Journal of Clinical Psychopharmacology
&
Volume 34, Number 3, June 2014
13. Sumiyoshi T, Matsui M, Yamashita I, et al. The effect of tandospirone, a serotonin 1A agonist, on memory function in schizophrenia. Biol Psychiatry. 2001;49:861Y868. 14. Sumiyoshi T, Park S, Jayathilake K, et al. Effect of buspirone, a serotonin1A partial agonist, on cognitive function in schizophrenia: a randomized, double-blind, placebo-controlled study. Schizophr Res. 2007;95:158Y168. 15. Higuchi Y, Sumiyoshi T, Kawasaki Y, et al. Effect of tandospirone on mismatch negativity and cognitive performance in schizophrenia: a case report. J Clin Psychopharmacol. 2010;30: 732Y734.
Effect of Aripiprazole Augmentation for Treatment-Resistant Somatoform Disorder A Case Series To the Editors:
A
lthough there is opposition, hypochondriasis is supposed to be included as an obsessive-compulsive spectrum disorder,1Y3 and the effectiveness of treatment with selective serotonin reuptake inhibitors (SSRIs) has been demonstrated.4,5 Because somatoform disorder has features common with hypochondriasis, the effectiveness of SSRIs for this disorder is significant.6,7 Besides, augmentation with antipsychotics is effective in case of SSRIresistant obsessive-compulsive disorder (OCD).8,9 Therefore, augmentation with antipsychotics may be effective in the treatment of SSRI-resistant somatoform disorder. However, except for body dysmorphic disorder,10Y13 few reports have evaluated the combined use of SSRIs and antipsychotics in patients with somatoform disorder.14 Accordingly, we present 2 patients with somatoform disorder who had insufficient therapeutic effect with SSRI but showed marked improvement with concomitant use of aripiprazole (APZ).
CASE 1 The patient was a 65-year-old woman living with her husband. She and her family had no history of psychiatric disorders. Over the past 20 years, she developed laryngopharynx discomfort, persistent abdominal pain, back pain, lumbago, and fatigue, and thus, she quit her job and was confined to bed most of the time. Although she consulted physicians in otorhinolaryngology, orthopedics, and internal medicine, no * 2014 Lippincott Williams & Wilkins
abnormality was found. After psychiatric consultations, she was prescribed 1.2 mg/d alprazolam, but her symptoms did not improve. She subsequently underwent psychiatric examination at another hospital, and 100 mg/d milnacipran was prescribed for possible masked depression; however, it was ineffective. She continued undergoing clinical examinations at the gastroenterology department of our hospital because of her uneasiness, and after no abnormality was found, she was eventually referred to our psychiatry department. She exhibited hypochondriacal fear of having pancreatic cancer and obsessive concern with her physical condition, without apparent signs of depression. According to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR), we diagnosed her with undifferentiated somatoform disorder. The treatment of 100 mg/d milnacipran was switched to 40 mg/d paroxetine. Although slight improvement was observed, her treatment was discontinued because of an adverse effect of sleepiness. She then revisited our department because of aggravated symptoms. We restarted her therapy with fluvoxamine, and improvement was observed after increasing the dosage to 300 mg/d. However, about half of the symptoms still persisted. Aripiprazole was added to the treatment 12 weeks later. Aripiprazole was initiated at 6 mg/d and was increased to 18 mg/d. Signs of improvement were observed within 4 weeks, and her symptoms disappeared without any adverse effects 8 weeks later. The patient was able to do household chores. Because the remission lasted for 2 years, we decreased and discontinued her medications successfully with no aggravation of symptoms.
