to 80% decrease in CL of the concurrently used medication
Letters to the Editors
patient ingested 1360 mg of lurasidone, along with 5 mg of clonazepam with minimal medical difficulties. One interesting finding was the transient increase in the patient’s TSH level that was discovered the day after the overdose. It will be important to continue in reviewing cases of lurasidone overdose over time to compare their outcomes. It would also be useful to monitor TSH levels in those patients who have overdosed on lurasidone to ascertain whether there is a true relationship between lurasidone overdose and TSH elevation.
AUC indicates area underneath the curve; CL, drug clearance.
spheres. He was in no acute distress and was breathing easily. His temperature was 36.4 -C, his blood pressure was 140/87, and he had a pulse of 85 beats per minute. A complete blood count, a complete metabolic profile, and urinalysis were all within normal limits. Amylase, lipase, troponin, creatine kinase-MB, and creatine kinase were all within normal limits. Urine drug screen was positive only for benzodiazepines. Of note, the patient’s thyrotropin (TSH) was elevated at 6.100 mIU/L from a documented 4.015 mIU/L 3 weeks prior. Free T3 and free T4 were both within normal limits at 2.60 pg/mL and 1.15 ng/dL, respectively. Electrocardiogram displayed normal sinus rhythm with a rate of 91 beats per minute and a QTc of 452 milliseconds. There was no recent electrocardiogram available for comparison. The finding of neurologic examination was normal, except for mild oral-buccal dyskinesia that was also noted on prior outpatient documentation. The patient was admitted to the medical intensive care unit (ICU) for observation and administration of fluids. No other medical treatment was required in the ICU. His hypertension resolved within 12 hours of the ingestion. He was transferred to the inpatient psychiatric unit, and his physical condition remained stable. While on the inpatient psychiatric unit, lurasidone was restarted. However, shortly afterward, the lurasidone was discontinued at the patient’s request and he was switched to ziprasidone. The patient’s hypertension resolved quickly, and he was subsequently discharged home. A repeat TSH drawn 17 days after the discharge was found to be within normal limits at 3.053 mIU/L.
DISCUSSION This is a report on a 31-year-old man with schizophrenia who overdosed on lurasidone (1360 mg) and clonazepam (5 mg) in a suicide attempt. His medical * 2014 Lippincott Williams & Wilkins
history was significant for obesity and hypertension, but there was no history of any endocrine dysfunction. There was also a negative history of substance abuse. The amount of lurasidone ingested was 8.5 times the maximum recommended dose and was equal to 10.32 mg/kg of body weight. The patient’s overdose took place shortly after lunch, so the presence of food in his stomach could have increased his absorption of the lurasidone. The patient initially presented with mild hypertension and an elevated TSH (6.100 mIU/L), but there were no other physical examination or laboratory findings. The patient recovered without any significant medical sequelae, and his TSH level had normalized when checked more than 3 weeks after the overdose. There is 1 documented case of lurasidone overdose (560 mg) in a patient who recovered without any medical issues. Our case had essentially the same outcome. The overdose (1360 mg) resulted in only mild hypertension and a single laboratory test abnormality (elevated TSH). It is difficult