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Medication-Induced Dystonias in Nine Patients With Dementia
Thomas M. Magnuson, M.D.; William H. Roccaforte, M.D.; Steven P. Wengel, M.D.; William J. Burke, M.D.
The Journal of Neuropsychiatry and Clinical Neurosciences 2000;12:219-225. doi:10.1176/appi.neuropsych.12.2.219
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DementiaDystoniaRisperidone

Received May 18, 1999; revised August 3, 1999; accepted September 1, 1999. From the Division of Geriatric Psychiatry, University of Nebraska Medical Center, Omaha, Nebraska. Address correspondence to Dr. Magnuson, University of Nebraska Medical Center, Division of Geriatric Psychiatry, 985580 Nebraska Medical Center, Omaha, NE 68198-5580.

Evidence from previous studies of neuroleptic side effects suggests that acute dystonic reactions are rare in elderly patients. The authors report 9 cases of dystonic reactions in patients with dementia following the initiation of antipsychotic medication. The cases are important in documenting that drug-induced dystonias do occur in patients with dementia, that risperidone appears to have contributed to dystonia among elderly patients, and that the categorization of dystonic reactions needs further clarification.

Abstract Teaser
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Adystonia is defined as a slow, sustained muscular contraction or spasm. Dystonias can involve the neck (torticollis or retrocollis), the jaw (forced opening leading to dislocation or trismus), the tongue (protrusions or twisting), or the entire body (opisthotonos). Involvement of the eyes can lead to an oculogyric crisis, manifested by upward, lateral movement of the eyes. Dystonias can also cause dysphagia, dysarthria, and even difficulty in breathing. Dystonias are alarming and often painful.1

Causes of dystonias include progressive neurological diseases such as Huntington's chorea, Parkinson's disease, and Wilson's disease, as well as trauma, tumors, basal ganglia strokes, seizures, idiopathic causes, and medications.1,2 Iatrogenic dystonias are a common phenomenon faced by psychiatric practitioners.3,4 Ten to 30 percent of patients treated with antipsychotic medications develop dystonias.5 The rapid blocking of dopaminergic receptors in the nigrostriatal tract by antipsychotic medications is the proposed mechanism leading to a dystonia.6 However, additional evidence has called this hypothesis into question.1,7

Traditional high-potency antipsychotics, such as haloperidol and fluphenazine, pose the highest risk for dystonia, although any antipsychotic can lead to the reaction.8 Novel antipsychotics such as risperidone and olanzapine are less likely to elicit dystonic symptoms.9 Men less than 40 years old have a greater chance of developing a dystonia from psychotropic medication, although reactions have occurred among both sexes at all ages.4

Drug-induced dystonias have been further classified into either acute or tardive categories based on the time of onset, treatability, and outcome. Acute dystonias, the most common type, develop hours to days after initiating a medication or increasing the dosage, respond favorably to interventions, and resolve quickly with appropriate treatment.1,10,11 Use of anticholinergic agents, such as benztropine or diphenhydramine, is the usual course of action taken to relieve acute dystonias.1,10 This treatment is based on an idea that the interaction of two neurotransmitters is involved in the development of this side effect. Dopamine blockade by antipsychotics theoretically disrupts the ratio between acetylcholine and dopamine in the basal ganglia. Acetylcholine-reducing drugs restore this ratio, thus eliminating the cause of the dystonia.12 In addition, acetylcholine-reducing medications may prevent the reuptake of dopamine. Unfortunately, employing anticholinergics is not always successful, leading to more speculation about the interplay of neurochemicals necessary to develop acute dystonia.7

Tardive dystonia is less recognized and less understood than acute dystonia. Generally when textbooks and articles refer to dystonia, they mean acute dystonia. Estimates of tardive dystonia among patients taking neuroleptic medications range from 1 to 2 percent.13,14 Tardive dystonias usually appear after months to years of neuroleptic administration, are more resistant to medical management, and can persist for a long time.2,15,16 Younger men appear at higher risk for tardive as well as acute dystonias, but all age ranges and both sexes have been documented to have tardive dystonia.2,16,17 Multiple treatment modalities, from anticholinergics to botulinum toxin, have been tried to relieve these late-appearing dystonic symptoms.2,16,17 No clear course of management has been outlined.2,16,17 In many cases the symptoms persist for years following discontinuation of the implicated medication.16,17

Discussion persists about whether the mechanism of tardive dystonia is closer to acute dystonia or tardive dyskinesia. As opposed to simply a blockade of dopaminergic receptors, tardive dyskinesia involves a supersensitivity of dopaminergic receptors in the basal ganglia, leading to uncontrollable, purposeless movements of the head, neck, and trunk.18,19 Tardive dyskinesia, like tardive dystonia, emerges following several years' use of antipsychotic medication.18

Reported rates of acute dystonias among older patients treated with neuroleptics are between 1.5 and 2.0 percent, as opposed to rates 10 to 15 times higher among younger individuals.4 Although acute dystonias have been reported among elderly patients receiving antipsychotic medications, few of these reports have included patients with dementia. The incidence of tardive dystonia among elderly patients is the same as the rate noted for acute dystonia.15 Again, few instances of demented patients with tardive dystonias have been noted.24,15,20,21

The cases that follow detail the onset, treatment, and outcome of drug-induced dystonic reactions in 9 patients with dementia. These reports are important to note for several reasons. Not only were the patients in these dystonia cases elderly, but the primary diagnosis in each instance was dementia. Highly serotonergic antipsychotics played a role in all of these cases, and novel antipsychotics were implicated in 7 of the 9. Finally, several patients had symptoms that mixed elements of both acute and tardive dystonia.

