ic patients.”* Of the very few geriatric subjects in the previous
`open trials, most could tolerate the final daily doses of 4-6 mg
`with slower dose increments.”* In the elderly, the half-lives
`Sir: Rispe idone, a recently introduced novel antipsychotic,
`of risperidone and its active metabolite, 9-hydroxyrisperidone,
`
`are prolonged; and the clearance of 9-hydroxyrisperidone is
`is associated
`.a low incidence of seizures. During
`reduced.’ Therefore, larger-scale and well-designed studies re-
`
`premarketing testing,’
`seizures occurred in 0.3% (9/2607) of
`
`garding the optimal dosing strategy (in terms of both efficacy
`risperidone-treated
`nts (with dosages unrevealed), two in
`
`and adverse drug effects) in geriatric schizophrenics are re-
`association with hyp
`emia.’ To our knowledge, no post-
`
`quired.
`marketing risperidone
`ated seizure has been reported. We
`describe an elderly schizophrenic woman who developed a
`Dueto ethical issues, a rechallenge with the initial dosing
`schedule was not applied to this patient. Nevertheless, the po-
`single seizure after 2 days of. coadministration of risperidone,
`
`
`tentially contributory role ofrisperidone in the seizure should
`
`be considered. High-dose therapy and rapid upward dosetitra-
`
`tion are associated with greater risks of seizures in patients
`
`treated with classical antipsychotics’ or clozapine''; and, ac-
`
`cordingly, might also increase the potential of risperidone-relat-
`
`ed seizures. This patient, experiencing no seizures on the
`
`second occasionofrisperidone treatment (with lower doses and
`
`y
`C
`slower dose titration), might lend partial support to this pre-
`
`curred incidentally on the same day. Sulfamethoxazol
`sumption. To prevent dose (and dose increment)-related side ef-
`
`fects, such as postural hypotension and possible seizures, we
`mg)-trimethoprim (80 mg) was thus coadininistered
`
`now recommend the guideline of “start low arid go slow” for
`Day 2, the dosage of risperidone was increased to 2 mg’b,i.
`
`*3 especially those with im-
`risperidone therapy in the elderly,
`’
`mild scalp itch appeared, and astemizole 10 mg/day wasthe
`
`°-2.13 or those using concomitant
`paired kidneyorliver functions
`prescribed. Surprisingly, 9 hours after taking the initial f
`12,13
`
`edicationsthat could affect the metabolism ofrisperidone.
`doses (1 mg, 1 mg, 2 mg, and 2 mg)ofrisperidone, she exper
`
`Supported by the National Science Council NSC 86-2314-
`enced a single, witnessed, 1-minute generalized tonic-clonic.
`B109- 101 (Dr. Chang).
`seizure with a 5-minute postictal confusion period. Risperidone
`
`wasdiscontinued immediately, and astemizole was withdrawn 1
`day later. Sulfamethoxazole-trimethoprim was continued for 7
`days. A thorough workup, including urine/bloodroutine, a bio-
`chemistry examination, an ECG and a head CT scan, produced
`negative findings, except bacteriuria and a mild fever. The elec-
`troencephalogram results before risperidone therapy and 1 day
`and 4 months after the seizure were all unremarkable, Her psy-
`chotic
`symptoms
`(e.g., auditory hallucinations)
`subsided
`abruptly after the seizure, but emerged again 15 days later. Con-
`sequently, risperidone was restarted at a lower dosage, 0.5 mg
`h.s., and wastitrated over 2 days to 0.5 mg b.i.d. The psychotic
`symptoms receded on this regimen. She has now been free of
`seizures for 4 months, Antiseizure medications were not added.
`
`
`
`REFERENCES
`
`Letters to the Editor
`
`Seizure During Risperidone Treatment in an Elderly
`WomanTreated With Concomitant Medications
`
`done). Physicians’ Desk Reference. 50th ed.
