atypical antipsychotics in the treatment of bipolar disorder

Atypical Antipsychotics in theTreatment of Bipolar DisorderPharmacological and Clinical Effects

Eduardo Dunayevich1 and Susan L. McElroy2

1 Clinical Psychobiology Program, Department of Psychiatry, University of Cincinnati, Cincinnati,Ohio, USA

2 Biological Psychiatry Program, Department of Psychiatry, University of Cincinnati, Cincinnati,Ohio, USA

ContentsAbstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4331. Clozapine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4342. Risperidone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4353. Olanzapine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4374. Quetiapine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4385. Ziprasidone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4396. Atypical Antipsychotics and Tardive Dyskinesia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4397. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 439

Abstract Atypical antipsychotics are characterised by a low propensity for causing acuteand tardive extrapyramidal symptoms and an increased efficacy against positiveand negative symptoms in schizophrenia. Agrowing literature suggests clozapineand other atypical antipsychotics, including olanzapine, risperidone, and possiblyquetiapine and ziprasidone, are also effective in the treatment of bipolar disorder,particularly the manic phase. Symptoms that are refractory to other drugs mayrespond to these agents. However, antipsychotic treatment can be associated withserious adverse effects, and caution needs to be exercised in the prescription ofthese agents.

REVIEW ARTICLE CNS Drugs 2000 Jun; 13 (6): 433-4411172-7047/00/0006-0433/$20.00/0

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Bipolar disorder is a recurrent, life-long illnessthat is associated with a high morbidity and mor-tality.[1] It has been estimated to affect, at the least,between 0.8 and 1.6% of the general population.[1]Up to 45% of patients with the illness fail to re-spond to standard mood stabilisers.[2] Although con-ventional antipsychotics are effective in the treatmentof bipolar disorder, particularly the manic phase, asubstantial proportion of patients also fail to re-spond adequately to these agents.[2] Additionally,

they are associated with extrapyramidal symptoms(EPS), such as parkinsonian symptoms, tardive dys-kinesia and the neuroleptic malignant syndrome.[3]Compared with conventional antipsychotics,

atypical antipsychotics are characterised by a lowpropensity for causing acute and tardive EPS andan increased efficacy against positive and negativesymptoms in schizophrenia.[3-5] The use of clozapine,the prototypical atypical antipsychotic, was initi-ally met with some scepticism, as many clinicians

expected that, for an antipsychotic to be efficac-ious, it had to cause tremor or rigidity.[6] In 1974,as the use of clozapine was becoming more wide-spread, 8 patients in Finland died from agranulocy-tosis while receiving it. As a result, it was taken offthe market in several countries. However, clinicianswho still had access to the drug noted that it ap-peared efficacious even in patients with treatment-refractory symptoms. This lead to the hallmark studyby Kane and colleagues[5] which demonstrated theefficacy of clozapine in patients with treatment-refractory schizophrenia.A growing literature suggests clozapine and other

atypical antipsychotics are also effective in bipolardisorder, particularly the manic phase, includingsymptoms that are refractory to other treatments.Atypical antipsychotics seem to be character-

ised by a higher binding to serotonin 5-HT2 than todopamine D2 receptors, and Meltzer[7] has hypoth-esised that atypical antipsychotics are distinguishedby at least a 13-fold higher affinity for 5-HT2 thanfor D2 receptors. Indeed, the in vitro ratio of affinityfor 5-HT2 versus D2 receptors for clozapine is 112[7]compared with 1.3 for thioridazine;[8] however, itis 5.1 for risperidone, and is even lower for olan-zapine (2.7) and quetiapine (0.54).[8] In vitro stud-ies may not reflect the actual in vivo binding or thepotential effects of active metabolites; however, thequestion of what pharmacological effects make anantipsychotic atypical remains unresolved.[9]In this paper we review the studies of currently

available atypical antipsychotics in the short termand maintenance treatment of bipolar disorder. Weconclude that these compounds have acute anti-manic, and possibly long term mood stabilising,properties. We discuss potential pharmacologicalmechanisms for these properties, and present pre-liminary guidelines for the use of the drugs in pa-tients with bipolar disorder.

