East Asian Arch Psychiatry 2010;20:186-9

CASE REPORT

Dr CSY Chong, MBBS, Department of Psychiatry, Kwai Chung Hospital, Hong Kong SAR, China.

Address for correspondence: Dr Catherine Shiu-Yin Chong, MBBS, Department of Psychiatry, Kwai Chung Hospital, Hong Kong SAR, China.
Tel: (852) 2959 8111; Email: csy319@ha.org.hk

Submitted: 19 April 2010; Accepted: 22 June 2010

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Introduction

Obesity is a pressing health concern in both developed and developing countries. The prevalence of obesity was as high as 33.9% in the USA in 2009.¹ Patients with schizophrenia are particularly at risk for obesity due to their sedentary lifestyles, poor diet, and side-effects of medications.

Sibutramine is a norepinephrine and serotonin reuptake inhibitor that was initially developed as an antidepressant. Sibutramine was licensed by the USA Food and Drug Administration (FDA) in 1997 and found its niche as a potent weight-reducing agent.² The drug was also found to be an effective treatment for olanzapine-treated obese patients with schizophrenia.³ Some of the adverse effects related to sibutramine include headache, insomnia, dry mouth, tachycardia, and hypertension,⁴ which are usually self-limiting. Given the favourable efficacy and side-effect profiles of sibutramine and the high rate of morbid obesity throughout the world, there has been increasing use of sibutramine during the past few years.

The neuropsychiatric complications of sibutramine are not well recognised. Sibutramine has been associated with various psychiatric complications, including mania, panic attacks, depression, and suicidal ideations.^5-7 Patients with sibutramine-associated psychosis have occasionally been reported. The following report describes 2 women with sibutramine-associated psychosis who took over-the-counter herbal slimming pills that were adulterated with sibutramine.

Case Reports

Patient 1

A 19-year-old woman with a history of borderline personality disorder and eating disorder (not otherwise specified) first presented to the mental health service in June 2007 when she was admitted to a regional hospital for sudden-onset paranoid ideations and self-harming behaviour. Initially, she presented with insomnia, increased energy, and talkativeness. She had many plans about her future, and had 3 jobs at one time. She believed that she was particularly smart and attractive. She dressed inappropriately and went to nightclubs every night to meet different men. When her parents stopped her from going out at night, she developed paranoid ideas that they were jealous of her beauty and wanted to persecute her.

Systemic examination was largely unremarkable apart from a transient derangement of thyroid function, with undetectable thyroid-stimulating hormone and slightly increased triiodothyronine, which spontaneously normalised 2 weeks later. She was diagnosed with bipolar affective disorder, mania with psychotic symptoms, according to the International Classification of Diseases, 10th edition criteria. She was given quetiapine 350 mg nocte and valproate 600 mg nocte. The psychotic symptoms rapidly subsided and she was discharged after uneventful home leave. Her drug compliance was reported by her parents to be good.

In September 2007, she was admitted to Pamela Youde Nethersole Eastern Hospital for a suspected relapse of bipolar affective disorder. She presented with irritable mood, poor sleep, increased energy level, overspending, and paranoid ideations. Similar to the previous episode, she had conflicts with her parents when they tried to stop her from going out at night to date different boyfriends. She believed that her parents would use ghosts to torture her as they were jealous of her. She was again found to have transient derangement in thyroid function. She was quickly settled in hospital. On further questioning, she revealed that she had taken some over-the-counter herbal slimming pills for 3 weeks prior to this admission. She was advised to stop the pills and was discharged with quetiapine 400 mg nocte and valproate 800 mg nocte. She was then followed up by her own psychiatrist.

In April 2008, she was re-admitted to the same hospital with irritability, poor sleep, paranoid delusions, auditory and visual hallucinations, and possession disorder for the previous 3 days. She believed that she was haunted by the ghost of her ‘little brother’, who had been aborted. She could see his face and hear his voice. When her parents brought her to a temple for exorcism, she dropped to the ground, her voice changed, and she talked as if her ‘little brother’ possessed her body. Her symptoms subsided 3 days after admission, and she volunteered that she had been taking herbal slimming pills for 3 days. She then admitted that, before her first admission, she had been taking the same slimming pills for 3 months. Thyroid function test revealed a mild derangement at admission.

Her slimming pills were sent to the Toxicology Reference Laboratory for identification. The active constituents found in the pills were sibutramine, animal thyroid tissue, and phenolphthalein. The patient’s diagnosis was revised to sibutramine-associated psychosis, and she was advised to stop taking the pills. The Department of Health was notified for further investigation.

Patient 2

A 37-year-old woman was admitted in May 2008 to the Pamela Youde Nethersole Eastern Hospital. She had good past health and no personal or family history of mental illness. She had no history of alcoholism or substance abuse.

She had started taking sibutramine and another herbal slimming pill 2 years before her admission. She noted that she became more irritable soon after taking the medications, but had no major psychiatric disturbance at that time. From September 2007, she became more irritable and developed paranoid ideations that her friends played tricks on her through inviting her to join a web-based social networking website, and that they could control her mind using this platform. She became more agitated and restless over time, and developed grandiose delusions that she was a secret agent with special talents. To verify her abilities, she drove on a busy street without wearing her corrective contact lenses, which almost resulted in a traffic accident. She was then brought to the same hospital by her husband who found her unmanageable at home.