`1. Economics; 1996:1301-1305
`
`
`, linumaK,et al. Proconvulsive effects of
`
`histamine H1. antagéni
`n electrically-induced seizure in develop-
`
`ry. 1993; 112:199-203
`ing mice. Psychopharmi
`3. Hoigne R, MalinvemiR, Soni
`R, Sulfonamides,other folic acid
`
`antagonists and miscellaneous:-antibaeterial drugs. In: Dukes MNG,
`ed, Meyler’s Side Effects of Drugs”‘12th ed. Amsterdam, The Nether-
`
`lands: Excerpta Medica; 1992:715—74:
`4., Jick H. Adverse reactions to trimethoprim-gulfamethoxazole in hospi-
`
`talized patients. Review of Infectious Disease
`5. Chouinard G, Jones B, Remington G,etal. A.Canadian multicenter
`placebo-controlled study offixed doses ofrisperidoneand haloperi-
`dol in the treatment of chronic schizophrenic patiénts:
`
`
`pharmacol 1993;13:25-40
`6. Marder SR, Meibach RC.Risperidonein the treatment
`nia. Am J Psychiatry 1994;151:828-835
`7, Madhusoodanan 8, Brenner R, Araujo L,etal. Efficacy ofrisperidone
`treatment for psychoses associated with schizophrenia, schizoaffec-
`tive disorder, bipolar disorder, or senile dementia in 1] geriatric pa-
`tients: a ease series. J Clin Psychiatry 1995;56:514-518
`8. BermanI, Merson A, Rachov-PavlovJ, et al. Risperidonein elderly
`schizophrenic patients. Am J Geriatr Psychiatry 1996;4:173-179
`9, Heykants J, Huang M-L, MannensG,et al. The pharmacokinetics of
`risperidone in humans: a summary. J Clin Psychiatry 1994;55(5,
`suppl):13—17
`10, Markowitz JC, Seizures with neuroleptics and antidepressants. Gen
`Hosp Psychiatry 1987;9:135—-141
`11. Devinsky O, Honigfeld G, Patin J. Clozapine-related seizures. Neu-
`tology 1991;41:396-371
`
`Astemizole, a peripherally acting H, antagonist, has not been
`reported to induce seizures in patients. In developing mice,
`astemizole, in contrast to other centrally acting H, antagonists,
`does not increase the durationsofelectrically inducedseizures.”
`Rare
`incidences of convulsions have been indicated in
`sulfamethoxazole-trimethoprim-treated
`patients.> However,
`among 1121 sulfamethoxazole-trimethoprim-treated inpatients
`participating in the Boston Collaborative Drug Surveillance
`Program, none developed seizures.’ Drug-drug interactions
`have not yet been reported amongrisperidone, astemizole, and
`sulfamethoxazole-trimethoprim. Studies to investigate the pos-
`sibilities of their drug interactions are needed in the future.
`The initial risperidone dosing schedule of the present case
`had been used in the North American multicenter studies with
`the subjects aged 18-65 years.*° Nonetheless,there is a paucity
`of datarelating to the use of risperidone in elderly schizophren-
`
`J Clin Psychiatry 59:2, February 1998
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`

`Letters to the Editor
`
`12. Ereshefsky L. Pharmacokinetics and drug interactions: update for
`new antipsychotics. J Clin Psychiatry 1996;57(11, suppl):12-25
`13, Grant 8, Fitton A. Risperidone: a review ofits pharmacology and
`therapeutic potential in the treatmentof schizophrenia. Drugs
`1994:48:253-273
`
`Hsien-Yuan Lane, M.D.
`Wen-Ho Chang, M.D.
`Taipei, Republic of China
`James C.-Y. Chou, M.D.
`New York, New York
`
`after therapeutic levels of the drug were achieved. The patient
`may have benefited from valproic acid treatment becauseofco-
`morbid depression, although OCD appearsto be his primary di-
`agnosis. There is evidence that clonazepam may be useful in
`augmenting SRI
`treatment
`in OCD,’ possibly implicating
`GABAergic mechanisms, which may account for therapeutic
`effects of valproic acid in this case. Controlled clinicaltrials are
`neededto establish the effectiveness of valproic acid monother-
`apy in OCD andother anxiety disorders.
`
`REFERENCES
`
`1, Deltito JA. Valproate pretreatmentfor the difficult-to-treat patient
`with OCD[letter]. J Clin Psychiatry 1994;55:500
`2. Goodman WK, McDougle CJ, Barr LC,et al. Biological approaches
`to treatment-resistant obsessive compulsive disorder. J Clin Psychia-
`try 1993;54(6, suppl): 16-26
`
`Gabriela Coraé-Locatelli, M.D.
`Benjamin D. Greenberg, M.D., Ph.D,
`Juliet D. Martin
`Dennis L. Murphy, M.D.
