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Harish K. Malhotra, MD, Nancy B. Isenberg, MD, and Louis Barash, PhD

Primary Psychiatry. 2003;10(8):74-76


Dr. Malhotra is clinical assistant professor of psychiatry at the University of Medicine and Dentistry of New Jersey (UMDNJ) in Newark, NJ, and an attending in the Department of Psychiatry at Overlook Hospital in Summit, New Jersey. Dr. Isenberg is a specialist in behavioral neurology and neuropsychiatry in the New Jersey Neuroscience Institute at JFK Medical Center in Edison. Dr. Barash is co-principal investigator in the Department of Microbiology and Microbial Genetics at UMDNJ.

Disclosure: Dr. Malhotra is on the speaker’s bureau of AstraZeneca, Eli Lilly, and Bristol-Myers Squibb; Dr. Isenberg is on the speaker’s bureau of Janssen, Novartis, and Pfizer.

Please direct all correspondence to: Harish K. Malhotra, MD, Department of Psychiatry, Overlook Hospital, 33 Overlook Rd, Suite 212, Summit, NJ 07901; Tel: 908-273-6164; Fax: 908-277-1439; E-mail:


Focus Points

It is recommended that whenever there are associated soft neurological symptoms and signs in a case of psychosis, medical causes should be considered in the etiology of the presenting psychosis.

Longitudinal progression of a psychosis can uncover previously hidden aspects of the disease.

Neurodegenerative disorders may become evident as psychiatric syndromes at different stages of life.



Niemann-Pick disease is a neurometabolic genetic disorder. Types A and B reflect a primary and severe acid sphingomyelinase (ASM) deficiency. The ASM enzyme is ordinarily found in lysosomes and is required to metabolize the lipid, sphingomyelin. If ASM is absent or not functioning properly, sphingomyelin cannot be metabolized properly and is accumulated within the cell, eventually causing cell death and the malfunction of major organ systems. Niemann-Pick type A (neurovisceral) is a severe neurological disease in infants, which generally leads to death by 2–3 years of age. Infants with Niemann-Pick disease type A have extremely low levels of ASM (generally <5% of normal). Niemann-Pick disease type B (visceral) generally has little or no neurological involvement and patients may survive into adulthood. Type B has higher levels of ASM (perhaps 10% to 60% of normal). Type A and B are both diagnosed by measuring the ASM activity in white blood cells.

Niemann-Pick disease type C (NPC) is a lipid storage disease that can present in infants, children, or adults. The classic presentation occurs in middle to late childhood with the insidious onset of ataxia, vertical supranuclear gaze palsy (VSGP), dementia, and liver and lung failure. Dystonia and seizures are common. Dysarthria and dysphagia become disabling, making oral feeding impossible. Types C and D are characterized by secondary and variable sphingomyelinase alterations.1-8 The diagnosis of NPC is assay for the deficiency, which shows impaired ability of cultured fibroblasts to esterify exogenously supplied cholesterol, and positive filipin staining. Types C1 and D are indistinguishable except for the occurrence of type D in patients of Nova Scotian Acadian ancestry.

Symptoms mimicking schizophrenia can present in many conditions.4 We describe a patient who carried a diagnosis of schizophrenia for 14 years requiring psychiatric hospitalizations. He was subsequently diagnosed with NPC. The characteristic features of adult-onset NPC and the obstacles to early diagnosis are presented here.


Case Study

Psychiatric History

J.S., a single caucasian male, was 32 years of age in 1999 when his case was reviewed. His psychiatric history dated back to 18 years of age. J.S. had been diagnosed as learning disabled and perceptually impaired, and had completed high school through special classes. At the onset of his illness, J.S. believed that people were changing into bears, dancing around him, and trying to scare him. From July 1996 through August 1997, he was hospitalized for psychiatric treatment three times. During those hospitalizations J.S. presented with bruises on his face, mumbling, and an inability to explain what happened to him. J.S. was casually attired, disheveled, nonspontaneous, incoherent, loud, and threatening. His speech was described as irrelevant. His mood was anxious and his affect was constricted. His behavior was destructive and required seclusion. J.S. showed grossly impaired judgment, loose association, tangential thinking, and no insight. He was unable to give goal-oriented answers. J.S. admitted to “buzzing noises” in his ears. His sensorium was clear, but he was unable to name recent or past dates. He showed no signs of suicidal or homicidal ideas.

