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Fatal water intoxication during olanzapine treatment: A case report
Legal Medicine 16 (2014) 89–91
Contents lists available at ScienceDirect
Legal Medicine journal homepage: www.elsevier.com/locate/legalmed
Case report
Fatal water intoxication during olanzapine treatment: A case report Sayaka Nagasawa ⇑, Daisuke Yajima, Suguru Torimitsu, Hiroko Abe, Hirotaro Iwase Department of Legal Medicine, Graduate School of Medicine, Chiba University, Japan
a r t i c l e
i n f o
Article history: Received 18 October 2013 Received in revised form 14 November 2013 Accepted 3 December 2013 Available online 12 December 2013 Keywords: Olanzapine Hyponatremia Water intoxication Side effect Therapeutic drug monitoring
a b s t r a c t A man in his twenties was diagnosed with schizophrenia in his late teens. The night before his death, his family reported he drank a large amount of water, vomited, collapsed, and snored loudly while sleeping, but they did not view the event seriously as he did it routinely. The following morning, he was found dead. Autopsy revealed hyponatremia by water intoxication as the cause of death. Water intoxication has various causes. In this case, 610 ng/mL olanzapine was detected in serum samples. Although this concentration is not as high as the fatal concentrations reported in past studies, it might have caused some adverse effects. Furthermore, the observation that excessive drinking behavior started after the dose of olanzapine was increased suggests a possibility that olanzapine aggravated water intoxication. Ó 2013 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Olanzapine is one of the most common antipsychotic drugs used for first-line treatment of schizophrenia in Japan. It is widely used worldwide as it can also be used to treat bipolar depression. Olanzapine has various affinities for multiple receptors, including those for dopamine D2, serotonin 5-hydroxytryptamine (HT)2A, 5-HT2C, 5-HT6, adrenaline alpha-1, histamine H1, and muscarine M1–M5 [1]. Therefore, olanzapine is associated with various clinical and toxic manifestations [2–6]. In particular, dry mouth caused by metabolic disorder, a known adverse effect of olanzapine, occurs significantly more frequently in patients treated with olanzapine than in those treated with other drugs. In this study, we report a case of death from water intoxication while receiving olanzapine treatment. Although various factors are known to cause water intoxication, an adverse effect of olanzapine in the present case might have aggravated water intoxication. 2. Case report A man in his twenties who was diagnosed with schizophrenia at in his late teens had over the few months preceding his death drunk such large amounts of water that his abdomen was expanded and he had been vomiting and collapsing. The night before ⇑ Corresponding author. Address: Department of Legal Medicine, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan. Tel.: +81 43 226 2078; fax: +81 43 226 2079. E-mail address: [email protected] (S. Nagasawa). 1344-6223/$ - see front matter Ó 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.legalmed.2013.12.003
his death, his family reported he drank a large amount of water, vomited, collapsed, and snored loudly while sleeping, but they did not view the event seriously as he did it routinely. The following morning, he was found dead. He had no history of smoking or drinking alcohol. Medication history included intramuscular injection of haloperidol on monthly hospital visits, with the last dose of 100 mg given 14 days before death. Details of his last prescription were olanzapine 15 mg/day before bedtime, risperdal 2 mg/dose and flunitrazepam 1 mg/dose as needed for insomnia, and sennoside 12 mg/ dose as needed for constipation.