Case 1. A 62-year-old white man with a 7-year history of alcoholic dementia was brought to the hospital because of agitation, wandering, restlessness, visual hallucinations, and delusions of intruders. The patient had been living at home with his wife while attending adult daycare. Lorazepam (dose unknown) had been initiated 3 months earlier but had been stopped because of increasing agitation and restlessness. Haloperidol (0.5 mg po bid) had been started approximately 3 weeks before hospitalization, but symptoms had worsened. There was no evidence of extrapyramidal side effects (EPSE) prior to admission. The patient had little concurrent illness except peptic ulcer disease and a history of bilateral lens implants.

Initial lab tests revealed a mild urinary tract infection, and trimethoprim/sulfamethoxazole was started.

Haloperidol was discontinued and loxapine (10 mg po tid) initiated. The patient continued to have psychotic symptoms, and 6 days after loxapine was begun, he displayed torticollis. The loxapine was discontinued immediately, and carbamazepine (50 mg po bid; increased to 300 mg po bid by discharge) was initiated. Seven days later the patient was noted to have a rigid right arm and hand. In concert with the neurology service, several medications were tried to alleviate the dystonia and rigidity: amantadine, benztropine, lorazepam, cyclobenzaprine, baclofen, diphenhydramine, and clonazepam. None proved helpful, and the condition persisted.

The patient's psychiatric symptoms improved, and he was placed in a rural nursing home; however, his condition rapidly deteriorated, and he was rehospitalized. Carbamazepine was no longer effective, and clozapine (6.25 mg po at hs, increased to 12.5 mg po am and 25 mg po pm) was unsuccessfully tried for 10 days. The patient was eventually placed on conjugated estrogen (0.625 mg po qd) and chlorpromazine (20 mg po am and 30 mg po at hs), and his psychiatric condition restabilized. Although no improvement in his torticollis occurred, rigidity of the limb appeared to be resolving. However, he later developed myoclonus of the entire body. Restarting lorazepam successfully treated the myoclonus in 2 days. The patient's wife was offered the option of treating his torticollis with botulinum toxin, but she refused. He eventually was discharged home with his wife, but within a few months his psychiatric symptoms worsened and he was placed in another rural nursing home. Two years postdischarge the patient continues to have torticollis.

Case 2. A 58-year-old white man with a 3-year history of Alzheimer's disease was brought into the hospital with symptoms of aggression, poor appetite, and decreased sleep. The patient was blind because of glaucoma and had lower back pain. His wife had placed him in a nursing home a few weeks prior to admission. Symptoms worsened following this placement.

The patient had been on fluoxetine (20 mg po qd) for 3 years. More recently, he was placed on haloperidol (0.5 mg po tid) for a few weeks before hospitalization. Initial labs were unremarkable. The patient was taken off haloperidol and fluoxetine and placed on valproic acid (125 mg po bid) and lorazepam (0.5 mg po tid and q6h prn). His psychiatric symptoms responded well, and discharge soon followed.

He returned after a few weeks with increasing aggression, restlessness, and sexually inappropriate behavior. Divalproex sodium dose was increased (250 mg po tid), and risperidone (0.5 mg po bid and q6h prn) and estrogen (0.625 mg po qd) were added to his regimen. Four days after starting risperidone, the patient developed torticollis. Both risperidone and valproic acid were discontinued. Diphenhydramine and lorazepam were given without resolution.

The patient's psychiatric symptoms persisted despite increasing the estrogen, and he was eventually transferred to a state hospital for care. He subsequently moved back into a nursing home, but after 9 months the torticollis had not improved.

Case 3. A 79-year-old white woman had a 5-year history of dementia of the Alzheimer's type, lower back pain, macular degeneration, gastroesophageal reflux disease, and hearing loss. She was 4 months status-post hip fracture. She showed episodic anger, tearfulness, and paranoia. The patient was taking acetaminophen, docusate, omeprazole, salsalate, calcium polycarbophil, and natural tears.

Several medications prescribed previously for mood control and behavioral problems (lorazepam, trazodone, thiothixene, buspirone, haloperidol, and sertraline) had been discontinued for lack of response.

The patient was placed on risperidone (0.5 mg po bid, increased to 1.0 mg po bid over 2—3 weeks). Two weeks after starting risperidone the patient was placed on donepezil (5 mg po at hs) to alleviate the cognitive symptoms of her dementia. Her mood and psychotic symptoms continued, but the patient experienced some benefit from donepezil. After 6 weeks on donepezil, she was able to write more clearly, speak more fluently, and more readily identify family and friends. The improvement made on donepezil led to an increase in dosage (10 mg po at hs). Subsequently, the patient began drooling and developed a shuffling gait. Her risperidone dosage was decreased (0.5 mg po am and 1.0 mg po at hs). However, within 2 weeks the patient exhibited facial grimacing and a stiff upper body and developed retrocollis. She was afebrile.