During another hospital admission J.S. was described as having auditory hallucinations, paranoid delusions, low frustration toleration, intrusiveness, poor speech communication, and difficulty following directions. J.S. was evaluated by a speech therapist and was found to have dysarthric speech. During that hospitalization, J.S. was diagnosed as having schizophrenia chronic undifferentiated type, polysubstance dependence, borderline intellectual functioning, phonological disorder, and mixed expressive language disorder.


Personal and Family History

Family history revealed that J.S.’s father was a 64-year-old electrician and his mother was a 58-year-old secretary who had been adopted. His mother suffered from a history of alcoholism, and the paternal side of family had a history of mental illness.

Personal history revealed that J.S. was a full-term baby, delivered by induction of labor. He had a poor APGAR score (measure of respiration, heart action, muscle tone, skin color, and reflexe adequacy in a newborn) and spoke and walked late. J.S. had suffered some traumatic experiences: he had been raped in 1995 (the rapist was apprehended and convicted). In addition, he had been a victim of a bus accident from which he sustained a head injury, but details were not available. He had a history of arrest for drug possession. He worked in Union County Vocational Rehabilitation as a cook and was on supplemental social security income. He lived in a group home.


Clinical Presentation

The first author (H.K.M.) had been treating J.S. for the last 2 years in a day program for the chronically mentally ill. In January 1999, H.K.M. noted that the patient complained of repeated falls, difficulty with balance, and difficulty controlling eye movements. Hence a referral was made to the second author (N.B.I.), a neurologist.

The patient was examined by N.B.I. on February 10, 1999, who noted the patient had a history of poor balance and was prone to falling, especially when attempting to climb stairs. Moreover, his balance had worsened over the last 2 years. J.S. had falling incidents almost daily and had difficulty rising from a chair and climbing or descending stairs. J.S. denied light-headedness, vertigo, akathisia, stiffness, dystonia, motor weakness, or auditory/visual hallucinations in the interval prior to the examinations. He also denied having any recent change in his speech, but said that he had problems with slurring of his speech for as long as he could remember.

N.B.I. noted that J.S. was taking divalproex 250 mg PO QID, thiothixene 5 mg QAM and 10 mg QHS, and benztropine 4 mg/day in divided doses.


Neurological Examinations

Neurological examinations revealed that J.S. was sitting comfortably in the chair without adventitious movements. His blood pressure was 100/70 mm Hg (mercury) when seated, with a pulse of 70, which was regular. He was alert. J.S.’s attention and concentration were easily distracted, but he was able to repeat six digits forward and four digits backward. When asked to say the months backward, he repeated them forward. J.S. was unable to spell “world” backward. On memory functions, J.S. was oriented to self, time, and place. He was able to immediately encode three words on the first try, and to recall three words at 5–10 minutes without any cues. His fund of knowledge was poor and he was unable to name the current president. His recollection of the king’s story (a one-paragraph story used to assess comprehension of narrative) was with poor details and lack of assimilation of the gestalt. His visual spatial memory showed that he was able to encode three objects on the first try and recall all three at 5 and 10 minutes as well. He had very good recall of lurid details of a movie he had seen the previous evening.

Language functioning showed that spontaneous speech was fluent without paraphasic errors, but with prominent lingual dysarthria. J.S. was able to follow simple commands (left/right, multi-step, and cross mid-line). Repetition was intact, as was naming both high- and low-frequency words. Reading was intact. When asked to write any sentence, he wrote, “I am smart.” Calculations were impaired with mistakes on simple subtractions, as well as making changes.

J.S. had no evidence of dyspraxia or apraxia. Visuospatial construction showed that pentagons were well constructed, while a cube gave some difficulty. Frontal executive function examination showed that his clock drawing demonstrated very poor organization, and writing of consecutive numbers up to fifteen. J.S. was able to make the clock hands say 10 minutes after two o’clock without difficulty.

Ramparts demonstrated stimulus-bound behavior and J.S.’s multiple loops demonstrated closing in, as well as perseverance. He was unable to learn the Luria hand sequence (frontal lobe evaluation where examiner asks patient to repeat the hand sequence fist, chop, flat) in less than five repetitions, and was unable to perform go/no/go (frontal lobe evaluation where examiner asks patient “When I tap my hand once, you tap twice; when I tap twice, do not tap at all”). Fluency was impaired for both semantic, as well as phonemic cues. Similarities were concrete. J.S. also had slowness noted on execution of movements and perseverance.