2.1. Autopsy findings Legal autopsy was performed about 4 days after death. Body height was 159 cm, body weight 63.5 kg, edematous brain weight 1620 g, heart weight 345 g, edematous right lung weight 560 g, edematous left lung weight 465 g, and 160 g brown, water-soluble, viscous stomach content. There were no signs of trauma, asphyxia or disease. Postmortem serum biochemistry showed C-reactive protein 0.3 mg/dL, glutamic acid pyrolysis products 227 mg/dL, glutamine urine 95 mg/dL, hemoglobin A1c 5.7% (international standard), and glycoalbumin 11.0%. Serum electrolyte concentrations were sodium 83 mEq/L, potassium 44.9 mEq/L, and chloride 55 mEq/L. Electrolyte concentrations in the vitreous humor of the left and right eyes were sodium 111 and 113 mEq/L, potassium 23.3 and 25.6 mEq/L, and chloride 83 and 85 mEq/L, respectively. Blood drug
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concentrations were haloperidol 15 ng/mL, olanzapine 610 ng/mL, and risperidone 22 ng/mL. 3. Cadaveric study To compare against the findings of the present case, postmortem changes in electrolyte concentrations were examined in the serum and vitreous humor obtained from 18 cadavers (15 males, 3 females; aged 25 ~ 86 years, mean age of 60.88 years at time of death) at 1–10 days postmortem (Table 1). Cadavers with causes of death that may have affected body fluid composition were excluded. 4. Results As shown in Table 2, the mean (±standard deviation) sodium concentration for the 18 cadavers was 108.4 ± 9.58 mEq/L in the serum, 129.44 ± 8.84 mEq/L in the right vitreous humor, and 132.76 ± 10.28 mEq/L in left vitreous humor, concentrations that were higher than in the present case. 5. Discussion Although there is currently no established diagnostic standard for water intoxication, a diagnosis is based on the observation of behavior such as polyposia, blood test results such as hyponatremia, and previous clinical history such as epileptic stroke and disturbance of consciousness [7]. In the present case, a large amount of water was consumed before death, autopsy revealed edema in the brain and lung, and the vitreous sodium concentration, which has been shown to be relatively resistant to postmortem change
[8], was low. In addition, the serum and vitreous electrolyte concentrations were lower than those in the 18 cadavers with similar postmortem periods and with causes of death unlikely to have influenced electrolyte concentrations. These results therefore suggested that hyponatremia resulting from water intoxication was the cause of death in the present case. Water intoxication is characterized by hyponatremia due to excessive water intake and is known to be common among schizophrenic patients [9,10]. However, the pathogenic mechanism of water intoxication is not yet clear, with some reports indicating the adverse effects of antipsychotic drugs and continued secretion of vasopressin, and others suggesting a direct association with psychosis [11,12]. In the present case, shown in Fig. 1, intramuscular injections of haloperidol were given on monthly hospital visits for about 1.5 years before death. Oral medication was changed from aripiprazole 12 mg/day to olanzapine 10 mg/day, followed by a dose increase to 15 mg/day. In addition, flunitrazepam, nitrazepam, risperidone, and loxoprofen were prescribed according to disease condition on needed basis. On autopsy, only haloperidol, risperidone, and olanzapine were detected in the blood. These three drugs are known to be associated with adverse effects of dry mouth and water intoxication, but olanzapine, as a multireceptor agonist, is more likely to cause anticholinergic effects and metabolic disorder than the other drugs [13]. Indeed, although haloperidol and risperidone were detected in the therapeutic range, olanzapine was detected high concentration (610 ng/mL). In previously reported cases of olanzapine overdose, the blood drug concentration in live patients with toxic manifestations was approximately 250–2800 ng/mL [14–16], and that in cadavers was approximately 2100–4500 ng/mL [17–19]. In the present case, the blood olanzapine concentration (610 ng/mL) was lower than the historic mean, suggesting that the cause of death was
Table 1 Results of electrolyte measurement in 18 normal cadavers at 1–10 days postmortem. Case
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
Age
42 76 65 81 85 70 25 44 75 86 69 39 80 48 54 78 32 47