CASE 2 The patient was a 69-year-old woman living with her husband. She and her family had no history of psychiatric disorders. She experienced numbness on the right side of her face and dizziness lasting for 5 years. She underwent multiple otorhinolaryngological, cardiological, and neurological examinations based on her self-diagnosis through medical books; however, no abnormality was observed. She visited our department because she was annoyed with the disturbing thought of having a serious brain disease. She exhibited hypochondriacal anxiety and obsessive concern with her physical state, without any apparent signs of depression. Her condition was diagnosed with undifferentiated somatoform disorder according to DSM-IV-TR and treated with 50 mg/d paroxetine. Although some improvement was observed, about half of the
Letters to the Editors
symptom still persisted. Then, 6 mg/d of APZ was added 12 weeks later. Signs of improvement were observed within 2 weeks, and her symptoms disappeared 4 weeks later without any adverse drug reaction. She was able to do household chores. After 6 months remission, her medication was decreased and then discontinued. We terminated the therapy with no aggravation of symptoms.
DISCUSSION As reported previously for OCD, our study suggested that antipsychotics are effective augmentation therapy for SSRIresistant somatoform disorder. Based on evidence of augmentation with APZ in SSRI-resistant OCD,15Y19 we consider APZ to be effective for patients who are closer to hypochondriasis (ie, similar to OCD). Olanzapine or quetiapine could be more effective for patients who are emotionally unstable with severe anxiety, restlessness, or anger and are closer to somatization disorder. Because patients with somatoform disorder are usually sensitive to adverse drug reactions, they often cannot tolerate drugs and discontinue medications or hospital visits. Therefore, it is necessary to note any adverse drug reactions when treating somatoform disorder. Aripiprazole is well tolerated and, in particular, has less of a sedative effect, which could be a common problem for patients except those with schizophrenia or a manic episode. Therefore, we selected APZ among antipsychotic agents for our cases, and no adverse drug reaction was observed. Although antipsychotic augmentation for OCD could show efficacy at a low dose, a comparatively high dose of APZ was required in case 1; this may have been the case because APZ is a partial dopamine agonist. AUTHOR DISCLOSURE INFORMATION The authors declare no conflicts of interest. Yasuhide Nagoshi, MD, PhD Department of Psychiatry (Psychosomatic Medicine) Kyoto First Red Cross Hospital Kyoto, Japan [email protected]
Toshiyuki Tominaga, MD Health Management Doctor’s Office (Mental Health), Salary, Personnel Health and Welfare Division, Kyoto Prefecture and Department of Psychiatry Graduate School of Medical Science Kyoto Prefectural University of Medicine Kyoto, Japan www.psychopharmacology.com
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
397
Letters to the Editors
Kenji Fukui, MD, PhD Department of Psychiatry Graduate School of Medical Science Kyoto Prefectural University of Medicine Kyoto, Japan
Journal of Clinical Psychopharmacology
body dysmorphic disorder. Clin Drug Investig. 2010;30:707Y710.
REFERENCES
14. Huang M, Luo B, Hu J, et al. Combination of citalopram plus paliperidone is better than citalopram alone in the treatment of somatoform disorder: results of 6-week randomized study. Int Clin Psychopharmacol. 2012;27:151Y158.
1. Abramowitz JS, Braddock AE. Hypochondriasis: conceptualization, treatment, and relationship to obsessive-compulsive disorder. Psychiatr Clin North Am. 2006;29:503Y519.
15. Masi G, Pfanner C, Millepiedi S, et al. Aripiprazole augmentation in 39 adolescents with medication-resistant obsessive-compulsive disorder. J Clin Psychopharmacol. 2010;30:688Y693.
2. Castle DJ, Phillips KA. Obsessive-compulsive spectrum of disorders: a defensible construct? Aust N Z J Psychiatry. 2006;40:114Y120.
16. Matsunaga H, Hayashida K, Maebayashi K, et al. A case series of aripiprazole augmentation of selective serotonin reuptake inhibitors in treatment-refractory obsessive compulsive disorder. Int J Psychiatry Clin Pract. 2011;15: 263Y269.
3. Bartz JA, Hollander E. Is obsessive-compulsive disorder an anxiety disorder? Prog Neuropsychopharmacol Biol Psychiatry. 2006;30:338Y352. 4. Greeven A, van Balkom AJ, Visser S, et al. Cognitive behavior therapy and paroxetine in the treatment of hypochondriasis: a randomized controlled trial. Am J Psychiatry. 2007;164:91Y99.