On examination of his cranial nerves, J.S.’s pupils were equally round and reactive to light and accommodation. His discs were bilaterally sharp. Visual fields were full. J.S. had a vertical supranuclear gaze palsy, which was most pronounced on downward gaze. He had absent optokinetic nystagmus in the vertical direction with a symmetrical intact vestibulo-ocular response. There was slight hypomimia with a symmetrical slow smile. The remainder of his cranial nerves, including hearing, was intact. No orobuccal or lingual dyskinesia were noted. Motor examination showed normal bulk, mildly increased tone with slight rigidity, and cog-wheeling bilaterally. Rapid alternating movements were clumsy and slowed, more on the right than on the left.

Sensory examination showed that J.S. was intact to all four modalities, including joint position sense, vibration, pinprick, and light touch. No axial rigidity was noted. Finger-to-nose and heel-to-shin was intact and without evidence of dysmetria. His reflexes were three plus throughout, with toes upgoing bilaterally. Glabellar and snout reflexes were present. J.S. had a wide-based gait. He was able to arise from a chair only with prominent retropulsion. He was able to walk on his toes and heels, exhibiting mildly reduced arm swing. The Romberg test was negative although he had a very prominent retropulsion. (Romberg test: patient stands with eyes open and then closed with feet approximated; sign is positive if closing eyes increases unsteadiness, indicating loss of proprioceptive control).

Magnetic resonance imaging was reviewed with a neuroradiologist and was thought to be most consistent with perinatal insult with mildly increased signal in T-2 in the periventricular region. Laboratory values were notable for normal ceruloplasmin, copper, complete blood count, SMAC (basic chemistry profile), vitamin B12 level, hexoscamidase-A levels and serum acanthocytes. Laboratory data was noted for a cholesterol count of 144, which was low. Vitamin E (α-tocopherol portion) was slightly low as well. In addition, fibroblast culture was notable for an abnormal cholesterol esterification, which was depressed by over 20%, confirming the diagnosis of NPC (Figures 1, 2, and 3).


J.S. had a constellation of signs and symptoms of ataxia and VSGP, which may be suggestive of NPC. Other possible causes of VSGP and dysarthria supranuclear gaze palsy include spinocerebellar degeneration, progressive supranuclear gaze palsy, ataxia, Huntington’s disease, and Parkinson’s disease, all of which were unlikely to be present in J.S. given his absence of the other commonly associated signs. A β-lipoproteinemia or vitamin E deficiency is also unlikely to be responsible for the symptoms, due to the absence of peripheral neuropathy. Although vitamin B12 deficiency could also present with psychosis, the absence of weakness, anterior and posterior columnar dysfunction, or peripheral neuropathy, further made this diagnosis unlikely as well. A blood smear for acanthocytes for β-lipoproteinemia was negative.

Cholesterol esterification and fibroblast assays may be abnormal and low in familial hypercholesterolemia, hyperlipidemia type 2, Wolman’s disease, and mucolipidosis type 2 and 3. The patient’s low peripheral cholesterol, however, was inconsistent with the initial two diagnoses, namely, hyperlipidemia type 2 and 3, and Wolman’s disease. Also, J.S. did not have any of the phenotypic features of mucolipidosis, which were disorders present in early childhood.

His life-long diagnoses of schizophrenia chronic undifferentiated type, borderline intellectual functioning, phonological disorder, and mixed expressive language disorder all could be explained by the slowly developing neurological disorder NPC which took 14 years to become severe enough to be correctly diagnosed. The new diagnosis of psychiatric disorder due to medical condition of NPC would not change the pharmacologic management but would help guide the future planning.

The final impression was that this 32-year-old gentleman, with a prior diagnosis of schizophrenia, showed disinhibition, frontal executive dysfunction, dementia, supranuclear vertical gaze palsy, dysarthria, and ataxia. All of them were slowly progressive with fibroblast culture abnormal for cholesterol esterification. The clinical picture was consistent with the diagnosis of NPC. It is recommended that whenever there are associated soft neurological symptoms and signs in a case of psychosis, medical causes should be considered in the etiology of the presenting psychosis.  PP



1. Shulman LM, Nobel DJ, Weiner WJ. Psychosis as the initial manifestation of adult-onset Niemann-Pick Disease Type C. Neurology. 1995;45:1739-1749.

2. Fox JT, Jr, Kane FJ, Jr. Niemann-Picks disease manifesting as schizophrenia. Dis Nerv Sys. 1967;28:194.

3. Cummings JL. Organic delusions: phenomenology, anatomical correlations and review. Br J Psychiatry. 1985;146:184-197.

4. Lanska DJ, Lanska MJ. Niemann-Picks disease type C in a middle-aged woman. Neurology. 1993;43:1435-1436.

5. Dunn HC, Sweeney VP. Progressive supranuclear palsy in an unusual juvenile variant of Niemann-Picks disease. Neurology. 1971;21:442.

