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Biological Psychiatry
Death From Opioid Overdose After Deep Brain Stimulation: A Case Report To the Editor: Deep brain stimulation (DBS) is a widely used procedure in which stereotactically implanted stimulatory electrodes are used to modulate the activity of specific neural circuits (1). Double-blind randomized controlled trials have indicated the efficacy of ventral capsule/ventral striatum (VC/VS) DBS in treating refractory depression and obsessive-compulsive disorder (2,3). DBS has also shown promise in the treatment of refractory opioid addictive disorders (4–7). However, extending the application of DBS to addictive disorders involves diseasespecific challenges, including the increased co-occurrence of antisocial personality disorders (ASPDs) and low socioeconomic status, which are common in this population (8). We present information on a patient who died of a heroin overdose over 3 months after DBS implantation to treat opioid addiction, despite initial opioid cessation after DBS activation. To the best of our knowledge, this is the first reported death caused by opioid overdose after VC/VS DBS. The therapeutic course postintervention was characterized by unique diseasespecific challenges, ultimately leading to death. This occurrence therefore warrants special attention and should inform future protocol development to enroll and inform appropriate prospective patients and relatives. While enrolled in a clinical trial for opioid addiction DBS (ClinicalTrials.gov identifier NCT02440152), a patient with a 17-year history of heroin dependence underwent DBS implantation on March 1, 2017, and died of a heroin overdose on June 21, 2017. The subject was a 39-year-old married man with a low level of literacy (primary education). His longstanding history of drug abuse began with small heroin doses, gradually increasing to 0.05 g per day. He received methadone maintenance treatment from 2010 until he underwent surgery, but relapsed with heroin approximately monthly. His medical history included hepatitis C, syphilis, and a comorbid psychiatric diagnosis of ASPD according to the Structured Clinical
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Interview for DSM-IV Axis II Personality Disorders conducted before DBS surgery. The DBS study protocol was approved by a local ethics committee. The patient and a relative provided informed consent regarding participation and data use. DBS was performed without previous detoxification. SceneRay 1241 electrodes (SceneRay, Suzhou, China) (9,10) were implanted (contact length, 3.0 mm; spacing between ventral and dorsal contacts, 2 mm, 4 mm, and 4 mm, respectively) and targeted the VC/VS area following previously established procedures (3). After implantation, the patient completed weekly follow-up examinations at a local hospital, including urine testing, DBS optimization, and unstructured psychotherapy. Two medial contacts in both electrodes were activated 2 weeks after implantation. Parameters were initiated at 3.5 V, 90 ms, 130 Hz (optimization outlined in Figure 1). Upon DBS activation, the patient reported reduced opiate cravings and decreased discomfort (based on the Withdrawal Symptom Rating Scale score). One and a half months after DBS activation, he had gained 6.5 kg in weight, decreased his cigarette consumption from 140 cigarettes to approximately 20 cigarettes per week, reported alleviated insomnia, and returned to work. Physiological dependence on opioids and withdrawal symptoms were gradually alleviated during this period. However, between the beginning of May and June 21, the patient relapsed on eight occasions. His opioid cravings and withdrawal syndrome reappeared, and DBS parameters were increased to alleviate them. At the end of May, the patient exhibited symptoms of mild hypomania. Thus, DBS parameters were lowered. However, because of his increasing cravings and repeated relapses, parameters were increased again at the beginning of June. In the 2 weeks before the patient’s fatal overdose, he consistently requested higher voltages to cope with his growing cravings; incidentally, his mania symptoms gradually disappeared. The patient discussed here exhibited a complex response to VC/VS DBS. Hypomania, and particularly impulsivity, is relatively common after VC/VS DBS (11–13). During the last 2 weeks of his life, the patient continually reported increasing
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Figure 1. Change in deep brain stimulation (DBS) parameters over time. (A) Parameter changes of contacts in the nucleus accumbens. Contacts 1 and 6 were negative, and case (C) was positive. (B) Parameter changes of contacts in the ventral capsule. Contacts 2 and 7 were negative, and case (C) was positive.
