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pISSN 1738-1088 / eISSN 2093-4327 Copyrightⓒ 2010, Korean College of Neuropsychopharmacology Case Report Clinical Psychopharmacology and Neuroscience 2010;8(3):170-174 Appetite Suppressor Induced Psychosis Soon-Jai Kwon2, Jong-Chul Yang1,2, Tae-Won Park1,2, Young-Chul Chung1,2 1 Department of Psychiatry, Chonbuk National University Medical School and Institute for Medical Sciences, 2Department of Psychiatry, Chonbuk National University Hospital and Research Institute of Clinical Medicine, Jeonju, Korea Amphetamine analogues are widely prescribed for the treatment of obesity; their therapeutic mechanisms are appetite suppression and sympathomimetic effects. However, due to their structural similarities to amphetamine, patients who take appetite suppressants may experience psychotic symptoms such as hallucinations or paranoid mental states. We report on a patient who had been taking the appetite suppressant, phentermine for 2 years and experienced a sudden onset of psychotic symptoms. She had no past history of psychiatric treatment and no familial history of psychiatric illness. She experienced continuous auditory hallucinations and paranoid delusions, without disordered thinking, and significant negative symptoms. She stopped taking medication immediately following the onset of symptoms, which lasted for about 10 days thereafter. This case illustrates that phentermine, the most commonly prescribed appetite suppressant, can cause psychotic symptoms; warnings about these possible side effects should be made explicit to all those considering the use of appetite suppressants. KEY WORDS: Amphetamine analogue; Diet pill; Phentermine; Psychosis. INTRODUCTION cuits involved in appetite, the importance of pharmacotherapy is increasing as an effective adjunctive measure, and anti-obesity drugs are being widely prescribed all over the world, including Korea. Anti-obesity drugs work by acting on one of two major mechanisms, central and peripheral. The drugs with a central mechanism control appetite by affecting brain neurotransmitters such as norepinephrine and serotonin. On the other hand, the drugs that act on peripheral pathways influence digestion or absorption of macronutrients and sometimes modify intermediary metabolic processes, like lipolysis or lipogenesis.2) Amphetamine analogues, represented by phentermine, phendimetrazine and diethylpropion, are centrally acting antiobesity drugs and have been widely prescribed since they were approved by the FDA in 1960, due to their outstanding antiobesity effect 2,3) and minimal side effects. Table 1 summarizes the amphetamine analogues commonly prescribed in Korea. Since the approval of amphetamine analogues by the FDA, several cases of psychotic symptoms induced by amphetamine analogues have been reported.4-8) In Asia, two cases have been reported of psychotic symptoms 9,10) brought on by amphetamine analogues. Here we report on a 35 year-old woman who experienced psychotic symptoms after taking phentermine for 2 years. Obesity has become a global issue due to its potent danger to public health; it is known to have a causal effect on metabolic syndrome as well as cardiovascular diseases. There has been a marked increase in levels of obesity amongst people in Korea, accompanied by rapid socioeconomic development and lifestyle modification. One large cohort study performed in Korea indicated that the mean BMI had increased by 0.8 kg/m2 in men and by 0.3 2 kg/m in women between 1992 and 2000. The BMI change showed the steepest slope amongst the youngest men (0.2 kg/m2 per year).1) Thus, the treatment of obesity has become a contemporary social issue in Korea. Lifestyle modifications that balance energy intake and expenditure are thought to be fundamental to the treatment of obesity. However, in some people, lifestyle modification is hard to achieve and it is not always thought to be a sufficient means of treating the problem. Due to recent major advances in our knowledge of the neural cirReceived: August 20, 2010 / Revised: November 4, 2010 Accepted: December 2, 2010 Address for correspondence: Young-Chul Chung, MD, PhD Department of Psychiatry, Research Institute of Clinical Medicine, Chonbuk National University Hospital, Geumam-dong, Jeonju 561-712, Korea Tel: +82-63-250-2185, Fax: +82-63-275-3157 E-mail: [email protected] 