to determine whether the elevation of TSH was an isolated incident or whether it was related to the overdose because there is no literature linking lurasidone therapy with thyroid dysfunction. In addition, as with other antipsychotic agents, lurasidone may decrease seizure threshold. In our patient’s case, concurrent ingestion of clonazepam may have played a protective role in the prevention of seizure activity. Our patient had no long-term problems due to his lurasidone overdose. In fact, other than receiving fluids in the ICU, he required no other treatment for the ingestion. Thus, in our patient’s case, the overdose of lurasidone was not life threatening. In conclusion, this is the largest single ingestion of lurasidone reported in the literature to date. To the best of our knowledge, it is also the first detailed case report described in the literature. The
AUTHOR DISCLOSURE INFORMATION The authors declare no conflicts of interest. Gabor P. Molnar, DO Department of Psychiatry and Behavioral Neurosciences Morsani College of Medicine University of South Florida Tampa, FL
Laura C. Grimsich, MD Mental Health and Behavioral Sciences Service James A. Haley Veterans Hospital and Department of Psychiatry and Behavioral Neurosciences Morsani College of Medicine University of South Florida Tampa, FL
Glenn Catalano, MD Mental Health and Behavioral Sciences Service James A. Haley Veterans Hospital and Department of Psychiatry and Behavioral Neurosciences Morsani College of Medicine University of South Florida Tampa, FL [email protected]
Maria C. Catalano, DO Ambulatory Care Service James A. Haley Veterans Hospital and Department of Psychiatry and Behavioral Neurosciences Morsani College of Medicine University of South Florida Tampa, FL
REFERENCES 1. Cruz MP. Lurasidone HCl (Latuda), an oral, once-daily atypical antipsychotic agent for the treatment of patients with schizophrenia. Proc Natl Acad Sci U S A. 2011;36: 489Y492. 2. Belmaker RH. Lurasidone and bipolar disorder. Am J Psychiatry. 2014;171: 131Y133. 3. Citrome L. Lurasidone in schizophrenia: new information about dosage and place in therapy. Adv Ther. 2012;29:815Y825.
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4. Preskorn S, Ereshefsky L, Chiu YY, et al. Effect of food on the pharmacokinetics of lurasidone: results of two randomized, open-label, crossover studies. Hum Psychopharmacol. 2013;28:495Y505. 5. Meyer JM, Loebel AD, Schweizer E. Lurasidone: a new drug in development for schizophrenia. Expert Opin Investig Drugs. 2009;18:1715Y1726. 6. Hussar DA. New drugs 2012 part I. Nursing. 2012;42:38Y45. 7. Kane JM. Lurasidone: a clinical overview. J Clin Psychiatry. 2011;72(suppl 1):24Y28. 8. Drug development and drug interactions: table of substrates, inhibitors and inducers [US Food and Drug Administration Web site]. September 16, 2011. Available at: http://www.fda.gov/drugs/ developmentapprovalprocess/ developmentresources/druginteractionslabeling/ ucm093664.htm#classInhibit. Accessed June 16, 2014. 9. Hopkins CR. ACS chemical neuroscience molecule spotlight on Latuda (lurasidone; SM-13,496). ACS Chem Neurosci. 2011;2:58Y59. 10. Citrome L, Cucchiaro J, Sarma K, et al. Long-term safety and tolerability of lurasidone in schizophrenia: a 12-month double blind, active controlled study. Int Clin Psychopharmacol. 2012;27:165Y176. 11. Stahl SM. Stahl’s Essential Psychopharmacology: the Prescriber’s Guide. 4th ed. New York, NY: Cambridge University Press; 2011. 12. Physicians’ Desk Reference. 67th ed. Montvale, NJ: Thomson PDR; 2013.