http://dx.doi.org/10.1016/j.biopsych.2017.07.018 ISSN: 0006-3223
ª 2017 Society of Biological Psychiatry. e9 Biological Psychiatry January 1, 2018; 83:e9-e10 www.sobp.org/journal
Biological Psychiatry
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cravings that required higher voltages to alleviate. It is unclear whether increased DBS voltage was a contributing factor to the overdose. Before the fatal incident, we cautioned that a stable DBS voltage must be maintained, combined with controlled quantities of methadone or buprenorphine. Despite our best efforts, the patient did not conform to these indications. Experimental animal studies and several case reports have demonstrated the clinical effectiveness of DBS in terms of reduced craving and drug abuse (14). Nevertheless, we were unable to achieve a positive clinical outcome for this patient using DBS treatment combined with other therapeutic interventions. The factors that contributed to the complexity of this case, and possibly its adverse outcome, include the patient’s ASPD and low socioeconomic status, which made DBS optimization and psychoeducation difficult. DBS system dysfunction was excluded as a contributing factor to the abrupt loss of DBS efficacy because impedance was tested weekly before parameter adjustment. External circumstances, including physical exhaustion due to long working hours and a lack of motivation, may have contributed to treatment ineffectiveness. In post-DBS psychotherapy, the patient confessed that he was unmotivated to undergo DBS, and that he had volunteered because of pressure from his friends and family. Based on the patient’s statements, he increased his heroin dose from 0.05 g pre-DBS to 0.1 g post-DBS because of a reduced response to the drugs in terms of pleasurability. In addition, he reported that alleviated withdrawal symptoms and feelings of calmness after surgery gave him the impression that he could safely use drugs again. It is likely that his deteriorating mental state was exacerbated by blame placed on him by his family for relapsing. Nevertheless, the patient did not meet the diagnostic criteria for major depressive disorder in his weekly follow-up assessments. Ultimately, this suggests an accidental death due to an intentional overdose. Comorbidity with ASPD is known to adversely affect the clinical course, treatment outcome, and prognosis of opiate-dependent patients (15). Moreover, dependence is often associated with adverse social and economic circumstances, including unemployment, lack of social support, unhealthy lifestyle habits, and health problems (15). The present case indicates that comorbidity with ASPD similarly requires special attention when considering DBS treatment for patients with addictive disorders. This poses a significant clinical challenge given that substantial comorbidity exists between ASPD and substance use disorders, and that ASPD itself is associated with high morbidity and premature mortality. Chencheng Zhang Yuhua Huang Fangchen Zheng Kristina Zeljic Jun Pan Bomin Sun
Acknowledgments and Disclosures This work was supported by National Key Research and Development Program of China Grant No. 2017YFC0803607 (to CCZ), the SHSMU-ION Research Center for Brain Disorders (to BMS), and National Natural Science Foundation of China Grant No. 81471387 (to BMS). We thank Xiaoyu Chen (Ph.D. student, Institute of Neuroscience), and Jiang Du (M.D., Shanghai Mental Health Center) for their assistance.
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The implant equipment was provided by SceneRay. BMS received research support from SceneRay (donated devices), and CZ has received honoraria and travel expenses from the deep brain stimulation industry (Medtronic, SceneRay, and PINS). The other authors report no biomedical financial interests or potential conflicts of interest.
Article Information From the Department of Functional Neurosurgery (CZ, BS), Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai; Departments of Psychiatry (YH) and Neurosurgery (JP), Hainan Danzhou People’s Hospital, Danzhou, Hainan; Institution of Neuroscience (KZ), Shanghai, China; and the Department of Psychology (FZ), University of Arizona, Tucson, Arizona. Address correspondence to Chencheng Zhang, M.D., Department of Functional Neurosurgery, Ruijin Hospital of the Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, China; E-mail:
[email protected]. Received Jul 23, 2017; revised and accepted Jul 25, 2017. ClinicalTrials.gov: The Effectiveness of Deep Brain Stimulation for Opioid Relapse Prevention; https://clinicaltrials.gov/ct2/show/NCT02440152; NCT02440152.
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