170 Appetite Suppressor Induced Psychosis 171 Table 1. Amphetamine analogues prescribed as antiobesity drug in Korea Trade name Panbesy SR Phentermine Kukje Nobse Dietamin Retis Metamax Vitupen Sinsphen Adipex Weltmine Fastin Penmin Phenkini Pentmin Primin Lofat Dietrin Adpen Phendirazine Phendithin Fenslim Phentin Phenhold Dipion Wellpion Tenuate Dosage (mg) Main ingredient 30 37.5 37.5 37.5 37.5 37.5 37.5 37.5 37.5 37.5 37.5 37.5 37.5 37.5 37.5 37.5 35 35 35 35 35 35 35 25 25 25 Phentermine hydrochloride Phentermine hydrochloride Phentermine hydrochloride Phentermine hydrochloride Phentermine hydrochloride Phentermine hydrochloride Phentermine hydrochloride Phentermine hydrochloride Phentermine hydrochloride Phentermine hydrochloride Phentermine hydrochloride Phentermine hydrochloride Phentermine hydrochloride Phentermine hydrochloride Phentermine hydrochloride Phentermine hydrochloride Phendimetrazine tartrate Phendimetrazine tartrate Phendimetrazine tartrate Phendimetrazine tartrate Phendimetrazine tartrate Phendimetrazine tartrate Phendimetrazine tartrate Diethylpropion hydrochloride Diethylpropion hydrochloride Diethylpropion hydrochloride CASE The patient was a 35 year-old woman who had worked in a bar in Gang-won province for the past eighteen months. She had divorced her husband 8 years ago, following an infidelity. She had no psychiatric treatment history and no family history of psychiatric disease. She was polite, with good manners, and usually got on well with her family and friends. Before she married, she had worked as an aerobics instructor. According to her family, she was sometimes overly concerned about her body shape, although she did not appear to be overweight. In 2007, she started taking 37.5 mg of phentermine, prescribed by her gynecologist, to control her body weight. Her gynecologist advised her not to take the pill for a period of time after 12 consecutive weeks of medication. Up until 2009, she had complied with the doctor’s suggestion by having a 1-week wash-out period every 12 weeks. However, from January 2009 she started taking the medicine continuously, without wash- out periods. Although she had not experienced any side effects previously, other than mild insomnia, she started to feel nervous during the day and felt dysphoric more easily. In August 2009, she inadvertently discovered that her boss’s boyfriend was Manufacturer Dreampharma Kukje Daewha Daewoong JRP Guju Boram Cho-A Kwangdong Seoul Daehan newpharm. Youngil Daewon Doctors mediline Dreampharma Sudo Youngil Korea Daewon Doctors mediline Hana Daehan newpharm. Boram Doctors mediline Huons Dreampharma sleeping with another female employee. For the next couple of weeks she felt troubled about whether or not to tell this to her boss. On August 16, just after getting out of bed in the morning, she suddenly heard voices, although she was alone. The voices sounded like her boss and her boss's boyfriend whispering and they continued all day long. The voices were usually talking to each other, commenting on her every behavior and sometimes blaming her directly for her unfaithfulness. She searched her room for concealed microphones or video cameras but found none. She decided to walk out of her workplace, but the voices kept talking to her and made her more agitated as she drove home to Iksan. After her psychotic symptoms occurred, she stopped taking phentermine. Even after she got home, the voices continued and made her more anxious and agitated. She could not sleep for more than 2∼3 hours. She was involuntarily admitted to Chonbuk National University hospital by her family. When admitted, she appeared thin with a BMI of 20.3 2 kg/m . She seemed alert but quite confused and agitated. She complained about severe anxiety and irritation but said that her auditory hallucinations had stopped on the day before the admission. However, she continued to display a persecutory and supervisory delusion that her boss 172 S.J. Kwon, et al. and her boss’s boyfriend were watching her using a concealed microphone and video camera. She believed that they were watching her because she knew too much about their private issues. She had not taken her appetite suppressant since August 16, 5 days before admission. On admission, her scores on the Positive and Negative Synd11) rome Scale (PANSS) and Beck Depression Inventory Depression Inventory (BDI)12) and Mini-Mental State Examination (MMSE)13) were 99, 17 and 30 respectively. Results of physical examination, hematological tests including syphilis screening test, and urinalysis were normal. In the special urinalysis test for narcotics, no positive results for amphetamine, methamine, heroin or cannabis were reported. Although she had not had any personal or familial history of possible neurological disease or head trauma, brain MRI was recommended to rule out neurological or organic causes. However, the patient and her family refused a brain imaging study for economic reasons. Although she was not showing any signs of abnormal perception, including auditory hallucination, she had a persistent persecutory and supervisory delusion that somebody had visited her room and tried to set up some kind of monitoring device. Because her psychotic symptoms were related to the use of appetite suppressant, we prescribed benzodiazepine. By the 4th day of admission, her delusion had subsided substantially. She felt less suspicious and her feeling of being watched was reduced. She was moved to an open ward and showed no further delusional symptoms, but watched TV in the recreational room or chatted with other patients. However, she sometimes complained of anxiety without any particular cause. On the 15th day of admission, the patient and her family demanded discharge. Just before the discharge, we put her on 5 mg/day of aripiprazole to prevent possible relapse. Following discharge, she quickly returned to her normal life, helping her family. Although she sometimes had transient insomnia or complained about hypersensitivity to noise, no evidence of recurrence of psychotic symptoms, including auditory hallucinations or delusions, was observed. She visited the outpatient clinic twice, after which she discontinued her visits. DISCUSSION Amphetamine analogues often cause sweating, dry mouth, blurred vision, agitation and hyperactivity. Although it is rare, some cases have been reported in which appetite suppressants consisting of amphetamine analogue have caused depressed mood, delirium and even psychotic 14) symptoms such as hallucinations and delusions. The possible mechanisms are related to the fact that they share a similar molecular structure to phenethylamine, the major building block of amphetamine, and modulate release and reuptake of dopamine. Compared to amphetamine, it is commonly accepted that amphetamine analogues work on norepinephrine more specifically than dopamine and, consequently, have less potential for inducing abusive usage or psychotic symptoms. However, it must be noted that a few studies have suggested its strong action on dopamine. For example, it has been reported that phentermine caused a marked elevation of extracellular dopamine 15) levels in rat nucleus accumbens. It has also been demonstrated that injections of phentermine 2 ml/kg and 5 ml/kg increased brain dopamine concentrations by 27% and 16) 85% respectively. Table 2 summarizes reported cases of psychotic symptoms induced by amphetamine analogue. Most of the cases were young women without any psychiatric treatment history or family history of psychiatric illness. All of them had taken amphetamine or amphetamine analogue for several months. The most frequent psychotic symptoms were auditory or visual hallucinations and delusions of persecution or supervision, which developed abruptly. Some cases showed mood symptoms such as depressed mood or anhedonia and, in rare cases, disorientation. Usually psychotic symptoms improved several days to weeks after discontinuing amphetamine analogue usage or after taking low doses of antipsychotics. Generally, it is difficult to distinguish psychotic symptoms induced by amphetamine analogue from those of schizophrenia. However, in most cases of amphetamine-induced psychosis, patients' premorbid social functions were normal and the psychotic symptoms subsided completely within 4 weeks of discontinuing amphetamine analogues and starting low doses of antipsychotics. This said, a few cases have progressed to chronic psychotic disorder, although the causal relationship with amphetamine analogues is unclear.17) Importantly, most cases did not show associative loosening or social withdrawal symptoms, both hallmarks of schizophrenia.18) Our case also showed no associative loosening and her premorbid social