Adding to Antidepressant Augmentation To the Editors: iterally, the term augmentation refers to the act of enlarging, increasing something. In psychopharmacology, this term is widely used to designate therapeutic strategies that aim at maximizing the efficacy of a monotherapy by adding a second drug. The accepted definition of antidepressant augmentation, validated by international guidelines,1 assumes that augmentation of antidepressants involves adding a second drug, other than an antidepressant, to the treatment regimen when no response or only partial response has been achieved, with the goal of enhancing treatment. Although enhancing the effectiveness of one another, the adding of an antidepressant to an ongoing antidepressant treatment is designated by the neutral generalist terms: association or combination. To test this definition against the literature, we performed a computerized
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literature search (National Library of Medicine/Medline) using the following words: ‘‘augmentation’’ and ‘‘antidepressant.’’ Articles included were both in English and non-English and up to January 2014. Abstracts of all retrieved occurrences were carefully read by F.M., F.H., and O.D. The corresponding publications were extracted and scrutinized when necessary. Articles retained had to deal with antidepressant combination strategies in treating depression as well as psychotic or anxiety disorders in humans. We ensured that the use of the term augmentation was not related to a translation error of nonEnglish articles. A total of 1388 occurrences were retrieved, and 531 were excluded as nonrelevant. In 768 publications, the use of the term augmentation was in accordance with the current definition. In 91 studies, the term augmentation was used to designate the combination of 2 antidepressants. The added antidepressant was bupropion in 32 articles, a tricyclic antidepressant in 21 articles, mirtazapine in 16 articles, an selective serotonin reuptake inhibitor (SSRI) in 8 articles, each of mianserin, agomelatine, and trazodone, as well as an monoamine oxidase inhibitor in 3 articles. Augmentation of an SSRI with nortriptyline was reported in 1 article. Although widely accepted as the definition of combining an antidepressant to another drug that is not an antidepressant, the concept of augmentation is used, in some cases, to designate the association of 2 antidepressants. The ‘‘augmenting’’ agent either adds a different mechanism of action (pharmacodynamic augmentation) or affects plasma concentration of the ongoing treatment by modifying its metabolism (pharmacokinetic augmentation). When added to an SSRI, bupropion augmentation is mainly pharmacodynamic because bupropion adds to serotonin reuptake inhibition, norepinephrine reuptake inhibition, and dopamine reuptake inhibition. Even for SSRIs, we could hardly omit that these drugs actually display different mechanisms of action. Fluoxetine is not only a serotonin reuptake inhibitor but also a potent 5-HT2C antagonist.2 Besides serotonin reuptake inhibition properties, paroxetine has mild anticholinergic (M1 receptor antagonism) and weak norepinephrine reuptake inhibition actions.2 Theoretically, adding fluoxetine to paroxetine enhances its antidepressant effectiveness by adding new pharmacodynamics mechanisms. Thus, paroxetine and fluoxetine combination should, theoretically, be considered as an augmentation strategy. With a view toward the development of a new antidepressant with innovating
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mechanism of action and for the sake of clarity, we suggest that the term augmentation should be used whenever the combination of 2 antidepressants results in the enhancement of pharmacodynamic or pharmacokinetic action of the ongoing treatment. AUTHOR DISCLOSURE INFORMATION The authors declare no conflicts of interest. Fayc¸al Mouaffak, MD, PhD Department of Psychiatry Biceˆtre University Hospital and Faculte´ de Me´decine Universite´ Paris XI Paris, France [email protected]
Franz Hozer, MD Olivia Delomel, MD Patrick Hardy, MD Department of Psychiatry Biceˆtre University Hospital and Faculte´ de Me´decine Universite´ Paris XI Paris, France
REFERENCES 1. Bauer M, Whybrow PC, Angst J, et al. World Federation of Societies Biological Psychiatry Task Force on Treatment Guidelines for Unipolar Depressive D. World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of Unipolar Depressive Disorders, Part 1: acute and continuation treatment of major depressive disorder. World J Biol Psychiatry. 2002;3(1):5Y43. 2. Stahl SM. Stahl’s Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. Cambridge, England: Cambridge University Press; 2013.