`Bethesda, Maryland
`
`
`Risperidone and Allergic Reactions
`
`
` ».Valproate Monotherapy in an
`SRI-Intolerant OCD Patient
`
`
`Sir: Many patie ts"“with obsessive-compulsive disorder
`(OCD)considered to'b
`satment refractory have prematurely
`discontinued serotonin reuptake’
`inhibitors (SRIs) due to side
`
`effects (such asirritability and,anxiety) and are not trulytreat-
`mentrefractory. Some OCD patients:intolerant of SRIs had de-
`creased adverse effects after pretréatiment, with valproic acid.’
`
`Wetherefore pretreated an OCD patient-intolerant of standard
`doses of fluoxetine, sertraline, and clom
`line with valproic
`acid,
`
`Case report. Mr. A, a 35-year-old singl
`
`15-year history of OcD, had stopped his job:
`Sir: Risperidone, the first benzisoxazole antipsychotic, has
`
`dopamine D, and serotonin 5-HT, antagonistic properties. °
`ents’ safety. He compulsively touched his parents7
`our knowledge, there have been only three case reports’?
`garding dermatologic side effects ofrisperidone. Two ofthe be
`
`per day, checking that
`they were alive. Mr.
`
`housebound and prevented his parents from answering:pphon
`tients’? suffered from edema, and the third? had bullous
`
`calls out of obsessional fears, which he acknowledged”were
`» pemphigoid. In this report, we present a case of severe allergic
`senseless, His mood was sad without neurovegetative sym
`‘actions to risperidone resulting in edema, eruption, and stri-
`
`toms. He had a family history of depression, with good treat.
`
`ment response to conventional antidepressants, but no family
`history of bipolar disorder or treatment with moodstabilizers.
`Baseline ratings revealed Yale-Brown Obsessive Compulsive
`Scale (Y-BOCS), Hamilton Rating Scale for Anxiety (HAM-A),
`and Hamilton Rating Scale for Depression (HAM-D)scores of
`24, 9, and 20, respectively.
`Westarted fluoxetine 5 mg/day, which Mr. A discontinued
`on his own because of feelings of anxiety and agitation. We then
`started low-dose valproic acid (250 mgt.i.d.), intendingto rein-
`troduce fluoxetine later. Although his anxiety decreased, he dis-
`continued valproic acid because of sedation after 1 week.
`Valproic acid wasrestarted (250 mg q.a.m., 500 mg g.h.s.), to-
`gether with fluoxetine 1 mg/day. Two weekslater, he appeared
`less anxious, “in control,” and had resumed working 5 to 10
`hours/day after not working for 6 months. His obsessions re-
`garding his parents’ safety ceased. His total Y-BOCS, HAM-A,
`and HAM-D scores decreased to 11, 6, and 12, respectively. His
`plasma valproic acid level was therapeutic at 85 ug/mL. Al-
`though weoriginally planned to increase the fluoxetine dose,
`we discontinuedit instead, believing valproic acid was respon-
`sible for the clinical improvement. The patient further improved
`on valproic acid monotherapy: his overall Y-BOCS, HAM-A,
`and HAM-Dscores decreasedto 8, 3, and 10, respectively. This
`apparent antiobsessional and antidepressant effect of valproic
`acid has continued for 10 weeks. His OCD symptomsare now
`mild, and he reports euthymic mood. He has resumed a normal
`work schedule,and his social interactions have improved.
`
`sport. Mr. A, a 67-year-old man with epileptic psy-
`been treated with the same combination of carba-
`mazepine, phe nytoin, phenobarbital, haloperidol, profenamine,
`
`idebenone, Vinpovetine, and diltiazem for several years. The
`
`function, and serum total protein ‘wére within normal range.
`Risperidone was discontinued 42 days.after its start. No
`changes were madein the other drugs. Ani ihistaminergic treat-
`ments were started; however, he developed’dis
`
`lopapular drug eruption 1 day after the dise
`
`’
`risperidone and stridor 4 days after discontinuation.
`tion had urticarial character. Seven days after discontinuation,
`the edema,eruption, and stridor persisted, and IgE was elevated
`at 261 IU/mL (normalrange, < 250 IU/mL), whereas C3 and C4
`were 101 mg/dL (normal, 55-115) and 29.7 mg/dL (normal,
`15.0-50.0), respectively. After 15 days, the edema had resolved
`completely, both the eruption andstridor had improved, and IgE
`was decreased to 205 [U/mL. After 21 days, the disseminated
`maculopapular eruption and stridor had also resolved com-
`pletely.