We first saw her 1 month after the latter dosage changes. She had a prominent tremor, a protruding tongue, limited upward gaze, increasing gait instability, continued drooling, cogwheel rigidity, and retrocollis. In addition, she remained paranoid, with angry outbursts and crying episodes. Many of the gains accompanying the lower dose of donepezil had been lost. The risperidone was discontinued and the donepezil was reduced (5 mg po at hs). Ten days to 2 weeks after making these medication changes, the patient's drooling and tongue movements were gone and the other symptoms had greatly improved. Two months later, a complete resolution of her extrapyramidal symptoms had occurred.

Case 4. A 72-year-old white man with a 6-year history of mixed dementia (elements of Alzheimer's disease and alcohol dementia) was admitted to the geriatric psychiatry inpatient service from a nursing home because of agitation, restlessness, and verbal threats to harm others. Concurrent medical problems included gout, third-degree arteriovenous block, coronary artery disease, and a recently diagnosed right lower lobe pneumonia. Medications included cephalexin (500 mg po qid), valproic acid (250 mg po bid), risperidone (0.5 mg po bid), acetaminophen (1,000 mg po tid), and ibuprofen (600 mg po tid). The patient had been placed on thiothixene (dose unknown) at some point in the past 6 months. He developed torticollis, and the thiothixene was discontinued. Risperidone was initiated; however, no improvement occurred in the patient's dystonia following the medication change. The patient's family history included a sibling with Parkinson's disease.

Initial lab tests were unremarkable aside from a mildly elevated sodium level (147 mg/dl). Following admission the valproic acid was increased (500 mg po bid), then stopped 11 days later because of lack of efficacy. Transdermal estrogen was started, discontinued, then restarted prior to discharge. Loxapine, trazodone, and clozapine were all subsequently used in the patient. The loxapine (5 mg po qd) was discontinued after 5 days because of a worsening of the neck dystonia and sialorrhea. Trazodone was employed (25 mg po tid and 150 mg po at hs) but later stopped due to oversedation. Clozapine was titrated over 6 days (to 12.5 mg po tid), which helped control the patient's presenting symptoms. In addition, there was a slight improvement in his torticollis after clozapine treatment began. Ten months after discharge, the patient was on clozapine (25 mg po tid), transdermal estrogen (0.1 mg patch qd), and lorazepam (1.0 mg po bid). He continued to display torticollis.

Case 5. A 95-year-old white woman with a less than 6-month history of dementia of the Alzheimer's type presented to the geriatric psychiatry inpatient unit with increased paranoia, delusions about others in her house, and irritability after a recent ankle surgery. The patient was felt to have a delirium superimposed on dementia. Attempts to treat the patient in the general hospital proved unsuccessful. Past medical history included bladder cancer, atrial fibrillation, hypothyroidism, status-post cerebrovascular accident, glaucoma, bilateral cataracts with lens implants, hysterectomy, and osteomyelitis of the ankle. Family history noted both parents losing their memory, but not until into their mid-80s. The patient was taking thyroxine (0.05 mg po qd), trimethoprim/sulfamethoxazole (Bactrim DS 1 tablet po qd), and timolol eye drops 0.5% (1 gt OU qd).

Following admission, she was placed on risperidone (1.0 mg po at hs, increased to 4 mg po at hs) and lorazepam (0.5 mg po q6h prn). In addition, if she refused the risperidone, intramuscular haloperidol was ordered to ensure antipsychotic administration. This IM medication was later changed to trifluoperazine (3 mg IM at hs if patient refuses risperidone). The patient improved, but at times was still quite paranoid. On a few occasions she claimed to hear telephones ringing or her name being called out. At discharge, the same medications were continued and trazodone (25 mg po at hs) was added to the regimen.

Six weeks after discharge to a nursing home, the patient displayed torticollis. At that time her psychotic symptoms had improved enough for a gradual decrease in her risperidone dosage. The patient was taking 2 mg po at hs of risperidone when the dystonia appeared. In the 6 weeks following discharge she had received only one dose of IM trifluoperazine. After the emergence of the torticollis, the patient's neuroleptics were all discontinued and she was prescribed benztropine to treat the dystonia. Two days later, improvement was noted in her dystonia. Complete resolution of the torticollis came 6 days after medications were stopped. The patient was placed on olanzapine (5 mg po at hs), and trazodone and lorazepam were restarted at the previous dosages. She fell and fractured her hip 4 days later, but fortunately did not suffer an exacerbation of her psychotic symptoms. Two months later, the patient was still free of psychotic and dystonic symptoms.

Case 6. A 75-year-old white woman with a 2-year history of dementia of the Alzheimer's type was hospitalized because of increasing irritability, delusions, and auditory and visual hallucinations. Her medical history included carpal tunnel surgery, bradycardia, degenerative joint disease, and visual impairment. Concurrent medications included docusate sodium (100 mg po tid) and hydrochlorothiazide 25 mg/triamterene 37.5 mg (1 tablet po qd). Complete blood count, chemistry profile, electrolytes, rapid plasma reagent test, thyroid panel, vitamin B12, folate, chest X-ray, and electrocardiogram were all normal. Family history was positive for dementia in her father.

Risperidone was initiated (0.5 mg po at hs, increased in 4 days to 1.0 mg po at hs) and proved effective in controlling her psychotic symptoms. A few weeks later, after her discharge, risperidone was decreased (0.5 mg po at hs) and donepezil was prescribed (5 mg po qd). Psychotic symptoms quickly recurred, leading to an increase in risperidone (1.0 mg po at hs). Noncompliance with donepezil led to its discontinuation. Three months after beginning risperidone, torticollis was noted in the patient. The risperidone was decreased (0.25 mg po at hs) and diphenhydramine added (25 mg po q8h prn) to treat the dystonic symptoms. Vitamin E (400 IU po qd) and benztropine (1.0 mg po q6h prn) also were prescribed. The patient was rehospitalized because of confusion, agitation, poor appetite, and suicidal ideation.