Atomoxetine-Associated Akathisia A Case Report To the Editors: tomoxetine is the first nonstimulant drug approved by the Food and Drug Administration for the treatment of attentiondeficit/hyperactivity disorder (ADHD) in patients older than 6 years.1 It works by blocking the presynaptic norepinephrine transporter, which leads to increased norepinephrine levels in the presynaptic gap.2 Common adverse effects of atomoxetine include nausea, vomiting, constipation, loss of appetite, weight loss, stomach pain, dizziness, headache, irritability, aggression, fatigue, and somnolence.3,4 In this
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Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Letters to the Editors
REFERENCES 1. Alexopoulos GS, Streim JE, Carpenter D. Expert consensus guidelines for using antipsychotic agents in older patients. J Clin Psychiatry. 2004;65:100Y102. 2. Washington NB, Brahm NC, Kissack J. Which psychotropics carry the greatest risk of QTc prolongation? Curr Psychiatry. 2012;11:36Y39. 3. Taylor DM. Antipsychotics and QT prolongation. Acta Psychiatr Scand. 2003;107:85Y95. 4. Meltzer HY, Cucchiaro J, Silva R, et al. Lurasidone in the treatment of schizophrenia: a randomized, double-blind, placebo- and olanzapine-controlled study. Am J Psychiatry. 2011;168:957Y967. 5. FDA. Clinical evaluation of QT/QTc interval prolongation and proarrhythmic potential for non-antiarrhythmic drugs. October 2005. Available at: http://www.fda.gov/downloads/ RegulatoryInformation/Guidances/ ucm129357.pdf. Accessed February 16, 2014. 6. Haddad PM, Anderson IM. Antipsychotic-related QTc prolongation torsade de pointes and sudden death. Drugs. 2002;62:1649Y1671. 7. Viskin S. Long QT syndromes and torsade de pointes. Lancet. 1999;354:1625Y1633. 8. Goodnick PJ, Jerry J, Parra F. Psychotropic drugs and the ECG: focus on the QTc interval. Expert Opin Pharmacother. 2002;3:479Y498. 9. Nelson S. Aripiprazole-induced QTc interval prolongation and torsades de pointes: a case report. Crit Care Med. 2011;39:257. 10. Robbins J, Nelson JC, Rautaharju PM, et al. The association between the length of the QT interval and mortality in the Cardiovascular Health Study. Am J Med. 2003;115:689Y694. 11. Haugaa KH, Bos J, Borkenhagen E, et al. Concomitant QT prolongation predicts all-cause mortality in patients with voltage-criteria for left ventricular hypertrophy on a 12-lead ECG. J Am Coll Cardiol. 2013;61. doi:10.1016/S0735-1097(13)61337-6. 12. Mallikaarjun S, Shoaf SE, Boulton DW, et al. Effects of hepatic or renal impairment on the pharmacokinetics of aripiprazole. Clin Pharmacokinet. 2008;47:533Y542. 13. Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981;30:239Y245. 14. Baumgartner RN, Koehler KM, Romero L, et al. Serum albumin is associated with skeletal muscle in elderly men and women. Am J Clin Nutr. 1996;64:552Y558. 15. Kitada M. Genetic polymorphism of cytochrome P450 enzymes in Asian populations: focus on CYP2D6. Int J Clin Pharmacol Res. 2003;23:31Y35. 16. Kim JR, Seo HB, Cho JY, et al. Population pharmacokinetic modelling of aripiprazole and its active metabolite, dehydroaripiprazole, in psychiatric patients. Br J Clin Pharmacol. 2008;66:802Y810.