17. Delle Chiaie R, Scarciglia P, Pasquini M, et al. Aripiprazole augmentation in patients with resistant obsessive compulsive disorder: a pilot study. Clin Pract Epidemiol Ment Health. 2011;7:107Y111.
5. Fallon BA, Petkova E, Skritskaya N, et al. A double-masked, placebo-controlled study of fluoxetine for hypochondriasis. J Clin Psychopharmacol. 2008;28:638Y645.
18. Muscatello MR, Bruno A, Pandolfo G, et al. Effect of aripiprazole augmentation of serotonin reuptake inhibitors or clomipramine in treatment-resistant obsessive-compulsive disorder: a double-blind, placebo-controlled study. J Clin Psychopharmacol. 2011; 31:174Y179.
6. Noyes R Jr, Happel RL, Muller BA, et al. Fluvoxamine for somatoform disorders: an open trial. Gen Hosp Psychiatry. 1998;20:339Y344. 7. Muller JE, Wentzel I, Koen L, et al. Escitalopram in the treatment of multisomatoform disorder: a double-blind, placebo-controlled trial. Int Clin Psychopharmacol. 2008;23:43Y48. 8. Bloch MH, Landeros-Weisenberger A, Kermendi B, et al. A systematic review: antipsychotic augmentation with treatment refractory obsessive-compulsive disorder. Mol Psychiatry. 2006;11:622Y632. 9. Skapinakis P, Papatheodorou T, Mavreas V. Antipsychotic augmentation of serotonergic antidepressants in treatment-resistant obsessive-compulsive disorder: a meta-analysis of the randomized controlled trials. Eur Neuropsychopharmacol. 2007;17: 79Y93. 10. Phillips KA, Albertini RS, Siniscalchi JM, et al. Effectiveness of pharmacotherapy for body dysmorphic disorder: a chart-review study. J Clin Psychiatry. 2001;62:721Y727. 11. Phillips KA. Olanzapine augmentation of fluoxetine in body dysmorphic disorder. Am J Psychiatry. 2005;162:1022Y1023. 12. Nakaaki S, Murata Y, Furukawa TA. Efficacy of olanzapine augmentation of paroxetine therapy in patients with severe body dysmorphic disorder. Psychiatry Clin Neurosci. 2008;62:370. 13. Uzun O, Ozdemir B. Aripiprazole as an augmentation agent in treatment-resistant
398
www.psychopharmacology.com
19. Sayyah M, Sayyah M, Boostani H, et al. Effects of aripiprazole augmentation in treatment-resistant obsessive-compulsive disorder (a double blind clinical trial). Depress Anxiety. 2012;29:850Y854.