Sex
M M M F M M M M F M M M M M M M M F
Time elapsed after death (days)
Cause of death
2–5 2–4 1–3 2–5 2–5 3–5 2–5 3–7 4–10 1–4 1–4 1–5 2–5 3–7 2–5 3–7 2–4 2–4
Brain damage due to head banging Traumatic subarachnoid hemorrhage Carbon monoxide poisoning Respiratory failure Traumatic subarachnoid hematoma Carbon monoxide poisoning Suffocation from lack of oxygen Unknown Hypoxic encephalopathy Acute subdural hematoma Intracerebral hemorrhage Monoxide poisoning Asphyxiation by neck compression Ischemic heart disease Unknown Acute interstitial pneumonia Asphyxiation by neck compression Unknown
Right vitreous humor
Left vitreous humor
Na
Serum K
Cl
Na
K
Cl
Na
K
Cl
92 113 126 113 107 112 108 98 91 116 123 98 111 112 109 100 108 115
55.3 32.6 27 44.7 37.8 44.2 43.4 53.8 42.6 39.1 28.2 47.6 40.4 39.9 41.5 37.3 47.2 33
85 85 94 92 86 85 84 86 69 102 87 83 80 85 90 79 88 85
130 125 134 138 116 112 132 129 115 129 147 124 133 126 137 132 131 140
27.5 13.4 13.4 18.1 20 19.8 25.4 27.3 22.2 22.9 13.5 22.7 17.9 26.4 23.9 16.6 28 13.7
106 100 108 115 90 90 105 104 78 101 117 100 108 98 111 98 112 109
130 134 162 137 137 125 127 130 115 – 142 123 130 130 136 131 125 143
27.5 14.1 16.4 19 22.4 21.8 25.4 2937 23.3 – 12.3 22.4 17.3 26.6 23.3 16 25.9 13.4
105 107 133 115 106 102 101 109 76 – 112 99 106 102 110 98 105 111
Concentrations are mEq/L.
Table 2 Comparison of electrolyte measurements of the present case with water intoxication and those of 18 normal cases. Present case of water intoxication
Serum Right vitreous humor Left vitreous humor Concentrations are mEq/L.
18 Cadavers (mean ± standard deviation)
Na
K
Na + K
Na
K
Na + K
83 113 111
44.9 25.6 23.3
127.9 138.6 134.3
108.4 ± 9.58 129.4 ± 8.84 132.76 ± 10.28
40.86 ± 7.69 20.7 ± 5.21 20.98 ± 5.18
149.26 ± 6.28 150.14 ± 8.96 153.74 ± 8.75
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Haloperidol 50 mg injecon at 2 months 1/2A
Blood test at 12 months 1A
2A
Abilify Risperidone 12 mg/day 2 mg/day at at 3 months 5 months
Abilify and risperidone stopped + olanzapine 10 mg/day at 8 months
Olanzapine 5 mg/day at 15 months
Family noced excessive drinking for about 6 months
Death at 24 months
Fig. 1. Medication was started 2 years before death. All drugs were given either orally or intravenously. After 9 months of treatment with an increased dose of olanzapine, family members noticed excessive drinking, even after which medication was continued.
unlikely to be olanzapine intoxication. However, it has been suggested that adverse effects are more prominent at concentrations above 80 ng/mL and that the range for optimal therapy may be narrow, at 20–40 ng/mL, as determined by 12 h postdose sampling [20]. Thus, the concentration of 610 ng/mL in the present case—a high concentration even when taking postmortem re-distribution into consideration—might have caused some adverse effects [21]. In the present case, blood tests performed 1 year before death (3 months after switching to olanzapine) revealed a relatively low serum potassium level and a tendency of hyponatremia (sodium 131 mEq/L, potassium 3.6 mEq/L, and chloride 89 mEq/L), indicating excessive water consumption at the time. The lack of earlier blood test results makes it difficult to determine when the hyponatremia started and whether it was directly associated with psychosis or was an adverse effect of olanzapine. However, the observation that excessive drinking behavior started after the dose of olanzapine was increased suggests a possibility that olanzapine aggravated water intoxication. 6. Conclusion The cause of death in this case was judged to be hyponatremia by water intoxication based on the results of the autopsy, biochemical examination, and drug test. Moreover, it is likely that an adverse effect of olanzapine in the present case might have aggravated water intoxication. References [1] Nagai N, Watanabe K. Olanzapine. Nihon Rinsho 2013;71:666–72. [2] De Hert M, Vancampfort D, Correll CU, Mercken V, Peuskens J, Sweers K, et al. Guidelines for screening and monitoring of cardiometabolic risk in schizophrenia: systematic evaluation. Br J Psychiatry 2011;199:99–105. [3] Rummel-Kluge C, Komossa K, Schwarz S, Hunger H, Schmid F, Lobos CA, et al. Head-to-head comparisons of metabolic side effects of second generation antipsychotics in the treatment of schizophrenia: a systematic review and meta-analysis. Schizophr Res 2010;123:225–33.