During her second hospitalization she displayed disorganized thinking, paranoia, and visual hallucinations. Risperidone was discontinued and clozapine (12.5 mg po at hs) was started. She improved and was again released from the inpatient unit. A few weeks after discharge the patient became depressed and voiced thoughts of "giving up." Sertraline (50 mg po qd) was initiated. Around this time a neurologist saw the patient for her continuing dystonic symptoms.

On the basis of clinical evidence and a "weakly positive" tensilon test, the neurologist gave the patient a diagnosis of myasthenia gravis. She was placed on pyridostigmine (60 mg po tid) as treatment for this condition. One month after the diagnosis of myasthenia gravis was made, the patient continued to display torticollis. Although she complains of neck pain, the patient can volitionally straighten her head for a short periods when asked to by her psychiatrist. Both sertraline (50 mg po qd) and clozapine (25 mg po at hs) have been increased after discharge.

Case 7. An 82-year-old white woman had a 2-year history of progressive cognitive decline with symptoms of impaired recent recall, time disorientation, geographic disorientation, and misplacing items. More recently, she had begun having both visual and auditory hallucinations. The visual hallucinations took the form of adults and children and were distressing to her. Her auditory hallucinations were musical. She lacked a family history of dementia. Her medical records indicated a carotid endarterectomy several years earlier, peripheral vascular disease, bruits, osteoarthritis of the hips, incontinence, ischemic heart disease, low vitamin B12, and a vague history of possible vertebrobasilar insufficiency. Her current medications included calcium (600 mg po qd), vitamin C (100 mg po qd), vitamin E (400 IU po qd), aspirin (325 mg po qd), ranitidine (75 mg po qd prn), and a fiber laxative.

She was placed on risperidone (0.5 mg po at hs), and the dosage was increased (0.5 mg bid) 8 days later. Almost 2 weeks following the increase, the family noted that she had "bright red cheeks." Nine days later she became extremely sedated and was unable to dress herself. Within 3 days she became agitated and flushed, she was drooling, and her head drooped forward. The risperidone was discontinued immediately. A month later she continued to show torticollis but was noted to be improved. Within 6 weeks her symptoms had nearly resolved.

Case 8. A 65-year-old white female with a 12-year history of cognitive decline and a diagnosis of dementia of the Alzheimer's type was seen at a nursing home for tearfulness, yelling, refusal to eat or drink, and aggression. Her medical history included a hysterectomy, hip fracture, tonsillectomy/adenoidectomy, and a shoulder fracture. She was being treated for osteoarthritis and hypertension. Medications included risperidone (0.5 mg po qd), lorazepam (0.5 mg po qd plus 0.5 mg q8h prn), metoprolol (50 mg po qd), calcium carbonate (600 mg po qd), vitamin D, miacalcin nasal spray, and a multivitamin. Sertraline (25 mg po qd) was added, but after an increase in the dose (to 50 mg po qd) it was discontinued when symptoms worsened. Trazodone was added (25 mg po qd) as a prn medication for agitation. Within 2 months of the initial visit, the patient fell and fractured her pelvis. Lorazepam and risperidone did not prove helpful, so those medications were stopped. Over the next several weeks trazodone was increased (25 mg po qam, 25 mg po q noon, and 50 mg po at hs). Agitation continued, so loxapine (10 mg po q6h prn) was added, and the as-needed lorazepam interval was decreased to every 6 hours. Five days later, a noted improvement was seen after daily loxapine dosing, leading to an increase (10 mg po bid plus 10 mg po q6h prn). Seven days later, nursing home staff reported the patient had torticollis.

The loxapine was discontinued, and a one-time dose of diphenhydramine was given (25 mg po). In addition, trazodone was again increased (50 mg po qam, 50 mg po q noon, and 100 mg po at hs). The patient was admitted to an inpatient geriatric psychiatry unit. Sertraline was discontinued and quetiapine was initiated (25 mg po qam and 50 mg po at hs). Within 10 days of discontinuing the loxapine, the torticollis resolved.

Case 9. An 82-year-old white female nursing home resident with a history of dementia of the Alzheimer's type presented with symptoms of wandering, restlessness, aggression, disrupted sleep, and paranoia. Past medical history was relatively unremarkable, aside from glaucoma and a seizure disorder. The patient's medications included zolpidem (10 mg po at hs), lorazepam (1.0 mg po q8h prn), phenytoin (250 mg po at hs), timolol eye drops 0.5% (1 gt OU qd), and latanoprost (1 gt OU qd). The patient had also been on risperidone (0.25 mg po at hs) for approximately 2 months before being seen.