Plasma Levels and Cerebrospinal Fluid Penetration of Venlafaxine in a Patient With a Nonfatal Overdose During a Suicide Attempt To the Editors:
CASE REPORT Variability in response to psychotropic drugs is due to genetic and environmental factors. Cytochrome P450 (CYP) isoforms are involved in the metabolism of drugs, whereas the P-glycoprotein transporter (P-gp), encoded by the ABCB1 gene, may influence both blood and cerebrospinal fluid (CSF) drug concentrations. We report the case of a genotyped 37-year-old female inpatient surviving a severe suicide attempt with 15 g of venlafaxine (VEN) without long-lasting negative effects. Therapeutic drug monitoring of VEN and
&
Volume 34, Number 3, June 2014
O-desmethylvenlafaxine (ODV) revealed extraordinary high drug levels in both plasma and CSF. Ms. A. is a 37-year-old female inpatient suffering from a severe episode of major depressive disorder (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition: 296.23, International Classification of Diseases, 10th Revision: F32.2) treated with a daily dose of 150 mg of VEN since the day of her admission. In suicidal ideation, she ingested 100 tablets of 150 mg VEN extended release equivalent to a total amount of 15 g. Shortly hereafter, she was found unconscious in her room with foam around the mouth, suggesting an epileptic seizure. Blood oxygen saturation was 92%, blood glucose level was 76 mg/dL, and pulse rate was accelerated to 130 beats/min. Starting basic life support, she had another epileptic seizure of 30 seconds’ duration and was intubated because of circulatory instability and respiratory insufficiency. Intracranial pathology and encephalitis as reasons for unconsciousness were excluded by computed tomography scan and lumbar puncture. Cerebrospinal fluid analysis 5 hours after intoxication revealed normal leukocyte count and physiological protein, glucose, and lactate levels. Therapeutic drug monitoring, using highperformance liquid chromatography, showed plasma levels for VEN of 18,138 ng/mL, ODV 2955 ng/mL (active moiety [VEN + ODV] 21,093 ng/mL; reference range, 100Y400 ng/mL).1 Cerebrospinal fluid levels were found to be 6488 ng/mL for VEN and 2154 ng/mL for ODV. The active moiety plasma/CSF ratio was 2.44. After some days at the ICU, the patient recovered well until she was readmitted to the psychiatric department where she then signed a written informed consent to do genetic testing on CYP isoenzymes and on ABCB1 genotype to get a deeper understanding of the pharmacokinetics and CSF penetration of VEN. For P450 2D6, she was found to be an extensive metabolizer with the genotype *1/*1, for CYP2C9 genetic testing revealed *1/*3 (intermediate metabolizer), and the genotype for CYP2C19 was *1/*1 (extensive metabolizer). Concerning the ABCB1 C3435T genotype, she was found to be CT, reflecting an intermediate phenotype, which is the most common one. For 2677, her genotype consists of GG, which corresponds to a higher activity, but there is an incomplete linkage disequilibrium between 2677 and 3435.
DISCUSSION The clinical efficacy of systemically administered drugs acting on the central nervous system depends on their ability to pass the blood-brain barrier, a process that is regulated * 2014 Lippincott Williams & Wilkins
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
&
Volume 34, Number 3, June 2014
13. Sumiyoshi T, Matsui M, Yamashita I, et al. The effect of tandospirone, a serotonin 1A agonist, on memory function in schizophrenia. Biol Psychiatry. 2001;49:861Y868. 14. Sumiyoshi T, Park S, Jayathilake K, et al. Effect of buspirone, a serotonin1A partial agonist, on cognitive function in schizophrenia: a randomized, double-blind, placebo-controlled study. Schizophr Res. 2007;95:158Y168. 15. Higuchi Y, Sumiyoshi T, Kawasaki Y, et al. Effect of tandospirone on mismatch negativity and cognitive performance in schizophrenia: a case report. J Clin Psychopharmacol. 2010;30: 732Y734.
Effect of Aripiprazole Augmentation for Treatment-Resistant Somatoform Disorder A Case Series To the Editors:
A
lthough there is opposition, hypochondriasis is supposed to be included as an obsessive-compulsive spectrum disorder,1Y3 and the effectiveness of treatment with selective serotonin reuptake inhibitors (SSRIs) has been demonstrated.4,5 Because somatoform disorder has features common with hypochondriasis, the effectiveness of SSRIs for this disorder is significant.6,7 Besides, augmentation with antipsychotics is effective in case of SSRIresistant obsessive-compulsive disorder (OCD).8,9 Therefore, augmentation with antipsychotics may be effective in the treatment of SSRI-resistant somatoform disorder. However, except for body dysmorphic disorder,10Y13 few reports have evaluated the combined use of SSRIs and antipsychotics in patients with somatoform disorder.14 Accordingly, we present 2 patients with somatoform disorder who had insufficient therapeutic effect with SSRI but showed marked improvement with concomitant use of aripiprazole (APZ).