[4] Thornton-Jones Z, Neill JC, Reynolds GP. The atypical antipsychotic olanzapine enhances ingestive behaviour in the rat: a preliminary study. J Psychopharmacol 2002;16:35–7. [5] Ota M, Mori K, Nakashima A, Kaneko YS, Fujiwara K, Itoh M, et al. Peripheral injection of risperidone, an atypical antipsychotic, alters the bodyweight gain of rats. Clin Exp Pharmacol Physiol 2002;29:980–9. [6] Hartfield AW, Moore NA, Clifton PG. Effects of clozapine, olanzapine and haloperidol on the microstructure of ingestive behaviour in the rat. Psychopharmacology 2003;167:115–22. [7] Radojevic N, Bojana B, Aleksic V, Rancic N, Samardzic M, Petkovic S, et al. Forensic aspects of water intoxication: four case reports and review of relevant literature. Forensic Sci Int 2012;220:1–5. [8] Byramji A, Cains G, Gilbert DJ, Byard RW. Hyponatremia at autopsy: an analysis of etiologic mechanisms and their possible significance. Sci Med Pathol 2008;4:149–52. [9] De lemon J, Verghese C, Tracy JI, Josiassen RC, Simpson GM. Polydipsia and water intoxication in psychiatric patients: a review of the epidemiological literature. Biol Psychiatry 1994;35:408–19. [10] Vieweg WV, David JJ, Rowe WT, Peach MJ, Veldhuis JD, Kaiser DL, et al. Psychogenic polydipsia and water intoxication—concepts that have failed. Biol Psychiatry 1985;20:1308–20. [11] Emsley R, Potgieter A, Taljaard F, Joubert G, Gledhill R. Water excretion and plasma vasopressin in psychotic disorders. Am J Psychiatry 1989;146:250–3. [12] Goldman MB, Robertson GL, Luchins DJ, Hedeker D, Pandey GN. Psychotic exacerbations and enhanced vasopressin secretion in schizophrenic patients with hyponatremia and polydipsia. Arch Gen Psychiatry 1997;54:443–9. [13] Dudeja SJ, McCormick M, Dudeja RK. Olanzapine induced hyponatremia. Ulster Med J 2010;79:104–5. [14] O’Malley GF, Seifert S, Heard K, Daly F, Daet RC. Pupillary effects of olanzapine overdose mimic opiate and a-2 agonists. Clin Toxicol 1998;36:523. [15] O’Malley GF, Seifert S, Heard K, Daly F, Daet RC. Olanzapine overdose mimicking opioid intoxication. Ann Emerg Med 1999;34:279–81. [16] Shrestha M, Hendrickson RG, Henretig FM. Striking extrapyramidal movements seen in large olanzapine overdose. Clin Toxicol 2001;39:282. [17] Stephens BG, Coleman DE, Baselt RC. Olanzapine-related fatality. J Forensic Sci 1998;43:1252–3. [18] Ereshefsky L. Pharmacokinetics and drug interactions: update for new antipsychotics. J Clin Psychiatry 1996;57:12–25. [19] Vance C, Mcintyre IM. Postmortem tissue concentrations of olanzapine. J Anal Toxicol 2009;33:15–26. [20] Schiff J, Cole E, Cantarovich M. Therapeutic monitoring of calcineurin inhibitors for the nephrologist. Clin J Am Soc Nephrol 2007;2:374–84. [21] Saar E, Beyer J, Gerostamoulos D, Drummer HO. The time-dependent postmortem redistribution of antipsychotic drugs. Forensic Sci Int 2012;222: 223–7.