functions were well maintained. Her psychotic symptoms only lasted for 10 days and rapidly remitted a week after discontinuing phentermine, without the use of antipsychotics. Most of the reported cases showing psychotic symptoms had taken more than the maximum dose of amphetamine analogue.6,7,9) In some cases, psychotic symptoms appeared after an abrupt increase in dosage of amphetamine analo- Appetite Suppressor Induced Psychosis 173 Table 2. Summary of case reports on amphetamine analogue-induced psychosis Author Age/Sex Amphetamine analogues Dosage/Periods Past psychiatric history Symptoms 4) 33/F Diethylpropion Therapeutic dose None Carney4) 40/F Diethylpropion Therapeutic dose None Brooke et 5) al 42/F Diethylpropion Therapeutic dose 1 year None Brooke et al 5) Devan6) 35/F Diethylpropion 30 mg×25 cap Bulimia nervosa 22/F Phentermine 30 mg for 9 months 90 mg for 3 months None Cleare7) 32/F Phentermine 30∼60 mg for 4 months None Auditory hallucination, delusion of control Zimmer et al 8) 42/F Phentermine/ Fenfluramine Bipolar disorder Depression, anhedonia, fatigue, insomnia 31/F Phendimetrazine Phentermine 30 mg Fenfluramine 60 mg for 4 days 240 mg for 2 years 720 mg for 1 year None Auditory hallucination, delusion of reference, depression Carney Kim et al 9) gue.7,9) Our case had also been taking phentermine 37.5 mg/day continuously for over 7 months. Several features of our case, described above, lead us to conclude that her diagnosis was psychotic disorder due to abuse of amphetamine analogue. There are several points of contention to be noted. Even though the urine test for narcotics was normal, it was not a specific test for phentermine. Moreover, the timing of the test was too late, given that the half-life of phentermine is 16 to 31 hours. In addition, this case could be considered as one of brief psychotic disorder, because she had been under considerable stress at the time. Prescription of aripiprazole during the outpatient follow-up period was another confounding factor, making it hard to know whether the remission of her symptoms was due to stopping amphetamine analogue or the effect of antipsychotics. A re-challenge test with phentermine would have been the most satisfactory way to prove a definite diagnosis. However, this was not feasible for ethical reasons. Prescription rates for appetite suppressants are ever increasing. However, careful consideration of their possible psychiatric side effects is often neglected. This case illustrates the sudden onset of psychotic symptoms after Auditory hallucination, delusion of persecution, idea of reference, delusion of thought insertion Personality change, delusion of persecution, depression Auditory/visual hallucination, idea of reference, delusion of persecution Auditory hallucination, delusion of persecution Auditory hallucination, delusion of persecution Treatment/Prognosis Relieved in 3 weeks with chlorpromazine, no recurrence No recurrence in 6 months with chlorpromazine No recurrence in 6 months with chlorpromzaine Relieved in 3 days with thioridazine Relieved in 15 days with trifluoperazine, psychotic symptom recurred in 1 week with phetermine 90 mg Relieved in 10 days with haloperidol, no recurrence Relieved in 6 weeks with tranylcypromine Spontaneously relieved in 25 days continuous use of phentermine and rapid remission following treatment. Therefore, when prescribing amphetamine analogue to treat obesity, clinicians should warn about possible psychiatric symptoms as side effects and perform careful assessments of patients’ psychiatric treatment histories or vulnerabilities, if indicated. Further studies are needed to establish a clear causal relationship between appetite suppressants and psychotic symptoms using more specific urine tests and long-term follow up. REFERENCES 1. Kwon JW, Song YM, Sung J, Sohn Y, Cho SI. Varying patterns of BMI increase in sex and birth cohorts of Korean adults. Obesity 2007;15;2735-2752. 2. Bray GA. A concise review on the therapeutics of obesity. Nutrition 2000;16:953-960. 3. Hendricks EJ, Rothman RB, Greenway FL. How physician obesity specialists use drugs to treat obesity. Obesity 2009;17:1730-1735. 4. Carney MW. Diethylpropion and psychosis. Clin Neuropharmacol 1988;11:183-188. 5. Brooke D, Kerwin R, Lloyd K. Diethylpropion hydrochloride-induced psychosis. 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