CASE 1 The patient was a 65-year-old woman living with her husband. She and her family had no history of psychiatric disorders. Over the past 20 years, she developed laryngopharynx discomfort, persistent abdominal pain, back pain, lumbago, and fatigue, and thus, she quit her job and was confined to bed most of the time. Although she consulted physicians in otorhinolaryngology, orthopedics, and internal medicine, no * 2014 Lippincott Williams & Wilkins
abnormality was found. After psychiatric consultations, she was prescribed 1.2 mg/d alprazolam, but her symptoms did not improve. She subsequently underwent psychiatric examination at another hospital, and 100 mg/d milnacipran was prescribed for possible masked depression; however, it was ineffective. She continued undergoing clinical examinations at the gastroenterology department of our hospital because of her uneasiness, and after no abnormality was found, she was eventually referred to our psychiatry department. She exhibited hypochondriacal fear of having pancreatic cancer and obsessive concern with her physical condition, without apparent signs of depression. According to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR), we diagnosed her with undifferentiated somatoform disorder. The treatment of 100 mg/d milnacipran was switched to 40 mg/d paroxetine. Although slight improvement was observed, her treatment was discontinued because of an adverse effect of sleepiness. She then revisited our department because of aggravated symptoms. We restarted her therapy with fluvoxamine, and improvement was observed after increasing the dosage to 300 mg/d. However, about half of the symptoms still persisted. Aripiprazole was added to the treatment 12 weeks later. Aripiprazole was initiated at 6 mg/d and was increased to 18 mg/d. Signs of improvement were observed within 4 weeks, and her symptoms disappeared without any adverse effects 8 weeks later. The patient was able to do household chores. Because the remission lasted for 2 years, we decreased and discontinued her medications successfully with no aggravation of symptoms.
CASE 2 The patient was a 69-year-old woman living with her husband. She and her family had no history of psychiatric disorders. She experienced numbness on the right side of her face and dizziness lasting for 5 years. She underwent multiple otorhinolaryngological, cardiological, and neurological examinations based on her self-diagnosis through medical books; however, no abnormality was observed. She visited our department because she was annoyed with the disturbing thought of having a serious brain disease. She exhibited hypochondriacal anxiety and obsessive concern with her physical state, without any apparent signs of depression. Her condition was diagnosed with undifferentiated somatoform disorder according to DSM-IV-TR and treated with 50 mg/d paroxetine. Although some improvement was observed, about half of the
Letters to the Editors
symptom still persisted. Then, 6 mg/d of APZ was added 12 weeks later. Signs of improvement were observed within 2 weeks, and her symptoms disappeared 4 weeks later without any adverse drug reaction. She was able to do household chores. After 6 months remission, her medication was decreased and then discontinued. We terminated the therapy with no aggravation of symptoms.
DISCUSSION As reported previously for OCD, our study suggested that antipsychotics are effective augmentation therapy for SSRIresistant somatoform disorder. Based on evidence of augmentation with APZ in SSRI-resistant OCD,15Y19 we consider APZ to be effective for patients who are closer to hypochondriasis (ie, similar to OCD). Olanzapine or quetiapine could be more effective for patients who are emotionally unstable with severe anxiety, restlessness, or anger and are closer to somatization disorder. Because patients with somatoform disorder are usually sensitive to adverse drug reactions, they often cannot tolerate drugs and discontinue medications or hospital visits. Therefore, it is necessary to note any adverse drug reactions when treating somatoform disorder. Aripiprazole is well tolerated and, in particular, has less of a sedative effect, which could be a common problem for patients except those with schizophrenia or a manic episode. Therefore, we selected APZ among antipsychotic agents for our cases, and no adverse drug reaction was observed. Although antipsychotic augmentation for OCD could show efficacy at a low dose, a comparatively high dose of APZ was required in case 1; this may have been the case because APZ is a partial dopamine agonist. AUTHOR DISCLOSURE INFORMATION The authors declare no conflicts of interest. Yasuhide Nagoshi, MD, PhD Department of Psychiatry (Psychosomatic Medicine) Kyoto First Red Cross Hospital Kyoto, Japan [email protected]
Toshiyuki Tominaga, MD Health Management Doctor’s Office (Mental Health), Salary, Personnel Health and Welfare Division, Kyoto Prefecture and Department of Psychiatry Graduate School of Medical Science Kyoto Prefectural University of Medicine Kyoto, Japan www.psychopharmacology.com
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
397
Letters to the Editors
Kenji Fukui, MD, PhD Department of Psychiatry Graduate School of Medical Science Kyoto Prefectural University of Medicine Kyoto, Japan
Journal of Clinical Psychopharmacology
body dysmorphic disorder. Clin Drug Investig. 2010;30:707Y710.