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Acute Lurasidone Overdose To the Editors: urasidone is a benzoisothiazol derivative that was approved for the treatment of schizophrenia by the Food and Drug Administration (FDA) in 2010.1 Since that time, it has also been approved for the treatment of bipolar depression.2 The maximum approved dose in the United States is 160 mg once daily.3 It should be taken with food to increase the absorption of lurasidone.1 A study by Preskorn et al4 found that lurasidone exposure increased between ‘‘2- to 3-fold’’ when taken with meals of at least 1465 kJ. Absorption of lurasidone was not influenced by the fat content of the meal.4 It is absorbed rapidly after oral administration, and it reaches its maximum concentration between 1 and 3 hours after ingestion. The bioavailability of lurasidone ranges from between 9% and 19%, and it is 99.8% protein bound.1,5 A study of patients with schizophrenia found that single doses of lurasidone (between 120 mg and 160 mg) had a mean half-life of between 28.8 and 37.4 hours.5 Elimination is primarily through the liver, and approximately 0.1% of lurasidone is excreted unchanged in the urine.5 Because lurasidone is primarily metabolized via the cytochrome P450 3A4 (CYP3A4) isoenzyme, its concentration would likely be affected when used concurrently with a CYP3A4 inhibitor or inducer.1,6 In fact, a number of interactions between lurasidone and both moderate and strong CYP3A4 inducers and inhibitors have been observed.1,6 Therefore, it has been recommended that lurasidone should not be used with strong CYP3A4 inhibitors or inducers.1,6 It has also been recommended that, when lurasidone is coadministered with a moderate CYP3A4 inhibitor (such as diltiazem), the lurasidone dose should not exceed 40 mg/d.6,7 The United States FDA definitions of moderate and strong inducers/ inhibitors are listed in Table 1.8 Lurasidone is metabolized into 2 active and 2 inactive metabolites.1 It acts as a D2 and 5HT2A receptor antagonist.1,9 It also has antagonistic effects at the >2C and >2A noradrenergic receptors.1,10 It blocks the 5HT7 receptor and acts as a partial agonist of the 5HT1A receptor.1,11 Lurasidone has little, if any, affinity for histamine H1 and acetylcholine M1 receptors.10 The adverse events associated with lurasidone treatment are similar to those seen with the other atypical antipsychotic agents. Commonly seen adverse effects include akathisia, agitation, Parkinsonism, anxiety, somnolence, and dystonia.6 As with other antipsychotic agents, there
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are rare reports of leukopenia or neutropenia. The lurasidone clinical trials found it effective for both positive and negative symptoms of schizophrenia and that the most common adverse events were movement abnormalities, akathisia, nausea, and drowsiness.9 A later study by Citrome et al10 examined more than 400 patients who were treated with lurasidone for 12 months. The lurasidone doses ranged from 40 mg to 120 mg daily. In this study, the most frequent adverse effects were nausea (16.7%), insomnia (15.8%), and sedation (14.6%).10 Studies have found that there is no significant QTc prolongation associated with lurasidone use.5 In fact, 1 study found that high-dose lurasidone (up to 600 mg daily) was associated with minimal QTc interval increases of between 4.4 and 6.4 milliseconds.5 Overall, the authors felt that lurasidone was ‘‘safe and well tolerated’’ with minimal effect on prolactin levels, weight, or metabolic variables.10 Lurasidone has been classified as pregnancy category B by the FDA.1 It has been recommended that mothers do not breast feed while taking lurasidone.1 There are minimal data regarding overdose on lurasidone. In fact, a literature search was unable to find any case reports of overdose in the literature to date. The only mention of lurasidone overdose was the brief description of a single case in the package insert.12 That patient ingested an estimated 560 mg of lurasidone and recovered without sequelae. We now report the case of a 31-year-old man who overdosed on a large amount of lurasidone in an attempt to commit suicide.
CASE REPORT The patient was a 31-year-old man with a history of schizophrenia who was brought to the emergency department 90 minutes after an intentional overdose on seventeen 80-mg lurasidone tablets and five 1-mg clonazepam tablets in an attempt to end his life. The ingestion occurred immediately after lunch and was witnessed by his caregiver. His caregiver was able to confirm the number of pills ingested. His history was negative for tobacco, alcohol, or illicit drug use. His medical history was significant for hypertension and obesity as well as negative for any respiratory or endocrine disorder. Twenty-two days before this overdose, the patient weighed 131.8 kg and had a body mass index of 39.4. The patient’s medication regimen consisted of lurasidone (160 mg nightly), trazodone (150 mg nightly), and clonazepam (1 mg every 8 hours as needed). Upon presentation to the emergency department, the patient was noted to be cooperative, alert, and oriented in all * 2014 Lippincott Williams & Wilkins
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Journal of Clinical Psychopharmacology
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TABLE 1. Definitions of Inducers and Inhibitors From the United States FDA Term
Definition
Strong inducer Moderate inducer Strong inhibitor
Moderate inhibitor
A medication that causes an 80% decrease or higher in the AUC of the concurrently used medication A medication that causes a 50% to 80% decrease in the AUC of the concurrently used medication A medication that causes a 5-fold increase or higher in AUC or greater than 80% decrease in CL of the concurrently used medication A medication that causes a 2- or higher but less than 5-fold increase in AUC or 50% to 80% decrease in CL of the concurrently used medication
Letters to the Editors
patient ingested 1360 mg of lurasidone, along with 5 mg of clonazepam with minimal medical difficulties. One interesting finding was the transient increase in the patient’s TSH level that was discovered the day after the overdose. It will be important to continue in reviewing cases of lurasidone overdose over time to compare their outcomes. It would also be useful to monitor TSH levels in those patients who have overdosed on lurasidone to ascertain whether there is a true relationship between lurasidone overdose and TSH elevation.