`
`This case suggests that valproic acid monotherapy may be
`useful in OCD patients who are intolerant of SRIs. The maxi-
`mum beneficial valproic acid effect in this patient occurred only
`
`In this case, the edema occurred 31 days after the com-
`mencement ofrisperidone and lasted 26 days, while the erup-
`tion and stridor began 43 and 46 daysafter starting risperidone
`
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`and lasted 20 and 17 days, respectively. Although the eruption
`and stridor occurred just after risperidone discontinuation, it
`seems likely that risperidone and/or its active metabolite,
`9-hydroxyrisperidone, remained in the patient’s body and in-
`duced the eruption and stridor. Strictly speaking, however,it is
`not clear whetherrisperidoneitself or the other components in
`the tablet contributed to Mr. A’s allergic reactions. It is thus
`worth noting that the Japanese version of the risperidone tablet
`includes wax in place of the pigment foundin the U.S. tablet.
`With regardto the types ofallergic reactions, Type I allergic
`reaction may be plausible because IgE was elevated, albeit
`slightly, during these reactions. Stridor is common in Type I
`allergic reaction, and the eruption was urticarial in character,
`whereas Type'Il and.Type III reactions are somewhat unlikely
`
`. Cooney C, Nagy A. Angio-oedemaassociat
`
`[letter]. BMJ 19953310: 1204
`
`Letters to the Editor
`
`tomsand the cognitive deficits remitted by the third day of hos-
`pitalization, at which time she wastransferred to the psychiatric
`floor. She was restarted on antidepressants and observed for 5
`days. The patient remained asymptomatic during the rest of her
`Stay.
`
`The prevalence of obesity in the United States has increased
`in the last few decades; around 30% of U.S. adults are consid-
`ered overweight.' Obesity contributes to many adverse health
`outcomes, such as cardiovascular disease, diabetes mellitus,
`and cancer” While earlier treatments for obesity consisted
`mainly of diet control and behavior modification, pharmaco-
`therapy has gained immense popularity after the recent reports
`by Weintraub et al.*4 that showed sustained weight loss with a
`combination of fenfluramine and phentermine. This increased
`popularity has led to the establishment of many weight loss
`clinics devoted to the prescription of weight loss pills such as
`fen-phen and dexfenfluramine.
`The rationale for using a combination therapy is that drugs
`with different mechanisms of action used together in smaller
`amounts provide equal or greater efficacy with fewer adverse
`effects than the same drugs used in monotherapy at higher
`doses. Fenfluramine acts by a serotonergic mechanism, whereas
`the stimulant anorexiant phentermine appears to decrease appe-
`tite through a dopaminergic and noradrenergic pathway.’ Al-
`though this combination has been relatively well tolerated, we
`report a case of diet pill-induced delirium with manic symp-
`toms in a patient with a long-standing history of depression.
`These diet pills may cause sufficient imbalance in the neuro-
`transmitters or their receptors to result in cognitive and mood
`disturbances in predisposed individuals. Thus, it may be neces-
`sary to exercise caution while prescribing these dict pills in in-
`dividuals with a prior history of mood disturbances.
`
`Hideki Kojima, M:D:
`Akira Eto;:M.
`
`Kitakyushu, Japan,
`
`REFERENCES
` Delirium With Manic Symptoms Induced by Diet Pills
`
`
`Sir: We report on a patient with chronic depression con-
`trolled by antidepressant medication who developed delirium
`with manic symptomsafter being started on diet pills contain-
`ing a combination of fenfluramine and phentermine.
`
`Case report. Ms. A, a 50-year-old overweight white woman
`with a history of major depression, had been stable on a combi-
`nation of imipramine 150 mg q.d. and venlafaxine 100 mgb.i-d.
`for more than 2 years with no adverse reactions. Two weeksbe-
`fore hospitalization, the patient’s internist prescribed dietpills
`consisting of fenfluramine 20 mgt.i.d. and phentermine 30 mg
`q.d. On Day 10 of the diet pill regimen, Ms. A became manic
`with elated mood, increased psychomotor activity, decreased
`sleep, racing thoughts, pressure of specch, and loosening of as-
`sociation. She was also hypersexual and appeared confused at
`times, but had neither grandiose delusions nor hallucinations.
`She had no past history of mania or family history of bipolar
`disorder.