She was agitated when admitted to the ward and was noted to have disorganised speech and flights of ideas. Systemic examination, including blood tests and brain imaging, was unremarkable. Urine toxicology results showed the presence of sibutramine and its metabolites in her urine. She was provisionally diagnosed with sibutramine- associated psychosis, with a differential diagnosis of mania with psychotic symptoms. She was given risperidone 1 mg nocte and her symptoms subsided within 1 week. She was advised to stop taking slimming pills and was discharged.

The herbal slimming pill was sent for further toxicology analysis. Apart from the herbal component of Absidia coerulea extract, the pill also contained phentermine, paracetamol, oleanolic acid, caffeine, sibutramine, and N- bisdesmethyl-sibutramine. The Department of Health of Hong Kong was notified for further investigation.

Discussion

Sibutramine, an appetite-suppressing agent, is a β- phenylethylamine drug structurally similar to the psychostimulants ketamine and amphetamine. In contrast to many other phenylethylamine agents, sibutramine was not associated with abuse potential or psychiatric morbidity in pre-marketing studies.^8,9 However, as the use of the drug has gradually become more widespread, sporadic cases of sibutramine-related psychiatric conditions and abuse have been reported.¹⁰ Since the first patient with sibutramine- associated psychosis was reported in the literature in 2000,¹¹ 11 such patients have been identified in the literature (Table).^11-19 Many of the patients with sibutramine- associated psychosis had symptoms that were strikingly similar to those induced by ketamine and amphetamine of mania-like psychosis.

The mechanism of sibutramine-associated psychosis is not clear, but may be explained by its blockade of reuptake of norepinephrine, serotonin and, to a lesser extent, dopamine, which are neurotransmitters related to psychosis. Alternatively, sibutramine may stimulate release of catecholamine at the presynaptic terminal in a manner similar to amphetamine.

Although patient 1’s slimming pills also contained thyroid tissue, hyperthyroidism was not a likely cause of her psychotic symptoms. Although hyperthyroidism may present as affective psychosis, this is a rare occurrence, and is usually associated with untreated Graves’ disease or toxic nodular goitre.²⁰ Moreover, the patient’s psychotic symptoms subsided well before her thyroid function normalised. Also, her psychotic symptoms during the last admission were not typical of those caused by hyperthyroidism. Phenolphthalein is a laxative with carcinogenic properties, but is not known to cause psychotic symptoms.

Patient 2’s psychotic illness was obviously caused by stimulant use, and the most likely source was sibutramine. N-bisdesmethyl-sibutramine is an active metabolite of sibutramine, and is not registered for use in Hong Kong or the USA. The presence of phentermine in the herbal pill casts doubt on a diagnosis of sibutramine-associated psychosis, as the diagnosis might also have been mania with psychotic symptoms.²¹ However, as phentermine was only present in small amounts in the slimming pill and sibutramine was taken by the patient in large amounts, the diagnosis of sibutramine-associated psychosis was more likely.

There was an interesting phenomenon noted for patient 1. The time interval between the initiation of sibutramine and the onset of psychotic symptoms decreased from months to days with subsequent episodes, although she took similar amounts of the slimming pills before each episode. Patient 1’s brain might have become more susceptible to the effects of sibutramine, such that the time to onset of illness decreased with each subsequent episode.

These 2 patients illustrate the dangerous phenomenon of prescription medications being found in over-the- counter preparations claiming to be herbal remedies. The adulteration of over-the-counter slimming products with pharmaceutical analogues seems to be an emerging threat to the physical and mental health of the citizens of Hong Kong, with 28 patients testing positive for such products between September 2004 and December 2006.¹³ This issue has been receiving attention in various overseas countries. Medsafe, the Ministry of Health’s medicines and medical devices regulator in New Zealand, has prosecuted several companies claiming to sell natural herbal products in the past few years, with a remark that “consumers simply can’t be assured about the safety or quality of the ‘natural’ health product they are purchasing”.²² The FDA also had a large- scale nationwide recall of tainted weight-loss pills in 2008, followed by additional enforcement steps.²³

As well as unlicensed use of prescription medications, manufacturers have added banned substances such as phenolphthalein and phentermine to the slimming pills taken by the 2 patients reported here to compound the slimming effect. While the government must act to enforce the law relating to such criminal acts, physicians should also be vigilant to the possibility of non-prescribed drug use when patients present with suspicious symptoms while they were taking herbal remedies.

Although the exact doses of sibutramine found in the herbal remedies in this report were not available, it has been postulated that a higher-than-recommended daily dose of sibutramine use made some individuals more susceptible to the development of psychotic symptoms.^17,18 Unfortunately, the technology needed for a quantitative study is still underdeveloped in Hong Kong, and refinement of the technology is needed before such a study can be conducted.