AUC indicates area underneath the curve; CL, drug clearance.
spheres. He was in no acute distress and was breathing easily. His temperature was 36.4 -C, his blood pressure was 140/87, and he had a pulse of 85 beats per minute. A complete blood count, a complete metabolic profile, and urinalysis were all within normal limits. Amylase, lipase, troponin, creatine kinase-MB, and creatine kinase were all within normal limits. Urine drug screen was positive only for benzodiazepines. Of note, the patient’s thyrotropin (TSH) was elevated at 6.100 mIU/L from a documented 4.015 mIU/L 3 weeks prior. Free T3 and free T4 were both within normal limits at 2.60 pg/mL and 1.15 ng/dL, respectively. Electrocardiogram displayed normal sinus rhythm with a rate of 91 beats per minute and a QTc of 452 milliseconds. There was no recent electrocardiogram available for comparison. The finding of neurologic examination was normal, except for mild oral-buccal dyskinesia that was also noted on prior outpatient documentation. The patient was admitted to the medical intensive care unit (ICU) for observation and administration of fluids. No other medical treatment was required in the ICU. His hypertension resolved within 12 hours of the ingestion. He was transferred to the inpatient psychiatric unit, and his physical condition remained stable. While on the inpatient psychiatric unit, lurasidone was restarted. However, shortly afterward, the lurasidone was discontinued at the patient’s request and he was switched to ziprasidone. The patient’s hypertension resolved quickly, and he was subsequently discharged home. A repeat TSH drawn 17 days after the discharge was found to be within normal limits at 3.053 mIU/L.
DISCUSSION This is a report on a 31-year-old man with schizophrenia who overdosed on lurasidone (1360 mg) and clonazepam (5 mg) in a suicide attempt. His medical * 2014 Lippincott Williams & Wilkins
history was significant for obesity and hypertension, but there was no history of any endocrine dysfunction. There was also a negative history of substance abuse. The amount of lurasidone ingested was 8.5 times the maximum recommended dose and was equal to 10.32 mg/kg of body weight. The patient’s overdose took place shortly after lunch, so the presence of food in his stomach could have increased his absorption of the lurasidone. The patient initially presented with mild hypertension and an elevated TSH (6.100 mIU/L), but there were no other physical examination or laboratory findings. The patient recovered without any significant medical sequelae, and his TSH level had normalized when checked more than 3 weeks after the overdose. There is 1 documented case of lurasidone overdose (560 mg) in a patient who recovered without any medical issues. Our case had essentially the same outcome. The overdose (1360 mg) resulted in only mild hypertension and a single laboratory test abnormality (elevated TSH). It is difficult to determine whether the elevation of TSH was an isolated incident or whether it was related to the overdose because there is no literature linking lurasidone therapy with thyroid dysfunction. In addition, as with other antipsychotic agents, lurasidone may decrease seizure threshold. In our patient’s