6. Cobcroft R. Images in haematology: type C Niemann-Pick disease. Br J Haematology. 2000;111:718.

7. Imrie J. Isolated splenomegaly as the presenting feature of Niemann-Pick disease type C. Arch Dis Child. 2001;84:427-429.

8. Vanier MT. Lipid changes in Niemann-Pick disease type C brain: personal experiences and review of the literature. Neurochemical Res.1999;24:481-489.


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Jonathan M. Metzl, MD, PhD, and Michelle Riba, MD

Primary Psychiatry. 2008;10(7):45-48


Dr. Chemali is director of the Neuropsychiatry Brigham Behavioral Neurology Group Memory Disorders Unit at Brigham and Women’s Hospital, Harvard Medical School, in Boston, Massachusetts.

Disclosure: The author reports no financial, academic, or other support for this work.

Please direct all correspondence to: Zeina Chemali, MD, Brigham and Women’s Hospital, Harvard Medical School, 221 Longwood Ave, Boston, MA 02115; Tel: 617-732-8060; Fax: 617-738-9122; E-mail:


Focus Points

This report of two case studies in elderly women represents the first published incidence of increased libido and hypersexuality associated with donepezil.

Physicians should be aware of the possibility of this side effect, which was distressing to the elderly patients in the presented cases.

A possible neurochemical mechanism of action of cholinesterase inhibitors leading to increased sexual arousal is presented.


Can donepezil affect the sexual response in the elderly population? Donezepil, an acetylcholine inhibitor, is commonly used in neuropsychiatry for the treatment of cognitive decline and dementia. This report addresses two elderly female patients who had an increase in their libido and experienced hypersexuality after starting donepezil treatment. Potential explanations for this previously unreported association are discussed.



Donepezil (Aricept) is a centrally active, selective piperidine acetylcholinesterase (AchE) inhibitor with no effect on butyrylcholinesterase (BuChE). Its action on AchE inhibition is reversible.1 The drug is given orally in the dose of 5–10 mg OD. Donepezil exhibits linear pharmacokinetics and reaches its peak plasma level within 3–4 hours after ingestion of the drug. It is metabolized in the liver via cytochrome P450 (CYP) and is preferentially excreted by the kidneys. The half-life of donepezil is 60 hours but can extend up to 100 hours in elderly subjects.

Donepezil is relatively well tolerated. Predominant adverse effects are nausea, vomiting, diarrhea, muscle cramps, insomnia, fatigue, and anorexia. Neurological side effects include dizziness, vertigo, ataxia, restlessness, paresthesia, tremor, seizures, drowsiness, extrapyramidal symptoms, and abnormal crying.2 The causes of these signs are unclear, although they are usually attributed to the drug’s direct cholinergic effects. A few cases of behavioral changes have been reported with donepezil.3-5 They include, but are not limited to, delirium, delusions, irritability, aggression, nervousness, paranoia, and abnormal dreams.

There is no report on the effect of donepezil on sexuality. This report describes two cases of increased libido and hypersexuality experienced by female patients 10 days after starting donepezil treatment targeting their cognitive symptoms.


Case 1: Mrs. N

Mrs. N, an 81-year-old right-handed woman, complained of cognitive changes that had been occurring over the last 3 years. Symptoms involved forgetfulness of names and dates of events, as well as word-finding difficulties. These symptoms later progressed to difficulty following conversations and balancing her checkbook. She also had a history of depression and anxiety treated with fluoxetine. She stopped taking fluoxetine a few months later, as she believed it exacerbated her cognitive symptoms. Later, she was placed on a lower dose of the drug without much success. It was then stopped. Her work-up lead to the diagnosis of mild mixed dementia. She was placed on donepezil 5 mg QOD, which was later increased to 5 mg/day. Her other medications included warfarin sodium crystalline, diltiazem, alendronate sodium, levothyroxine, simvastatin, and a multivitamin.

She noticed an increase in her sexual libido 1 week after beginning the regular dose of donepezil 5 mg/day. She described the feeling as overwhelming. She described obsessive sexual thoughts and the urge to have sex many times during the day. She felt very embarrassed and asked to stop donepezil. An attempt to decrease the donepezil dose to alleviate the symptoms while continuing the medication, was unsuccessful. She stopped taking donepezil and her symptoms abated a few days later. At 6-month follow-up, she noted that she had no recurrence of these symptoms since she stopped taking the drug.