Contents lists available at ScienceDirect
Legal Medicine journal homepage: www.elsevier.com/locate/legalmed
Case report
Fatal water intoxication during olanzapine treatment: A case report Sayaka Nagasawa ⇑, Daisuke Yajima, Suguru Torimitsu, Hiroko Abe, Hirotaro Iwase Department of Legal Medicine, Graduate School of Medicine, Chiba University, Japan
a r t i c l e
i n f o
Article history: Received 18 October 2013 Received in revised form 14 November 2013 Accepted 3 December 2013 Available online 12 December 2013 Keywords: Olanzapine Hyponatremia Water intoxication Side effect Therapeutic drug monitoring
a b s t r a c t A man in his twenties was diagnosed with schizophrenia in his late teens. The night before his death, his family reported he drank a large amount of water, vomited, collapsed, and snored loudly while sleeping, but they did not view the event seriously as he did it routinely. The following morning, he was found dead. Autopsy revealed hyponatremia by water intoxication as the cause of death. Water intoxication has various causes. In this case, 610 ng/mL olanzapine was detected in serum samples. Although this concentration is not as high as the fatal concentrations reported in past studies, it might have caused some adverse effects. Furthermore, the observation that excessive drinking behavior started after the dose of olanzapine was increased suggests a possibility that olanzapine aggravated water intoxication. Ó 2013 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Olanzapine is one of the most common antipsychotic drugs used for first-line treatment of schizophrenia in Japan. It is widely used worldwide as it can also be used to treat bipolar depression. Olanzapine has various affinities for multiple receptors, including those for dopamine D2, serotonin 5-hydroxytryptamine (HT)2A, 5-HT2C, 5-HT6, adrenaline alpha-1, histamine H1, and muscarine M1–M5 [1]. Therefore, olanzapine is associated with various clinical and toxic manifestations [2–6]. In particular, dry mouth caused by metabolic disorder, a known adverse effect of olanzapine, occurs significantly more frequently in patients treated with olanzapine than in those treated with other drugs. In this study, we report a case of death from water intoxication while receiving olanzapine treatment. Although various factors are known to cause water intoxication, an adverse effect of olanzapine in the present case might have aggravated water intoxication. 2. Case report A man in his twenties who was diagnosed with schizophrenia at in his late teens had over the few months preceding his death drunk such large amounts of water that his abdomen was expanded and he had been vomiting and collapsing. The night before ⇑ Corresponding author. Address: Department of Legal Medicine, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan. Tel.: +81 43 226 2078; fax: +81 43 226 2079. E-mail address: [email protected] (S. Nagasawa). 1344-6223/$ - see front matter Ó 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.legalmed.2013.12.003
his death, his family reported he drank a large amount of water, vomited, collapsed, and snored loudly while sleeping, but they did not view the event seriously as he did it routinely. The following morning, he was found dead. He had no history of smoking or drinking alcohol. Medication history included intramuscular injection of haloperidol on monthly hospital visits, with the last dose of 100 mg given 14 days before death. Details of his last prescription were olanzapine 15 mg/day before bedtime, risperdal 2 mg/dose and flunitrazepam 1 mg/dose as needed for insomnia, and sennoside 12 mg/ dose as needed for constipation.