`Ms. A wasbrought to the emergency room and,afterinitial
`evaluation, was admitted to the medical floor. Her mentalstatus
`examination showed impaired recent memory, loosening ofas-
`sociation, and anirritable affect. Physical examination results
`were normal, and all routine laboratory test results were within
`normallimits except for an elevated WBC count. No evidence
`of infection was found on blood cultures, chest x-ray, and CSF
`analysis. A CT scan of the brain showed no abnormalities.
`While Ms. A was on the medical floor, both psychotropic
`medication and the diet pills were withdrawn. The manic symp-
`
`
`, Mushlin Al, et al. A double-blind clinical
`é of fenfluramine and phentermine alone
`and in combination. Arch:Intern Med 1984;38:763~768
`4, Weintraub M, Bray G. Drig:
`atment of obesity. Med Clin North Am
`
`1989;73:237-249
`3. Jespersen 5, Scheel-KrugerJ. Evidence for a difference in mechanism
`of action between fenfluramine- andamphetamine-induced anorexia.
`J Pharm Pharmacol 1973;25:49-54
`
`
`Sushil Bagri, M.D.
`
`
`Editor’s Nate: The letter by Drs. Bagri and Reddy
`was submitted before fenfluramine was withdrawn
`from the U.S. market.
`
`
`
`Rapid Efficacy of Olanzapine Augmentation in
`Nonpsychotic Bipolar Mixed States
`
`Sir: Traditional antipsychotics are potent acute antimanic
`agents. However, their utility is limited by acute and chronic
`neurologic toxicity, which appears to be more prevalent in
`mood disorder than in schizophreniapatients.'? In addition, in
`
`J Clin Psychiatry 59:2, February 1998
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`
`some patients older antipsychotics may either exacerbate or fail
`to relieve or to prevent depressive symptoms.
`The introduction of atypical antipsychotics with less poten-
`tial for neurologic adverse effects and greater potential for relief
`of negative symptoms (which resemble depression) has led to
`preliminary clinical exploration of the roles of such agents in
`the management of patients with both psychotic and nonpsy-
`chotic bipolar disorders. Clozapine appears to stabilize mood,’
`while risperidone may yield a complex patternofalleviating de-
`pression* as well as mania** in some patients yet exacerbating
`or inducing mania*’ in others. The latter profile to some extent
`resembles that.of an antidepressant (rather than a mood stabi-
`
` seen with risperidone.
`a recently marketed atypical antipsychotic
`
`ai iperior to that of clozapine. Emerging ev-
`idence suggests that
`Ja
`apine may relieve mood symptoms
`
`in patients with sch
`renia, schizoaffective disorder, and
`
`psychotic mood disorders. wre
`inzapine has a receptor antago-
`nism profile more like that
`zapine than that of risperi-
`
`done.” In particular, olanzap
`s,the predominant 5-HT,
`receptor blockade seen with rispefidone. Thus, olanzapine
`
`could provideless risk of mania, mixed,states, or rapid cycling
`than risperidone. We present our experie
`th our first two
`
`bipolar patients treated with olanzapine. Thes
`olar I patients
`with nonpsychotic mixed states (as diagnosed’Usi1
`criteria) had rapid dramatic improvement
`olanzapine to moodstabilizers.
`
`Case 2. Ms. B, a 47-year-old married white female profes-
`sional, has had bipolar I disorder since age 22 and abused drugs
`in her early 20s. She had never been psychotic or hospitalized,
`but manic episodes had resulted in job loss and markedrelation-
`ship difficulties. In the prior year she had been rapidly cycling
`between major depression and hypomania despite taking carba-
`mazepine 800 mg/day (serum level = 8.4 g/mL) and levothy-
`roxine 100 g/day and minimizing antidepressant (paroxetine
`and bupropion) use.
`Carbamazepine was discontinued due to neurotoxicity and
`inefficacy. Over a 2-week period while being switched from
`carbamazepine to divalproex sodium, Ms. B escalated into a
`mixed mood state with marked affective lability. Her mood
`gradually shifted from predominantly euphoric with very brief
`periods ofirritability and depression (particularly during inter-
`actions with her husband)to irritable and dysphoric mostof the
`time and in most social interactions with only brief periods of
`euphoria. She developed decreased sleep (3 hours) and need for
`sleep and variable appetite along with psychomotoragitation,
`distractibility, and passive thoughts of death, but no psychotic
`symptoms. She took medical leave from work, and problemsat
`homeintensified so that her husband considered moving out of
`the house. The above occurred despite therapy with divalproex
`sodium 375 mg/day, lorazepam 3 mg/day, and levothyroxine
`100 pg/day. Both the patient and her husband agreed to having
`
`her admitted to the hospital.