By history she had been on doxepin, but this had been discontinued after three near-syncopal episodes. In addition, she had experienced torticollis and a shuffling gait 6 months previously while taking "some medicine." On examination the patient was restless, suspicious, and irritable. No overt hallucinations or paranoia were noted. Trazodone was initiated (50 mg po at hs) and risperidone was increased (0.5 mg po at hs). Over the next few weeks the risperidone was again increased (1.0 mg po at hs), although the trazodone and lorazepam remained at their initial doses. The wandering and agitation continued, so the risperidone was further increased (1.0 mg po bid), and the trazodone dosage was also raised (100 mg po at hs). One to 2 weeks later the patient was noted to have torticollis. She did not display any upper extremity rigidity, tremor, or gait problems. Her risperidone was immediately decreased (1.0 mg po at hs) and later discontinued. The trazodone was also stopped shortly after the onset of torticollis. Continued problems with agitation led to the initiation of olanzapine (2.5 mg po qd) by the primary care physician. This was discontinued within a few weeks, and no other antipsychotic medication has been prescribed. Ultimately, a regimen consisting of mirtazepine (15 mg po at hs), buspirone (10 mg po tid), and valproic acid (625 mg po bid) led to a decrease in wandering and agitation. However, the torticollis has not improved.

Few cases of demented patients with dystonic reactions to psychotropic medications have been recorded. Here we have identified 9 cognitively impaired patients with medication-associated dystonic reactions. Acute medication-induced dystonias develop hours to days following the initial administration or increase in dosage of a neuroleptic.1 These dystonic reactions usually resolve quickly after stopping the offending agent and can be ameliorated by the administration of several classes of medication.1,5 Tardive dystonias emerge after months to years of neuroleptic exposure, do not usually respond to interventions, and either remain chronic or resolve spontaneously after several years.2,16,17 Burke2 argues that to receive a diagnosis of tardive dystonia a patient must have evidence of a chronic dystonia, a concurrent history of antipsychotic use, no other potential causes of the dystonia, and no family history of dystonia.

Among our dystonia cases, 1 case presented as an acute dystonia, and another had definite tardive dystonia. The other 7 had mixed symptom presentations: 4 had an acute onset, ranging from 4 days to 2 weeks; 2 others took about 6 weeks to display symptoms; and 1 case had little available history about onset. Likewise, resolution of symptoms among these 7 patients varied from 10 days to ongoing. This mix of symptoms calls into question whether these 7 cases are simply a variant of acute or tardive dystonia or an altogether separate phenomenon. Confusion about the classification and lack of understanding about the mechanism of tardive dystonia (a dystonia or a subtype of tardive dyskinesia) contribute to this dilemma.

Six of the 9 patients had been exposed to psychiatric medications prior to being placed on the agent associated with their dystonia. Range of previous exposure varied from months to years. These medications included antipsychotics, benzodiazepines, antidepressants, and mood stabilizers. No medication or class of medication was noted in all cases. Haloperidol, risperidone, and thiothixene were all noted to have been used before the implicated agent. A previous study on tardive dystonia indicated that all but 5 of 107 affected patients had used neuroleptics prior to taking the offending medication.17

Only 1 patient in our group had a history of extrapyramidal symptoms. Kiriakakis et al.17 found that only 9% of their population experienced EPSE before the onset of tardive dystonia. Of the 6 psychotropic "veterans," 5 displayed mixed-type dystonic symptoms and 1 exhibited an acute dystonia.

Three of the cases were men, with 2 males being diagnosed with dementias in their mid-50s. All 3 men had a mix of acute and tardive symptoms. Of the 6 women, 4 had mixed-type dystonias, 1 had an acute presentation, and 1 had tardive dystonia. Agewise, one patient was 58, 2 patients were between 62 and 65, 3 were in their 70s, 2 in their 80s, and 1 in her 90s. (Overall, the average age at onset of tardive dystonia is between the third and fourth decade.2,16,17) Two of the men and 1 woman had been diagnosed with dementia in their 50s. Length of time since diagnosis varied among the patients from 2 months to 12 years. Three of the patients had a history of mood symptoms. At the time the extrapyramidal symptoms occurred, 5 were or had been on medications defined as antidepressants or mood stabilizers. In no case among this group do mood symptoms constitute a separate diagnosis.

One patient developed rigidity of his right arm and a subsequent myoclonus following his torticollis. The arm rigidity eventually waned, and the myoclonus resolved with a benzodiazepine. Two other patients had family histories of Parkinson's disease.

Six of the 9 patients had a diagnosis of Alzheimer's disease, 2 had mixed dementias (1 had elements of vascular and Alzheimer's dementia; the other had elements of alcohol and Alzheimer's dementia), and 1 had alcohol dementia. Three of the cases involved visual hallucinations, although none of the cases fit criteria for a diagnosis of Lewy body dementia.

All 9 of the cases are associated with the initiation of antipsychotic drugs with dopaminergic- and serotonergic-blocking properties. Seven of the 9 were being treated with risperidone, the other 2 with loxapine. Theoretically, blocking serotonin 5-HT2 receptors in the nigrostriatal pathway reverses the blockade of dopamine D2 receptors, thereby reducing the risk of extrapyramidal symptoms.22 All 7 of the risperidone-treated patients were on low dosages, ranging from 0.5 mg twice a day to 4.0 mg once a day. Limiting risperidone doses to less than 6 mg per day has been suggested to be protective against the development of extrapyramidal symptoms.23 However, Katz et al.24 reported that more adverse events were noted among patients with dementia who took 2 mg of risperidone per day than among those who took 1 mg per day.