Case 2: Mrs. M

Mrs. M is a 72-year-old right handed woman who had once had a motor vehicle accident. Subsequent to her accident, she had complained of short-term memory loss and word-finding difficulties. She was diagnosed with mild cognitive impairment of the amnestic type. In addition, she suffered from depression and was on citalopram 20 mg/day when she started donepezil 5 mg QOD which was increased to 5 mg/day. Mrs. M became restless, had pressured speech, and complained of increased libido and obsessive sexual thoughts 1 week after she started donepezil. A hypomanic state was diagnosed and her citalopram was tapered off and stopped. Her agitation and pressured speech abated but she continued to complain of the same sexual distressing thoughts leading to frequent masturbation. These thoughts and actions were intolerable to her. She stopped taking donepezil. The symptoms of sexual hyperactivation, increased libido, and compulsive masturbation abated a few days later. At a 3-month follow-up she was found to be moderately depressed, but no other complaints were made. She was treated with bupropion. A year later, the depression was in remission with no recurrence of the unwanted sexual behaviors.



Donepezil is considered to be an essential drug in the treatment of dementia. Its action is due to acetylcholinesterase inhibition and the increase of acetylcholine available to neurons. Donepezil’s affect on sexuality has not been described. One may advance that it is due to the direct cholinergic effect on sexual end organ as the parasympathetic postganglionic neurons and their neurotransmitter acetylcholine are stimulatory to the genitourinary system. This stimulation leads to bladder contraction and increases sexual arousal causing vasodilatation of blood vessels and an increase in blood flow to the sexual organs.

In addition, acetylcholine as a central neurotransmitter is involved in sexual arousal along with nitrous oxide. This type of arousal follows the stage of libido activation and prepares the genitalia for penetration and intercourse. The message of arousal starts in the brain and is relayed in the spinal cord to sympathetic and parasympathetic nerve fibers, vascular tissue, and genitalia.

Previous reports by Kawashima and Yamada3 noted delirium and increased diurnal and nocturnal activation after the use of donepezil. In addition, Wengel and colleagues4 described behavioral complications associated with donepezil, while another report described violent behavior associated with donepezil.5

It is worth noting that both women presented in these cases had a history of depression and were treated with selective serotonin reuptake inhibitors (SSRIs). In case 2, competition for CYP with the addition of donepezil may have triggered a hypomanic state with hypersexuality, gregariousness, and disinhibition by raising SSRI levels. While the rest of the hypomanic symptoms abated when the patient stopped the SSRI, the hypersexuality did not abate until she stopped donepezil.

The two women were very disturbed by their behaviors and found it to be distressing and unacceptable. Decreasing the dose did not make any difference and the behavior abated only when the medication was completely stopped. No subsequent sexual problems were noted at follow-up visits.



Two cases of donepezil treatment associated with side effects of increase libido and hypersexuality were presented. Because of the high frequency use of donepezil and the special elderly population it targets, physicians should be cognizant of this possible side effect along with or in the absence of major mental status changes. In addition, when donepezil is added to other agents, pharmacokinetics and drug interaction must be considered. Further research in this area is needed.  PP



1. Stahl S. Essential Psychopharmacology. Neuroscientific Basis and Practical Applications. 2nd ed. New York, NY: Cambridge University Press: 2000:479-489.

2. Physicians Desk Reference. Montvale, NJ: Medical Economics Company, Inc.; 2002:2469-2473.

3. Kawashima T, Yamada S. Delirium caused by donepezil. J Clin Psychiatry. 2002;63:250-251.

4. Wengel SP, Roccaforte WH, Burke WJ, Bayer BL, McNeilly DP, Knop D. Behavioral complications associated with donepezil. Am J Psychiatry. 1998;155:1632-1633.

5. Bouman WP, Pinner G. Violent behavior associated with donepezil. Am J Psychiatry. 1998;155:1626-1627.


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Laurence M. Westreich, MD

Primary Psychiatry. 2008;10(7):65-72


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Charles DeBattista, MD, and Alan F. Schatzberg, MD

Primary Psychiatry. 2003;10(7):80-96


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Kathryn J. Zerbe, MD

 Primary Psychiatry. 2003;10(6):76-78



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Kimberli E. McCallum, MD, and Judy R. Bruton, BA, JD

Primary Psychiatry. 2003;10(6):48-54


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Anne E. Becker, MD, PhD

Primary Psychiatry. 2008;10(6):75-79