`In view of gastrointestinal discomfort (diarrhea), which was
`limiting the rate of divalproex introduction, and Ms. B’s psychi-
`atric acuity, olanzapine 10 mg at bedtime was added, and that
`night she slept well for the first time in 10 days. Her mood was
`
`improved the next morning, but she complained of sedation and
`
`current drug and alcohol abuse. He was hospitalized once’ for-
`»
`_
`light-headedness, which attenuated enough the following day to
`
`allow discharge home with partial (day) hospitalization. Thus,
`nonpsychotic mania, and, on lithium monotherapy, he had-a
`Il (inpatient) hospitalization was limited to 2 days. Her hus-
`2-month mixed moodstate episode and required intermitten
`
`antidepressantor thioridazine for subsyndromal depressive and_
`hypomanic symptoms, which initially resolved with the addi-
`tion of divalproex sodium.
`
`gradually titrated so that, on lithium 600 ma/day
`However, after a 4-month period of euthymia while taking
`5 mEq/L), divalproex sodium 750 mg/day (se-
`lithium 900 mg/day (serum level = 0.7 mEq/L) and divalproex
`
`g/mL), and levothyroxine 100 [tg/day, her
`sodium 750 mg/day (serum level = 51 ug/mL), and during a pe-
`
`r,.she returned to work, and' lanzapme
`riod of increased occupational and familialstress, Mr. A entered
`a nonpsychotic mixed moodstate that gradually worsened over
`a 6-week period. Symptomsincluded markedirritability (he had
`nottalked to his wife for several days), psychomotoragitation,
`distractibility (he stopped driving after a minor motor vehicle
`accident), episodic passive suicidal
`ideation, and decreased
`sleep (4 hours), need for sleep, appetite, and ability to enjoy ac-
`tivities. He denied psychotic symptoms, but admitted marked
`pessimism regarding the chances of survival of his marriage,
`despite the repeated assurances ofhis distraught wife that she
`wasfirmly committed to their relationship. Hospitalization was
`offered, but Mr. A and his wife expressed a strong desire to ad-
`dress these difficulties with outpatient treatment.
`Dosesof lithium and divalproex had previously been limited
`by gastrointestinal (diarrhea) and neurologic (tremor) adverse
`effects. Thus, olanzapine 10 mg at bedtime was added, and the
`patient slept well after the initial dose for the first time in over 2
`weeks. On awakening the next morning, he reported complete
`remission of symptoms, and thus hospitalization was avoided.
`His wife even expressed some anxiety around how suddenlyhis
`mood had completely returned to euthymia. He experienced
`very mild sedation onfirst awakening in the morning, which re-
`solved after 3 days of therapy, but denied any other adverse ef-
`fects. Six months later, Mr. A continues improved, and a gradual
`taper of olanzapine will be considered once the ongoing occu-
`pational and familial stressors resolve.
`
`
`Taprove gastrointestinal tol-
`
`“symptoms and insomnia,
`
`anzapine at bedtime
`
`
`
`stabilizers in patients with nonpsychotic bipol
`may yield rapid affective improvement and m
`erated. It is not clear whether olanzapine yielded direct mood
`stabilization or indirect benefit by improving sleep. Hospital-
`ization was avoided in one case and limited to only 2 days in the
`other. Thus, olanzapine augmentation appeared to limit not only
`patient suffering, but also hospitalization costs.
`Our two open treatment cases need to be considered with
`caution, particularly in view of the early positive experience
`with risperidone, which waslater qualified with the possibility
`that this agent may induce or exacerbate mania in some pa-
`tients.” However, mixed states are among the mostdifficult
`treatment challenges in bipolar disorders, and this very limited
`initial experience suggests that further clinical exploration and
`ultimately controlled trials may be warranted to examine the
`
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`
`efficacy and tolerability of olanzapine in patients with bipolar
`disorders, even in the absence of psychotic symptoms.
`This research was supported by the Stanley Foundation Re-
`search Awards Program.