Time to onset of symptoms for the risperidone-associated cases ranged from less than 48 hours to 3 months. Although most symptoms resolved with the discontinuation of risperidone, 2 of the 7 patients continued to display dystonias months after the risperidone was discontinued. Only 2 of the 7 had any previous dystonic or dyskinetic symptoms. Case #3 developed symptoms only after the addition of donepezil. We are not aware of another case that implicates the combination of risperidone and donepezil in a dystonic reaction.25 In addition, we are aware of only one other incident of risperidone's being associated with tardive dystonia.26

Regarding other atypical agents, no torticollis or other dystonic symptoms were reported in these patients with the use of clozapine or olanzapine. Quetiapine was not employed among these patients.

Both of the remaining cases occurred in patients taking loxapine. Loxapine has significant serotonin antagonism in addition to its dopamine-blocking properties.27 In one loxapine-related case, dystonic symptoms appeared in days; in the other, in months. Among our patients the symptoms completely resolved in one case; the other patient still had torticollis 18 months after the loxapine was discontinued. A study of loxapine in elderly cognitively impaired patients (10 had vascular dementia, 2 had senile dementia) reported that 7 of 12 could not complete a course because of tremor, akathisia, excessive salivation, and rigidity.28

Elderly patients have a reduced risk for developing medication-induced dystonias.4 In fact, one of the authors (W.J.B.) had gone more than 10 years without seeing a case of dystonia in an elderly person. It is intriguing that this group of cases is associated with presence of medications with significant serotonin antagonism in all 9 cases. Prolonged neuroleptic use has been proposed to lead to toxic CNS effects by increasing free radicals,29 disrupting nerve cell membranes,30 inhibiting cellular respiration,31 causing loss of striatal cells,32 and increasing levels of metals in the basal ganglia.33 Changes in the number or sensitivity of serotonin receptors in the nigrostriatal tract may lessen the power of serotonin blockade to prevent the emergence of extrapyramidal symptoms following a reduction in dopaminergic activity. In addition, age-related reductions in dopaminergic neurons in the basal ganglia may lessen the threshold of blocked dopamine D2 receptors necessary to develop dystonic reactions. As well, the decrease in acetylcholine among dementia patients could potentially alter the ratio between cholinergic and dopaminergic activity in the CNS. Subsequent iatrogenic reductions in dopamine levels may further alter the ratio of these two neurotransmitters, leading to the onset of dystonia. The emergence of extrapyramidal symptoms after the addition of donepezil in a demented patient on risperidone suggests more than changes in just the acetylcholine—dopamine ratio. All of the cases seem to involve interplay among acetylcholine, dopamine, and serotonin. Further, these patients, especially those with more nontraditional dystonic presentations, may suffer from a type of neuroleptic sensitivity, like that described for Lewy body patients,34 that contributed to the onset of their dystonias.

The cases noted above are important for several reasons. Little evidence exists about dystonias in patients with dementia, but these cases do document that these side effects can occur in cognitively impaired individuals. The role of novel neuroleptics in the development of EPSE has so far been minimal, and thus the apparent association of an atypical neuroleptic, risperidone, with dystonia in patients with dementia is striking. The appearance of mixed tardive and acute dystonic symptoms among our case studies indicates that the categorization of dystonic reactions may need further clarification. These cases also highlight that the roles played by previous exposure to psychiatric medications, gender, age, age at onset, length of cognitive impairment, hallucinations, and mood symptoms have not been fully explored in assessing the risk of dystonia in patients with dementia.

Lishman WA: Organic Psychiatry: The Psychological Consequences of Cerebral Disorder, 3rd edition. Oxford, UK, Blackwell Science, 1998
 
Burke RE, Fahn S, Jankovic J, et al: Tardive dystonia: late onset and persistent dystonia caused by antipsychotic drugs. Neurology 1982; 32:1335—  1346
 
Gilmore R: Movement disorders in the elderly. Geriatrics  1984; 39:65—76
[PubMed]
 
Addonizio G, Alexopoulos GS: Drug-induced dystonia in young and elderly patients. Am J Psychiatry  1988; 145:869—871
[PubMed]
 
Rupniak NMJ, Jenner P, Marsden CD: Acute dystonia induced by neuroleptic drugs. Psychopharmacology  1986; 88:403—419
[PubMed]
 
Marsden CD, Jenner P: The pathophysiology of extrapyramidal side-effects of neuroleptic drugs. Psychol Med  1980; 10:55—72
[CrossRef] | [PubMed]
 
Casey DE: Motor and mental aspects of acute extrapyramidal syndromes. Acta Psychiatr Scand 1994; 89(suppl 380):14—20
 
Wirshing WC, Marder SR, Van Puten T, et al: Acute treatment of schizophrenia, in Psychopharmacology: The Fourth Generation of Progress, edited by Bloom FE, Kupfer DJ. New York, Raven, 1995, pp 1259—1266
 
Barnes TR, McPhillips MA: Novel antipsychotic side effects and tardive dyskinesia. Int Clin Psychopharmacol 1998; 13(suppl 3):549—557
 
Sramek JJ, Simpson GM, Morison RL, et al: Anticholinergic agents for prophylaxis of neuroleptic-induced dystonic reactions: a prospective study. J Clin Psychiatry  1986; 47:305—309
[PubMed]
 
Fahn S, Eldridge R: Definition of dystonia and classification of the dystonic states. Adv Neurol  1976; 14:1—5
[PubMed]
 
Snyder S, Greenberg D, Yamamura H: Antischizophrenic drugs and brain cholinergic receptors. Arch Gen Psychiatry  1974; 31:58—61
[PubMed]
 
Yassa R, Nair V, Dimitry R: Prevalence of tardive dystonia. Acta Psychiatr Scand  1986; 73:629—633
[CrossRef] | [PubMed]
 