2.1. Autopsy findings Legal autopsy was performed about 4 days after death. Body height was 159 cm, body weight 63.5 kg, edematous brain weight 1620 g, heart weight 345 g, edematous right lung weight 560 g, edematous left lung weight 465 g, and 160 g brown, water-soluble, viscous stomach content. There were no signs of trauma, asphyxia or disease. Postmortem serum biochemistry showed C-reactive protein 0.3 mg/dL, glutamic acid pyrolysis products 227 mg/dL, glutamine urine 95 mg/dL, hemoglobin A1c 5.7% (international standard), and glycoalbumin 11.0%. Serum electrolyte concentrations were sodium 83 mEq/L, potassium 44.9 mEq/L, and chloride 55 mEq/L. Electrolyte concentrations in the vitreous humor of the left and right eyes were sodium 111 and 113 mEq/L, potassium 23.3 and 25.6 mEq/L, and chloride 83 and 85 mEq/L, respectively. Blood drug
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S. Nagasawa et al. / Legal Medicine 16 (2014) 89–91
concentrations were haloperidol 15 ng/mL, olanzapine 610 ng/mL, and risperidone 22 ng/mL. 3. Cadaveric study To compare against the findings of the present case, postmortem changes in electrolyte concentrations were examined in the serum and vitreous humor obtained from 18 cadavers (15 males, 3 females; aged 25 ~ 86 years, mean age of 60.88 years at time of death) at 1–10 days postmortem (Table 1). Cadavers with causes of death that may have affected body fluid composition were excluded. 4. Results As shown in Table 2, the mean (±standard deviation) sodium concentration for the 18 cadavers was 108.4 ± 9.58 mEq/L in the serum, 129.44 ± 8.84 mEq/L in the right vitreous humor, and 132.76 ± 10.28 mEq/L in left vitreous humor, concentrations that were higher than in the present case. 5. Discussion Although there is currently no established diagnostic standard for water intoxication, a diagnosis is based on the observation of behavior such as polyposia, blood test results such as hyponatremia, and previous clinical history such as epileptic stroke and disturbance of consciousness [7]. In the present case, a large amount of water was consumed before death, autopsy revealed edema in the brain and lung, and the vitreous sodium concentration, which has been shown to be relatively resistant to postmortem change
[8], was low. In addition, the serum and vitreous electrolyte concentrations were lower than those in the 18 cadavers with similar postmortem periods and with causes of death unlikely to have influenced electrolyte concentrations. These results therefore suggested that hyponatremia resulting from water intoxication was the cause of death in the present case. Water intoxication is characterized by hyponatremia due to excessive water intake and is known to be common among schizophrenic patients [9,10]. However, the pathogenic mechanism of water intoxication is not yet clear, with some reports indicating the adverse effects of antipsychotic drugs and continued secretion of vasopressin, and others suggesting a direct association with psychosis [11,12]. In the present case, shown in Fig. 1, intramuscular injections of haloperidol were given on monthly hospital visits for about 1.5 years before death. Oral medication was changed from aripiprazole 12 mg/day to olanzapine 10 mg/day, followed by a dose increase to 15 mg/day. In addition, flunitrazepam, nitrazepam, risperidone, and loxoprofen were prescribed according to disease condition on needed basis. On autopsy, only haloperidol, risperidone, and olanzapine were detected in the blood. These three drugs are known to be associated with adverse effects of dry mouth and water intoxication, but olanzapine, as a multireceptor agonist, is more likely to cause anticholinergic effects and metabolic disorder than the other drugs [13]. Indeed, although haloperidol and risperidone were detected in the therapeutic range, olanzapine was detected high concentration (610 ng/mL). In previously reported cases of olanzapine overdose, the blood drug concentration in live patients with toxic manifestations was approximately 250–2800 ng/mL [14–16], and that in cadavers was approximately 2100–4500 ng/mL [17–19]. In the present case, the blood olanzapine concentration (610 ng/mL) was lower than the historic mean, suggesting that the cause of death was
Table 1 Results of electrolyte measurement in 18 normal cadavers at 1–10 days postmortem. Case
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
Age
42 76 65 81 85 70 25 44 75 86 69 39 80 48 54 78 32 47
Sex
M M M F M M M M F M M M M M M M M F
Time elapsed after death (days)
Cause of death
2–5 2–4 1–3 2–5 2–5 3–5 2–5 3–7 4–10 1–4 1–4 1–5 2–5 3–7 2–5 3–7 2–4 2–4
Brain damage due to head banging Traumatic subarachnoid hemorrhage Carbon monoxide poisoning Respiratory failure Traumatic subarachnoid hematoma Carbon monoxide poisoning Suffocation from lack of oxygen Unknown Hypoxic encephalopathy Acute subdural hematoma Intracerebral hemorrhage Monoxide poisoning Asphyxiation by neck compression Ischemic heart disease Unknown Acute interstitial pneumonia Asphyxiation by neck compression Unknown
Right vitreous humor
Left vitreous humor
Na
Serum K
Cl
Na
K
Cl
Na
K
Cl
92 113 126 113 107 112 108 98 91 116 123 98 111 112 109 100 108 115
55.3 32.6 27 44.7 37.8 44.2 43.4 53.8 42.6 39.1 28.2 47.6 40.4 39.9 41.5 37.3 47.2 33
85 85 94 92 86 85 84 86 69 102 87 83 80 85 90 79 88 85
130 125 134 138 116 112 132 129 115 129 147 124 133 126 137 132 131 140
27.5 13.4 13.4 18.1 20 19.8 25.4 27.3 22.2 22.9 13.5 22.7 17.9 26.4 23.9 16.6 28 13.7
106 100 108 115 90 90 105 104 78 101 117 100 108 98 111 98 112 109
130 134 162 137 137 125 127 130 115 – 142 123 130 130 136 131 125 143
27.5 14.1 16.4 19 22.4 21.8 25.4 2937 23.3 – 12.3 22.4 17.3 26.6 23.3 16 25.9 13.4
105 107 133 115 106 102 101 109 76 – 112 99 106 102 110 98 105 111
Concentrations are mEq/L.