`
`REFERENCES
`
`bate manic symptoms owingto its putative antidepressantactiv-
`ity?* The mixed data (and the underlying etiologies) on its
`moodeffects need to be clarified. We here report two schizo-
`phrenic patients who developed manic symptoms at specific
`doses ofrisperidone, but not at other doses. We propose a poten-
`tial mechanism to account for this probable dose-related phe-
`nomenon as well as the prior inconsistent reports concerning
`risperidone’s moodeffects.'~*
`
`. Nasrallah HA, Churchill CM, Hamdan-Allan GA. Higher frequency
`of neuroleptic-induced dystonia in mania than in schizophrenia, Am J
`Psychiatry 1988;145:1455-1456
`Case I. Ms. A, a 48-year-old Chinese woman,had suffered
`. Woemer MG,Kane JM, LiebermanJA,et al. The prevalence oftar-
`from schizophrenia for 10 years without treatment. She had
`dive dyskinesia. J Clin Psychopharmacol 1991;11:34-42
`been physically healthy and devoid of any seizure or substance
`. Banov MD? Zarate CA Ji, Tohen M,et al. Clozapine therapyin refrac-
`abuse history. Recently, she wasfirst hospitalized for acute ex-
`tory affective.disorders: polarity predicts response in long-term fol-
`acerbation with prominent positive and negative symptoms,
`
`low-up. J Clin Psychiatry 1994;55:295-300
`including auditory hallucinations, persecutory delusions, so-
`. Keck PE Jr, Wil8onDR, Strakowski SM,et al. Clinical predictors of
`matic delusions, apathy, alogia, anergia, and anhedonia. Physi-
`acute risperidone respol e in schizophrenia, schizoaffective disorder,
`cal examinations, ECG, chest x-ray, urinalysis, hematology,
`and psychotic mood.dis ders. In: New Research and Abstracts of the
`
`serum chemistry, and hepatitis B serology all produced negative
`148th Annual Meeting of
`the’‘Am rican Psychiatric Association; May
`24, 1995; Miami, Fla. Abstraé
`findings.
`. Jacobsen FM. Risperidoneiin there
`
`Risperidone alone was initiated and gradually titrated to 6
`and refractory OCD. In: New Regeartt pand Abstracts of the 148th
`mg/day over 3 days. Adverse drug effects,
`including sinus
`Annual Meeting of the American Psych jatri Association; May 23,
`tachycardia, dizziness, acute tongue dystonia, tremor, and sia-
`
`1995; Miami, Fla. Abstract NR275:129
`.
`lorrhea, developed without reductions in the positive and nega-
`
`. Dwight MM, Keck PE Jr, Stanton SP,et alAntid:
`tive psychotic symptoms. Three weeks later, the dosage was
`and mania associated with risperidone treatment
`
`reduced to 4 mg/day because of the intolerable adverse effects.
`disorder[letter]. Lancet 1994;344:554-555.
`
`The positive symptoms subsided; however, the negative symp-
`. Sajatovic M, DiGiovanni SK, Bastani B,
`
`toms and the side effects continued. Consequently, we further
`treatment refractory acute bipolar and schizoaft
`decreased the dosage to 3 mg/day after 2 more weeks. A manic
`RW.Bull 1996;32:33-61
`
`state with grandiosity, hyperactivity,
`increased talkativeness,
`
`flight of ideas, and elated mood emerged 2 dayslater.
`
`[abstract]. Psychopharmacol Bull 1995;31:549
`The EEG performed 4 days after the initial presentation of
`
`
`. Tollefson GD, Beasley CM Jr, Tran PV, et al. Olanzapineve:
`manic symptoms showed generalized intermittent theta waves
`peridol in the treatment of schizophrenia and schizoaffective and
`and generalized spike-and-wave complexes. To prevent poten-
`
`schizophreniform disorders: results of an international collaborative:
`seizures, risperidone was withdrawn temporarily. The manic
`trial. Am J Psychiatry 1997;154:457-465
`. Tohen M, SangerT, Tollefson GD,et al. Olanzapine versus haloperi-
`‘features,receded soon, and the positive and negative psychotic
`ymptoms recurred, A normal EEG pattern returned 9 days after
`dolin the treatment of schizoaffective bipolar patients. In: New Re-
`search and Abstracts of the 150th Annual Meeting of the American
`Psychiatric Association; May 20, 1997; San Diego, Calif. Abstract
`NR206:123-124
`Zarate CA, Narendran R, Madrid A,et al. Olanzapine response in
`acute schizophrenia, schizoaffective disorder and psychotic mood
`disorders. In: New Research and Abstracts of the 150th Annual Meet-
`ing of the American Psychiatric Association; May 20, 1997; San Di-
`ego, Calif. Abstract NR211:125
`Bymaster FP, Hemrick-Luecke SK, Perry KW, et al. Neurochemical
`evidence for antagonism by olanzapine of dopamine,serotonin, alpha
`l-adrenergic and muscarinic receptors in vivo in rats. Psychopharma-
`cology (Berl) 1996;124:87-94
`
`11.