In conclusion, sibutramine is associated with an array of neuropsychiatric complications, and these 2 patients had florid psychotic symptoms. Further studies are needed to explore this aspect of the side-effects of sibutramine and to establish any causal relationship between sibutramine and psychosis. For the time being, meticulous care should be taken when sibutramine is prescribed for patients with psychosis, and to avoid using the drug in patients with a history of psychotic illness. For clinicians encountering new patients with manic psychosis, it is worthwhile enquiring about recent use of slimming agents, including allegedly herbal products. Such simple questioning may have profound effects on the diagnosis, management, and prognosis for these patients.

Acknowledgement

We would like to express our gratitude to the staff of the Toxicology Reference Laboratory, Princess Margaret Hospital, Hong Kong, for their input in the management of the patients.

References

1. Global Database on Body Mass Index: an interactive surveillance tool for monitoring nutrition transition. World Health Organization website: http://www.who.int/bmi/index.jsp Accessed 19 Apr 2010.
2. Arterburn DE, Crane PK, Veenstra DL. The efficacy and safety of sibutramine for weight loss: a systematic review. Arch Intern Med 2004;164:994-1003.
3. Henderson DC, Copeland PM, Daley TB, Borba CP, Cather C, Nguyen DD, et al. A double-blind, placebo-controlled trial of sibutramine for olanzapine-associated weight gain. Am J Psychiatry 2005;162:954-62.
4. Werneke U, Taylor D, Sanders TA. Options for pharmacological management of obesity in patients treated with atypical antipsychotics. Int Clin Psychopharmacol 2002;17:145-60.
5. Cordeiro Q, Vallada H. Sibutramine-induced mania episode in a bipolar patient. Int J Neuropsychopharmacol 2002;5:283-4.
6. Binkley K, Knowles SR. Sibutramine and panic attacks. Am J Psychiatry 2002;159:1793-4.
7. Benazzi F. Organic hypomania secondary to sibutramine-citalopram interaction. J Clin Psychiatry 2002;63:165.
8. Heal DJ, Frankland AT, Gosden J, Hutchins LJ, Prow MR, Luscombe GP, et al. A comparison of the effects of sibutramine hydrochloride, bupropion and methamphetamine on dopaminergic function: evidence that dopamine is not a pharmacological target for sibutramine. Psychopharmacology (Berl) 1992;107:303-9.
9. Cole JO, Levin A, Beake B, Kaiser PE, Scheinbaum ML. Sibutramine: a new weight loss agent without evidence of the abuse potential associated with amphetamines. J Clin Psychopharmacol 1998;18:231- 6.
10. Arfken CL, Cicero TJ. Postmarketing surveillance for drug abuse. Drug Alcohol Depend 2003;70(3 Suppl):S97-105.
11. Taflinski T, Chojnacka J. Sibutramine-associated psychotic episode. Am J Psychiatry 2000;157:2057-8.
12. Fernández P, Peiró AM. A sibutramine-induced delusional disorder relapse. J Neuropsychiatry Clin Neurosci 2007;19:88-9.
13. Yuen YP, Lai CK, Poon WT, Ng SW, Chan AY, Mak TW. Adulteration of over-the-counter slimming products with pharmaceutical analogue — an emerging threat. Hong Kong Med J 2007;13:216-20.
14. Rosenbohm A, Bux CJ, Connemann BJ. Psychosis with sibutramine. J Clin Psychopharmacol 2007;27:315-7.
15. Litvan L, Alcoverro-Fortuny O. Sibutramine and psychosis. J Clin Psychopharmacol 2007;27:726-7.
16. Gazdag G, Szabó Z. Sibutramine-associated psychosis (case report). Neuropsychopharmacol Hung 2008;10:107-10.
17. Dogangun B, Bolat N, Rustamov I, Kayaalp L. Sibutramine-induced psychotic episode in an adolescent. J Psychosom Res 2008;65:205-6.
18. Lee J, Teoh T, Lee TS. Catatonia and psychosis associated with sibutramine: a case report and pathophysiologic correlation. J Psychosom Res 2008;64:107-9.
19. Müller D, Weinmann W, Hermanns-Clausen M. Chinese slimming capsules containing sibutramine sold over the Internet. Dtsch Arztebl Int 2009;106:218-22.
20. Brownlie BE, Rae AM, Walshe JW, Wells JE. Psychoses associated with thyrotoxicosis — ‘thyrotoxic psychosis’. A report of 18 cases, with statistical analysis of incidence. Eur J Endocrinol 2000;142:438- 44.
21. Raison CL, Klein HM. Psychotic mania associated with fenfluramine and phentermine use. Am J Psychiatry 1997;154:711.
22. New Zealand Medicines and Medical Devices Safety Authority. Health warning issued under Section 98 of the Medicines Act 1981 — Chinese Products. Medsafe website: http://www.medsafe.govt.nz/hot/media/media2008.asp. Accessed 19 Jun 2010.
23. FDA expands warning to consumers about tainted weight loss pills. List increases from 28 to 69 products; Agency seeking recalls. US Food and Drug Administration website: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2008/ucm116998.htm. Accessed 19 Jun 2010.