REFERENCES
14. Huang M, Luo B, Hu J, et al. Combination of citalopram plus paliperidone is better than citalopram alone in the treatment of somatoform disorder: results of 6-week randomized study. Int Clin Psychopharmacol. 2012;27:151Y158.
1. Abramowitz JS, Braddock AE. Hypochondriasis: conceptualization, treatment, and relationship to obsessive-compulsive disorder. Psychiatr Clin North Am. 2006;29:503Y519.
15. Masi G, Pfanner C, Millepiedi S, et al. Aripiprazole augmentation in 39 adolescents with medication-resistant obsessive-compulsive disorder. J Clin Psychopharmacol. 2010;30:688Y693.
2. Castle DJ, Phillips KA. Obsessive-compulsive spectrum of disorders: a defensible construct? Aust N Z J Psychiatry. 2006;40:114Y120.
16. Matsunaga H, Hayashida K, Maebayashi K, et al. A case series of aripiprazole augmentation of selective serotonin reuptake inhibitors in treatment-refractory obsessive compulsive disorder. Int J Psychiatry Clin Pract. 2011;15: 263Y269.
3. Bartz JA, Hollander E. Is obsessive-compulsive disorder an anxiety disorder? Prog Neuropsychopharmacol Biol Psychiatry. 2006;30:338Y352. 4. Greeven A, van Balkom AJ, Visser S, et al. Cognitive behavior therapy and paroxetine in the treatment of hypochondriasis: a randomized controlled trial. Am J Psychiatry. 2007;164:91Y99.
17. Delle Chiaie R, Scarciglia P, Pasquini M, et al. Aripiprazole augmentation in patients with resistant obsessive compulsive disorder: a pilot study. Clin Pract Epidemiol Ment Health. 2011;7:107Y111.
5. Fallon BA, Petkova E, Skritskaya N, et al. A double-masked, placebo-controlled study of fluoxetine for hypochondriasis. J Clin Psychopharmacol. 2008;28:638Y645.
18. Muscatello MR, Bruno A, Pandolfo G, et al. Effect of aripiprazole augmentation of serotonin reuptake inhibitors or clomipramine in treatment-resistant obsessive-compulsive disorder: a double-blind, placebo-controlled study. J Clin Psychopharmacol. 2011; 31:174Y179.
6. Noyes R Jr, Happel RL, Muller BA, et al. Fluvoxamine for somatoform disorders: an open trial. Gen Hosp Psychiatry. 1998;20:339Y344. 7. Muller JE, Wentzel I, Koen L, et al. Escitalopram in the treatment of multisomatoform disorder: a double-blind, placebo-controlled trial. Int Clin Psychopharmacol. 2008;23:43Y48. 8. Bloch MH, Landeros-Weisenberger A, Kermendi B, et al. A systematic review: antipsychotic augmentation with treatment refractory obsessive-compulsive disorder. Mol Psychiatry. 2006;11:622Y632. 9. Skapinakis P, Papatheodorou T, Mavreas V. Antipsychotic augmentation of serotonergic antidepressants in treatment-resistant obsessive-compulsive disorder: a meta-analysis of the randomized controlled trials. Eur Neuropsychopharmacol. 2007;17: 79Y93. 10. Phillips KA, Albertini RS, Siniscalchi JM, et al. Effectiveness of pharmacotherapy for body dysmorphic disorder: a chart-review study. J Clin Psychiatry. 2001;62:721Y727. 11. Phillips KA. Olanzapine augmentation of fluoxetine in body dysmorphic disorder. Am J Psychiatry. 2005;162:1022Y1023. 12. Nakaaki S, Murata Y, Furukawa TA. Efficacy of olanzapine augmentation of paroxetine therapy in patients with severe body dysmorphic disorder. Psychiatry Clin Neurosci. 2008;62:370. 13. Uzun O, Ozdemir B. Aripiprazole as an augmentation agent in treatment-resistant
398
www.psychopharmacology.com
19. Sayyah M, Sayyah M, Boostani H, et al. Effects of aripiprazole augmentation in treatment-resistant obsessive-compulsive disorder (a double blind clinical trial). Depress Anxiety. 2012;29:850Y854.