`
`12.
`
`Terence A. Ketter, M.D.
`Miréne E. Winsberg, M.D.
`Sallie G. DeGolia, M.D.
`Magdolna Dunai, M.D.
`Debbie L. Tate
`Connie M. Strong, MLS.
`Stanford, California
`
`Mania Induced by Risperidone:
`Dose Related?
`
`speridone.was discontinued, We thusrestarted eee at 2
`
`positive and thenegat Ve psychotic symptoms as well as the ad-
`
`verse drug effectsdimninished greatly. A euthymic mood re-
`sumed, and EEGresultswéré’normal.
`
`Case 2. Mr. B, a 36-year-old Chinese man with chronic
`schizophrenia, was hospitalized if auditory and somatic hallu-
`
`
`cinations and persecutory delusions.Neither comorbid medical
`
`conditions nor substance abuse w
`ted. He was prescribed
`risperidoneafter failure to respond to four.classesoftraditional
`antipsychotic drugs. The dosage was titratedup to,6 mg/dayin 3
`
`days. After 6 more days, the psychotic sympt
`s receded, but
`severe akathisia emerged even after the gradual addition of
`
`benztropine up to 6 mg/day over another 3 days.
`days, the dose of risperidone was decreased to 4 nig/day. The
`akathisia lessened, but a manic state appeared 3 days later. Eu-
`phoric mood, hyperactivity, pressured speech, flight of ideas,
`and grandiosity were evident over the next 10 days. Therisperi-
`done dosage was further reduced to 2 mg/day. Mr. B then be-
`came euthymic and free from psychotic symptoms and side
`effects. No other concomitant medications were prescribed.
`
`Sir: Risperidoneis a serotonin-2/dopamine-2 (5-HT-,/D,) re-
`ceptor antagonist that has demonstrated efficacy in the treat-
`ment of schizophrenia, It has also been suggested to possess
`acute antimanic effects in some patients.’ Other preliminary
`data, however, indicate that risperidone mayinitiate or exacer-
`
`At least two treatment-related factors could have affected
`the development of mania in our two patients: the dose before
`the manic features and the treatment duration after risperidone
`was initiated. First, it is possible that the mania might appear at
`specific doses; doses that are too high or extremely low may be
`
`J Clin Psychiatry 59:2, February 1998
`
`85
`
`5 of 7
`
`Alkermes, Ex. 1012
`
`5 of 7
`
`Alkermes, Ex. 1012
`
`

`

`Letters to the Editor
`
`less likely to generate manic symptoms. The dose-response re-
`lationships appeared clear by virtue of the careful ABAB (A:
`the doses unlikely to cause mania, B: those tending to) case de-
`sign in Ms. A, and the ABA design in Mr. B. Risperidone at
`lower doses shows marked preference for the 5-HT, receptors,
`whereas at high doses both the D, and the 5-HT, receptors are
`completely blocked and the 5-HT,/D, differenceis negligible.”
`It has been suggested that the blockade of 5-HT, receptors could
`bear antidepressant effects and induce mania, whereas anti-
`dopaminergic activities might result in the antimanic property.'
`We further propose that the mood state might be a function
`
` Q,ow) doses, risperidone might haveaa greater
`potential to initiate orexacerbate manic symptoms. Extremely
`low doses, however
`
`would lead to enhanceddopat nergic transmission in the pre-
`
`frontal| cortex.” Therefore, with
`
`
`action as well as the ensuing dopathine disinhibiting effects. In
`
`contrast, at high doses, risperidone’s dopaininergic blockade ac-
`
`REFERENCES
`
`1. McElroy SL, Keck PE Jr, Strakowski SM. Mania, psychosis, and
`antipsychotics. J Clin Psychiatry 1996;57(suppl 3):14-26
`2. Dwight MM,Keck PE,Stanton SP,et al. Antidepressantactivity and
`mania associated with risper