Sachdev P: The prevalence of tardive dystonia in patients with chronic schizophrenia (letter). Aust NZ J Psychiatry  1991; 25:446—448
 
Kang UJ, Burke RE, Fahn S: Tardive dystonia. Adv Neurol  1988; 50:415—429
[PubMed]
 
Kang UJ, Burke RE, Fahn S: Natural history and treatment of tardive dystonia. Mov Disord  1986; 1:193—208
[CrossRef] | [PubMed]
 
Kiriakakis V, Bhatia KP, Quinn NP, et al: The natural history of tardive dystonia: a long-term follow-up study of 107 cases. Brain 1998; 121:2053—  2066
 
Miller LG, Jankovic J: Drug-induced dyskinesias: an overview, in Movement Disorders in Neurology and Neuropsychiatry, 2nd edition, edited by Joseph A, Young R, Malden MA. Boston, Blackwell Science, 1999, pp 5—30
 
Jenner P, Marsden CD: Adaptive changes in brain dopamine function as a result of neuroleptic treatment. Adv Neurol  1988; 44:417—431
 
Yassa R, Nastase C, Dupont D, et al: Tardive dyskinesia in elderly psychiatric patients: a five year study. Am J Psychiatry 1992; 149:1206—  1211
 
Wojcik JD, Falk WE, Fink JS, et al: A review of 32 cases of tardive dystonia. Am J Psychiatry 1991; 148:1055—  1059
 
Meltzer HY: The role of serotonin in the mechanism of action of antipsychotic drugs: does 5-HT also have a role in the etiology of schizophrenia? Schizophr Res  1989; 2:212—213
 
Chouinard G, Jones B, Remington G: A Canadian multicenter placebo-controlled study of fixed doses of risperidone and haloperidol in the treatment of chronic schizophrenic patients. J Clin Psychopharmacol  1993; 13:36S—44S
 
Katz IR, Jeste DV, Mintzer JE, et al: Comparison of risperidone and placebo for psychosis and behavioral disturbances associated with dementia: a randomized, double-blind trial. J Clin Psychiatry  1999; 60:107—115
[CrossRef] | [PubMed]
 
Magnuson TM, Keller BK, Burke WJ: Extrapyramidal side-effects in a patient treated with risperidone plus donepezil (letter). Am J Psychiatry 1998; 155:1458—  1459
 
Vercueil L, Foucher J: Risperidone-induced tardive dystonia and psychosis (letter). Lancet  1999; 553:881
 
Kupur S, Zipursky R, Remington G, et al: PET evidence that loxapine is an equipotent blocker of 5-HT2 and D2 receptors: implications for the therapeutics of schizophrenia. Am J Psychiatry 1997; 154:1525—  1529
 
Branchey MH, Lee JH, Simpson GM: Loxapine succinate as a neuroleptic agent: evaluation in two populations of elderly psychiatric patients. J Am Geriatr Soc  1978; 26:263—267
[PubMed]
 
Cadet JL, Lohr JB: Possible involvement of free radicals in neuroleptic movement disorders: evidence from treatment of tardive dyskinesia with vitamin E. Ann NY Acad Sci  1989; 570:176—185
[CrossRef] | [PubMed]
 
Desci L: Further studies on the metabolic background of tranquilizing drug action. Psychopharmacologia  1961; 2:224—242
[CrossRef] | [PubMed]
 
Richter D: Mode of action of the phenothiazines, in The Scientific Basis of Drug Therapy in Psychiatry, edited by Marks J, Pare CMB. Oxford, UK, Pergamon, 1965, pp 63—69
 
Nielson EB, Lyon M: Evidence for cell loss in the corpus striatum after long-term treatment with a neuroleptic drug (flupenthixol) in rats. Psychopharmacology  1978; 59:85—89
[CrossRef] | [PubMed]
 
Weiner WJ, Nausieda PA, Klawans HL: Effects of chlorpromazine on central nervous system concentrations of manganese, iron and copper. Life Sci 1977; 20:1181—  1186
 
McKeith IG, Fairbairn AF, Perry RH, et al: Neuroleptic sensitivity in patients with dementia of Lewy body type. BMJ  1992; 305:673—678
[CrossRef] | [PubMed]
 
+

References

Lishman WA: Organic Psychiatry: The Psychological Consequences of Cerebral Disorder, 3rd edition. Oxford, UK, Blackwell Science, 1998
 
Burke RE, Fahn S, Jankovic J, et al: Tardive dystonia: late onset and persistent dystonia caused by antipsychotic drugs. Neurology 1982; 32:1335—  1346
 
Gilmore R: Movement disorders in the elderly. Geriatrics  1984; 39:65—76
[PubMed]
 
Addonizio G, Alexopoulos GS: Drug-induced dystonia in young and elderly patients. Am J Psychiatry  1988; 145:869—871
[PubMed]
 
Rupniak NMJ, Jenner P, Marsden CD: Acute dystonia induced by neuroleptic drugs. Psychopharmacology  1986; 88:403—419
[PubMed]
 
Marsden CD, Jenner P: The pathophysiology of extrapyramidal side-effects of neuroleptic drugs. Psychol Med  1980; 10:55—72
[CrossRef] | [PubMed]
 
Casey DE: Motor and mental aspects of acute extrapyramidal syndromes. Acta Psychiatr Scand 1994; 89(suppl 380):14—20
 