case, concurrent ingestion of clonazepam may have played a protective role in the prevention of seizure activity. Our patient had no long-term problems due to his lurasidone overdose. In fact, other than receiving fluids in the ICU, he required no other treatment for the ingestion. Thus, in our patient’s case, the overdose of lurasidone was not life threatening. In conclusion, this is the largest single ingestion of lurasidone reported in the literature to date. To the best of our knowledge, it is also the first detailed case report described in the literature. The
AUTHOR DISCLOSURE INFORMATION The authors declare no conflicts of interest. Gabor P. Molnar, DO Department of Psychiatry and Behavioral Neurosciences Morsani College of Medicine University of South Florida Tampa, FL
Laura C. Grimsich, MD Mental Health and Behavioral Sciences Service James A. Haley Veterans Hospital and Department of Psychiatry and Behavioral Neurosciences Morsani College of Medicine University of South Florida Tampa, FL
Glenn Catalano, MD Mental Health and Behavioral Sciences Service James A. Haley Veterans Hospital and Department of Psychiatry and Behavioral Neurosciences Morsani College of Medicine University of South Florida Tampa, FL [email protected]
Maria C. Catalano, DO Ambulatory Care Service James A. Haley Veterans Hospital and Department of Psychiatry and Behavioral Neurosciences Morsani College of Medicine University of South Florida Tampa, FL
REFERENCES 1. Cruz MP. Lurasidone HCl (Latuda), an oral, once-daily atypical antipsychotic agent for the treatment of patients with schizophrenia. Proc Natl Acad Sci U S A. 2011;36: 489Y492. 2. Belmaker RH. Lurasidone and bipolar disorder. Am J Psychiatry. 2014;171: 131Y133. 3. Citrome L. Lurasidone in schizophrenia: new information about dosage and place in therapy. Adv Ther. 2012;29:815Y825.
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4. Preskorn S, Ereshefsky L, Chiu YY, et al. Effect of food on the pharmacokinetics of lurasidone: results of two randomized, open-label, crossover studies. Hum Psychopharmacol. 2013;28:495Y505. 5. Meyer JM, Loebel AD, Schweizer E. Lurasidone: a new drug in development for schizophrenia. Expert Opin Investig Drugs. 2009;18:1715Y1726. 6. Hussar DA. New drugs 2012 part I. Nursing. 2012;42:38Y45. 7. Kane JM. Lurasidone: a clinical overview. J Clin Psychiatry. 2011;72(suppl 1):24Y28. 8. Drug development and drug interactions: table of substrates, inhibitors and inducers [US Food and Drug Administration Web site]. September 16, 2011. Available at: http://www.fda.gov/drugs/ developmentapprovalprocess/ developmentresources/druginteractionslabeling/ ucm093664.htm#classInhibit. Accessed June 16, 2014. 9. Hopkins CR. ACS chemical neuroscience molecule spotlight on Latuda (lurasidone; SM-13,496). ACS Chem Neurosci. 2011;2:58Y59. 10. Citrome L, Cucchiaro J, Sarma K, et al. Long-term safety and tolerability of lurasidone in schizophrenia: a 12-month double blind, active controlled study. Int Clin Psychopharmacol. 2012;27:165Y176. 11. Stahl SM. Stahl’s Essential Psychopharmacology: the Prescriber’s Guide. 4th ed. New York, NY: Cambridge University Press; 2011. 12. Physicians’ Desk Reference. 67th ed. Montvale, NJ: Thomson PDR; 2013.