Plasma Levels and Cerebrospinal Fluid Penetration of Venlafaxine in a Patient With a Nonfatal Overdose During a Suicide Attempt To the Editors:
CASE REPORT Variability in response to psychotropic drugs is due to genetic and environmental factors. Cytochrome P450 (CYP) isoforms are involved in the metabolism of drugs, whereas the P-glycoprotein transporter (P-gp), encoded by the ABCB1 gene, may influence both blood and cerebrospinal fluid (CSF) drug concentrations. We report the case of a genotyped 37-year-old female inpatient surviving a severe suicide attempt with 15 g of venlafaxine (VEN) without long-lasting negative effects. Therapeutic drug monitoring of VEN and
&
Volume 34, Number 3, June 2014
O-desmethylvenlafaxine (ODV) revealed extraordinary high drug levels in both plasma and CSF. Ms. A. is a 37-year-old female inpatient suffering from a severe episode of major depressive disorder (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition: 296.23, International Classification of Diseases, 10th Revision: F32.2) treated with a daily dose of 150 mg of VEN since the day of her admission. In suicidal ideation, she ingested 100 tablets of 150 mg VEN extended release equivalent to a total amount of 15 g. Shortly hereafter, she was found unconscious in her room with foam around the mouth, suggesting an epileptic seizure. Blood oxygen saturation was 92%, blood glucose level was 76 mg/dL, and pulse rate was accelerated to 130 beats/min. Starting basic life support, she had another epileptic seizure of 30 seconds’ duration and was intubated because of circulatory instability and respiratory insufficiency. Intracranial pathology and encephalitis as reasons for unconsciousness were excluded by computed tomography scan and lumbar puncture. Cerebrospinal fluid analysis 5 hours after intoxication revealed normal leukocyte count and physiological protein, glucose, and lactate levels. Therapeutic drug monitoring, using highperformance liquid chromatography, showed plasma levels for VEN of 18,138 ng/mL, ODV 2955 ng/mL (active moiety [VEN + ODV] 21,093 ng/mL; reference range, 100Y400 ng/mL).1 Cerebrospinal fluid levels were found to be 6488 ng/mL for VEN and 2154 ng/mL for ODV. The active moiety plasma/CSF ratio was 2.44. After some days at the ICU, the patient recovered well until she was readmitted to the psychiatric department where she then signed a written informed consent to do genetic testing on CYP isoenzymes and on ABCB1 genotype to get a deeper understanding of the pharmacokinetics and CSF penetration of VEN. For P450 2D6, she was found to be an extensive metabolizer with the genotype *1/*1, for CYP2C9 genetic testing revealed *1/*3 (intermediate metabolizer), and the genotype for CYP2C19 was *1/*1 (extensive metabolizer). Concerning the ABCB1 C3435T genotype, she was found to be CT, reflecting an intermediate phenotype, which is the most common one. For 2677, her genotype consists of GG, which corresponds to a higher activity, but there is an incomplete linkage disequilibrium between 2677 and 3435.
DISCUSSION The clinical efficacy of systemically administered drugs acting on the central nervous system depends on their ability to pass the blood-brain barrier, a process that is regulated * 2014 Lippincott Williams & Wilkins
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