Table 2 Comparison of electrolyte measurements of the present case with water intoxication and those of 18 normal cases. Present case of water intoxication
Serum Right vitreous humor Left vitreous humor Concentrations are mEq/L.
18 Cadavers (mean ± standard deviation)
Na
K
Na + K
Na
K
Na + K
83 113 111
44.9 25.6 23.3
127.9 138.6 134.3
108.4 ± 9.58 129.4 ± 8.84 132.76 ± 10.28
40.86 ± 7.69 20.7 ± 5.21 20.98 ± 5.18
149.26 ± 6.28 150.14 ± 8.96 153.74 ± 8.75
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S. Nagasawa et al. / Legal Medicine 16 (2014) 89–91
Haloperidol 50 mg injecon at 2 months 1/2A
Blood test at 12 months 1A
2A
Abilify Risperidone 12 mg/day 2 mg/day at at 3 months 5 months
Abilify and risperidone stopped + olanzapine 10 mg/day at 8 months
Olanzapine 5 mg/day at 15 months
Family noced excessive drinking for about 6 months
Death at 24 months
Fig. 1. Medication was started 2 years before death. All drugs were given either orally or intravenously. After 9 months of treatment with an increased dose of olanzapine, family members noticed excessive drinking, even after which medication was continued.
unlikely to be olanzapine intoxication. However, it has been suggested that adverse effects are more prominent at concentrations above 80 ng/mL and that the range for optimal therapy may be narrow, at 20–40 ng/mL, as determined by 12 h postdose sampling [20]. Thus, the concentration of 610 ng/mL in the present case—a high concentration even when taking postmortem re-distribution into consideration—might have caused some adverse effects [21]. In the present case, blood tests performed 1 year before death (3 months after switching to olanzapine) revealed a relatively low serum potassium level and a tendency of hyponatremia (sodium 131 mEq/L, potassium 3.6 mEq/L, and chloride 89 mEq/L), indicating excessive water consumption at the time. The lack of earlier blood test results makes it difficult to determine when the hyponatremia started and whether it was directly associated with psychosis or was an adverse effect of olanzapine. However, the observation that excessive drinking behavior started after the dose of olanzapine was increased suggests a possibility that olanzapine aggravated water intoxication. 6. Conclusion The cause of death in this case was judged to be hyponatremia by water intoxication based on the results of the autopsy, biochemical examination, and drug test. Moreover, it is likely that an adverse effect of olanzapine in the present case might have aggravated water intoxication. References [1] Nagai N, Watanabe K. Olanzapine. Nihon Rinsho 2013;71:666–72. [2] De Hert M, Vancampfort D, Correll CU, Mercken V, Peuskens J, Sweers K, et al. Guidelines for screening and monitoring of cardiometabolic risk in schizophrenia: systematic evaluation. Br J Psychiatry 2011;199:99–105. [3] Rummel-Kluge C, Komossa K, Schwarz S, Hunger H, Schmid F, Lobos CA, et al. Head-to-head comparisons of metabolic side effects of second generation antipsychotics in the treatment of schizophrenia: a systematic review and meta-analysis. Schizophr Res 2010;123:225–33.
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