Wirshing WC, Marder SR, Van Puten T, et al: Acute treatment of schizophrenia, in Psychopharmacology: The Fourth Generation of Progress, edited by Bloom FE, Kupfer DJ. New York, Raven, 1995, pp 1259—1266
 
Barnes TR, McPhillips MA: Novel antipsychotic side effects and tardive dyskinesia. Int Clin Psychopharmacol 1998; 13(suppl 3):549—557
 
Sramek JJ, Simpson GM, Morison RL, et al: Anticholinergic agents for prophylaxis of neuroleptic-induced dystonic reactions: a prospective study. J Clin Psychiatry  1986; 47:305—309
[PubMed]
 
Fahn S, Eldridge R: Definition of dystonia and classification of the dystonic states. Adv Neurol  1976; 14:1—5
[PubMed]
 
Snyder S, Greenberg D, Yamamura H: Antischizophrenic drugs and brain cholinergic receptors. Arch Gen Psychiatry  1974; 31:58—61
[PubMed]
 
Yassa R, Nair V, Dimitry R: Prevalence of tardive dystonia. Acta Psychiatr Scand  1986; 73:629—633
[CrossRef] | [PubMed]
 
Sachdev P: The prevalence of tardive dystonia in patients with chronic schizophrenia (letter). Aust NZ J Psychiatry  1991; 25:446—448
 
Kang UJ, Burke RE, Fahn S: Tardive dystonia. Adv Neurol  1988; 50:415—429
[PubMed]
 
Kang UJ, Burke RE, Fahn S: Natural history and treatment of tardive dystonia. Mov Disord  1986; 1:193—208
[CrossRef] | [PubMed]
 
Kiriakakis V, Bhatia KP, Quinn NP, et al: The natural history of tardive dystonia: a long-term follow-up study of 107 cases. Brain 1998; 121:2053—  2066
 
Miller LG, Jankovic J: Drug-induced dyskinesias: an overview, in Movement Disorders in Neurology and Neuropsychiatry, 2nd edition, edited by Joseph A, Young R, Malden MA. Boston, Blackwell Science, 1999, pp 5—30
 
Jenner P, Marsden CD: Adaptive changes in brain dopamine function as a result of neuroleptic treatment. Adv Neurol  1988; 44:417—431
 
Yassa R, Nastase C, Dupont D, et al: Tardive dyskinesia in elderly psychiatric patients: a five year study. Am J Psychiatry 1992; 149:1206—  1211
 
Wojcik JD, Falk WE, Fink JS, et al: A review of 32 cases of tardive dystonia. Am J Psychiatry 1991; 148:1055—  1059
 
Meltzer HY: The role of serotonin in the mechanism of action of antipsychotic drugs: does 5-HT also have a role in the etiology of schizophrenia? Schizophr Res  1989; 2:212—213
 
Chouinard G, Jones B, Remington G: A Canadian multicenter placebo-controlled study of fixed doses of risperidone and haloperidol in the treatment of chronic schizophrenic patients. J Clin Psychopharmacol  1993; 13:36S—44S
 
Katz IR, Jeste DV, Mintzer JE, et al: Comparison of risperidone and placebo for psychosis and behavioral disturbances associated with dementia: a randomized, double-blind trial. J Clin Psychiatry  1999; 60:107—115
[CrossRef] | [PubMed]
 
Magnuson TM, Keller BK, Burke WJ: Extrapyramidal side-effects in a patient treated with risperidone plus donepezil (letter). Am J Psychiatry 1998; 155:1458—  1459
 
Vercueil L, Foucher J: Risperidone-induced tardive dystonia and psychosis (letter). Lancet  1999; 553:881
 
Kupur S, Zipursky R, Remington G, et al: PET evidence that loxapine is an equipotent blocker of 5-HT2 and D2 receptors: implications for the therapeutics of schizophrenia. Am J Psychiatry 1997; 154:1525—  1529
 
Branchey MH, Lee JH, Simpson GM: Loxapine succinate as a neuroleptic agent: evaluation in two populations of elderly psychiatric patients. J Am Geriatr Soc  1978; 26:263—267
[PubMed]
 
Cadet JL, Lohr JB: Possible involvement of free radicals in neuroleptic movement disorders: evidence from treatment of tardive dyskinesia with vitamin E. Ann NY Acad Sci  1989; 570:176—185
[CrossRef] | [PubMed]
 
Desci L: Further studies on the metabolic background of tranquilizing drug action. Psychopharmacologia  1961; 2:224—242
[CrossRef] | [PubMed]
 
Richter D: Mode of action of the phenothiazines, in The Scientific Basis of Drug Therapy in Psychiatry, edited by Marks J, Pare CMB. Oxford, UK, Pergamon, 1965, pp 63—69
 
Nielson EB, Lyon M: Evidence for cell loss in the corpus striatum after long-term treatment with a neuroleptic drug (flupenthixol) in rats. Psychopharmacology  1978; 59:85—89
[CrossRef] | [PubMed]
 
Weiner WJ, Nausieda PA, Klawans HL: Effects of chlorpromazine on central nervous system concentrations of manganese, iron and copper. Life Sci 1977; 20:1181—  1186
 
McKeith IG, Fairbairn AF, Perry RH, et al: Neuroleptic sensitivity in patients with dementia of Lewy body type. BMJ  1992; 305:673—678
[CrossRef] | [PubMed]
 
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