Adding to Antidepressant Augmentation To the Editors: iterally, the term augmentation refers to the act of enlarging, increasing something. In psychopharmacology, this term is widely used to designate therapeutic strategies that aim at maximizing the efficacy of a monotherapy by adding a second drug. The accepted definition of antidepressant augmentation, validated by international guidelines,1 assumes that augmentation of antidepressants involves adding a second drug, other than an antidepressant, to the treatment regimen when no response or only partial response has been achieved, with the goal of enhancing treatment. Although enhancing the effectiveness of one another, the adding of an antidepressant to an ongoing antidepressant treatment is designated by the neutral generalist terms: association or combination. To test this definition against the literature, we performed a computerized
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literature search (National Library of Medicine/Medline) using the following words: ‘‘augmentation’’ and ‘‘antidepressant.’’ Articles included were both in English and non-English and up to January 2014. Abstracts of all retrieved occurrences were carefully read by F.M., F.H., and O.D. The corresponding publications were extracted and scrutinized when necessary. Articles retained had to deal with antidepressant combination strategies in treating depression as well as psychotic or anxiety disorders in humans. We ensured that the use of the term augmentation was not related to a translation error of nonEnglish articles. A total of 1388 occurrences were retrieved, and 531 were excluded as nonrelevant. In 768 publications, the use of the term augmentation was in accordance with the current definition. In 91 studies, the term augmentation was used to designate the combination of 2 antidepressants. The added antidepressant was bupropion in 32 articles, a tricyclic antidepressant in 21 articles, mirtazapine in 16 articles, an selective serotonin reuptake inhibitor (SSRI) in 8 articles, each of mianserin, agomelatine, and trazodone, as well as an monoamine oxidase inhibitor in 3 articles. Augmentation of an SSRI with nortriptyline was reported in 1 article. Although widely accepted as the definition of combining an antidepressant to another drug that is not an antidepressant, the concept of augmentation is used, in some cases, to designate the association of 2 antidepressants. The ‘‘augmenting’’ agent either adds a different mechanism of action (pharmacodynamic augmentation) or affects plasma concentration of the ongoing treatment by modifying its metabolism (pharmacokinetic augmentation). When added to an SSRI, bupropion augmentation is mainly pharmacodynamic because bupropion adds to serotonin reuptake inhibition, norepinephrine reuptake inhibition, and dopamine reuptake inhibition. Even for SSRIs, we could hardly omit that these drugs actually display different mechanisms of action. Fluoxetine is not only a serotonin reuptake inhibitor but also a potent 5-HT2C antagonist.2 Besides serotonin reuptake inhibition properties, paroxetine has mild anticholinergic (M1 receptor antagonism) and weak norepinephrine reuptake inhibition actions.2 Theoretically, adding fluoxetine to paroxetine enhances its antidepressant effectiveness by adding new pharmacodynamics mechanisms. Thus, paroxetine and fluoxetine combination should, theoretically, be considered as an augmentation strategy. With a view toward the development of a new antidepressant with innovating
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mechanism of action and for the sake of clarity, we suggest that the term augmentation should be used whenever the combination of 2 antidepressants results in the enhancement of pharmacodynamic or pharmacokinetic action of the ongoing treatment. AUTHOR DISCLOSURE INFORMATION The authors declare no conflicts of interest. Fayc¸al Mouaffak, MD, PhD Department of Psychiatry Biceˆtre University Hospital and Faculte´ de Me´decine Universite´ Paris XI Paris, France [email protected]
Franz Hozer, MD Olivia Delomel, MD Patrick Hardy, MD Department of Psychiatry Biceˆtre University Hospital and Faculte´ de Me´decine Universite´ Paris XI Paris, France
REFERENCES 1. Bauer M, Whybrow PC, Angst J, et al. World Federation of Societies Biological Psychiatry Task Force on Treatment Guidelines for Unipolar Depressive D. World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of Unipolar Depressive Disorders, Part 1: acute and continuation treatment of major depressive disorder. World J Biol Psychiatry. 2002;3(1):5Y43. 2. Stahl SM. Stahl’s Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. Cambridge, England: Cambridge University Press; 2013.
Atomoxetine-Associated Akathisia A Case Report To the Editors: tomoxetine is the first nonstimulant drug approved by the Food and Drug Administration for the treatment of attentiondeficit/hyperactivity disorder (ADHD) in patients older than 6 years.1 It works by blocking the presynaptic norepinephrine transporter, which leads to increased norepinephrine levels in the presynaptic gap.2 Common adverse effects of atomoxetine include nausea, vomiting, constipation, loss of appetite, weight loss, stomach pain, dizziness, headache, irritability, aggression, fatigue, and somnolence.3,4 In this
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