1. Clozapine

Agrowing clinical literature suggests clozapinemay have anti-manic and long term mood stabilis-ing properties in bipolar disorder, including in pa-tients with treatment-refractory symptoms. Zarate

et al.[10] reviewed 10 of these studies and reportedthat of 94 patients with bipolar disorder and 221with schizoaffective disorder receiving clozapine,71% of patients with bipolar disorder and 70% ofpatients with schizoaffective disorder displayed aclinically significant response. For example, in aretrospective chart review,[11] our group reportedthat 12 of 14 patients with highly treatment-resistantbipolar disorder had a moderate to marked responseafter at least 6 weeks of open-label treatment withadjunctive clozapine. In another retrospective chartreview of 18 hospitalised patients (11 with bipolarand 7 with schizoaffective disorder) who had symp-toms that were refractory to conventional treatment,15 responded to clozapine monotherapy. 11 weresuccessfully maintained on clozapine monotherapyand required no further hospitalisation during the6-month follow-up period.[12]There are no double-blind studies of clozapine

in the treatment of bipolar disorder. Prospective stu-dies, however, also support the effectiveness of clo-zapine in the illness. In one study of 10 patientswith bipolar and 15 with schizoaffective disorderthat was refractory to conventional treatment whowere treated with clozapine monotherapy, 18 (72%)displayed a marked response. Patients with bipolardisorder displayed significantly greater improve-ment on the Brief Psychiatric Rating Scale (BPRS)than patients with schizoaffective disorder.[13]In another prospective, open-label trial, 30 hos-

pitalised patients who were manic were randomisedto treatment with clozapine or chlorpromazine for3 weeks. Despite significantly lower Young ManiaRating Scale (YMRS) scores in clozapine-treatedpatients at week 2, there were no significant differ-ences between the 2 groups at the end of the study.A significant limitation of this study, however, wasthe low dosage of clozapine (166 mg/day), as com-pared with the relatively high dosage of chlorprom-azine (310 mg/day).[14]In a third study, patients with treatment-refractory

bipolar (n = 26) or schizoaffective (n = 12) disorderwere randomised to clozapine add-on therapy orusual treatment. Patients randomised to clozapinedisplayed significant improvement in Clinical Glo-

434 Dunayevich & McElroy

© Adis International Limited. All rights reserved. CNS Drugs 2000 Jun; 13 (6)

bal Impression Scale (CGI), Scale for the Assess-ment of Positive Symptoms (SAPS), Scale for As-sessment of Negative Symptoms (SANS), Abnor-mal Involuntary Movement Scale (AIMS), BechRafelson Mania Scale and BPRS, and a decreasein total medication use. Patients with schizoaffec-tive disorder needed higher dosages of clozapine(mean of 623 [standard deviation (SD) = 260] mg/day) than did patients with bipolar disorder [meanof 234 (SD = 114) mg/day].[15]Open studies and case reports suggest that, in

addition to psychotic and nonpsychotic mania, clo-zapine is effective in patients with dysphoric ma-nia[16] and rapid-cycling bipolar disorder.[17,18] Itmay also be effective in adolescent mania[19] and,in low doses, in the treatment of geriatric patientswith bipolar disorder.[20]Clinical characteristics associated with good re-

sponse to clozapine include: (i) bipolar disorder,manic type; (ii) non-rapid cycling; and (iii) bipolardisorder rather than schizoaffective disorder. In oneretrospective review of 52 patients with bipolar dis-order receiving clozapine for a mean of 18.4 (SD= 11.6) months, the manic type of the illness wasassociated with higher rates of favourable outcomeat follow-up (73%) than were the mixed (58%) ordepressed (44%) types.[21] Depressive episodes priorto initiation of clozapine therapy were associatedwith eventual discontinuation of clozapine treat-ment.[21]In addition to the potential for agranulocytosis

and need for weekly blood counts in the first 6months of treatment and bi-weekly counts thereaf-ter, clozapine has a number of other drawbacks.These include:• sedation• bodyweight gain• sialorrhoea• anticholinergic effects such as constipation,blurred vision and urinary hesitancy or urinaryretention.Myoclonus and tonic-clonic seizures can also

occur at higher dosages, and it is a common prac-tice to add valproate semisodium (divalproex so-dium) to clozapine therapy when dosages equal or

exceed 500 mg/day.[6] Recently, myocarditis in pa-tients with schizophrenia receiving clozapine hasbeen described.[22] The use of carbamazepine isgenerally viewed as a contraindication in patientsreceiving clozapine, due to the increased risk ofagranulocytosis. However, there have been descrip-tions in the literature of patients successfully re-ceiving both drugs without ill effects.[23]

2. Risperidone

Before risperidone was studied in the treatmentof bipolar disorder, questions were raised about itsrole in the treatment of mania. A report by Dwightand colleagues[24] described the exacerbation orinduction of manic symptoms in 8 patients withschizoaffective disorder who were receiving ris-peridone. Six of these patients had a diagnosis ofschizoaffective disorder, bipolar type. Four werereceiving risperidone monotherapy, while 2 werereceiving concomitant mood stabiliser therapy. Allpatients with the bipolar subtype experienced onsetor exacerbation of manic symptoms as measuredby the YMRS.Further reports of similar phenomena include:

1 patient with schizoaffective disorder and 1 patientwith bipolar disorder in whommania worsened uponaddition of risperidone to ongoing mood stabilisertreatment;[25] and 2 patients with schizophrenia whodeveloped manic symptoms upon initiation of ris-peridone therapy.[26,27] A pilot study evaluated theefficacy of risperidone in 6 patients with bipolar Idisorder who had symptoms that were treatmentresistant or who were treatment intolerant (mono-therapy in 5 patients and combined perphenazineand risperidone therapy in 1 patient) and in 1 pa-tient with schizoaffective disorder.[28] 5 of 6 pa-tients discontinued risperidone therapy because ofadverse drug effects, including 3 due to a lack ofsignificant drug response or clinical worsening. Onepatient with schizoaffective disorder improved.In 2 of 3 other cases (1 patient with schizophrenia,

1 with schizoaffective disorder and 1 with bipolardisorder) manic symptoms noted upon initiation ofrisperidone therapy abated with dose reduction.[29]

Atypical Antipsychotics for Bipolar Disorder 435


A similar finding was reported in 10 outpatientswith bipolar disorderwhohad hypomanic symptoms.Risperidone was added to ongoing mood-stabilisingtreatment: 5 patients experienced response to low(0.5to 1 mg/day) dosages, with 3 experiencing activat-ing effects upon an increase of dosage. The remaining5 patients failed to achieve satisfactory response, 3of these due to an increase in manic symptoms.[30]No cases of induction or worsening of mania havebeen reported when risperidone was prescribed incombination with mood-stabiliser agents.Despite this initial adverse experience, several

case reports and case series have suggested thatrisperidone may indeed have a role in the treatmentof schizoaffective and bipolar disorders. In an out-patient private practice, 16 patients with bipolardisorder had risperidone added to ongoing mood-stabilising treatment, 10 on an as-needed and 6 ona scheduled basis, for the treatment of manic symp-toms. Seven patients (44%) had a complete clinicalresponse, while 6 has a partial response. Risperi-done had to be discontinued in 4 patients (25%) dueto adverse effects.[31]Patients with refractory mania have also experi-

enced symptomatic improvement (n = 2[32] and 5of 7[33]) when risperidone was added to their ongo-ing treatment regimen, without the induction of cy-cling or manic symptoms. Indeed, in a study thatsurveyed 144 charts of patients consecutively treatedwith risperidone at a state hospital, a diagnosis ofbipolar disorder was associated with a higher like-lihood of responding to risperidone than other di-agnoses.[34] A second retrospective chart review of35 patients with either bipolar or schizoaffectivedisorder treated with either risperidone or olanzap-ine showed no significant differences between eithertreatment group in CGI ratings, precipitation ofmania, duration of treatment or adverse effects.[35]An open-label, prospective pilot study of ris-

peridone and concurrent mood-stabilising drugs in15 acutely manic patients with psychotic featuresshowed 8 patients with 50% or higher improve-ment of the BPRS by week 2. 10 had at least a 50%improvement, as measured by the YMRS, and 13had at least a 25% improvement. Of the 8 patients

who completed 6 weeks of treatment, 7 had a 50%improvement, and all 8 had a 75% improvement byweek 12. No worsening of symptoms was repor-ted.[36] A similar study in 14 outpatients with typeI bipolar disorder reported that 9 (64%) patientswere ‘much improved’ based on CGI scores after2 weeks of treatment, and no patient experiencedworsening of mood symptoms while receiving ris-peridone.[37] A 6-month follow-up of 12 patientsshowed that 4 patients dropped out of the study dueto adverse effects or lack of efficacy, but another4 experienced a 10- to 25-point improvement inGlobal Assessment of Functioning (GAF) scoresand were rated ‘much better’ on the CGI. No pa-tient experienced a worsening of mania.[38]Controlled studies of risperidone include a re-

cently completed double-blind trial of patients withschizoaffective disorder.[39] 62 patients were ran-domised to treatment with risperidone, up to 10mg/day, or haloperidol, up to 20mg/day. Both agentswere equally effective in ameliorating psychoticand manic symptoms, but risperidone was signifi-cantly more effective in reducing depressive symp-toms and did not display a propensity to precipitatemania.Two controlled comparisons of risperidone in

the treatment of mania have also been conducted.In the first, 45 inpatients with DSM-IV[40]–diag-nosed bipolar disorder and an acute exacerbationof manic symptoms were randomised to risperidone6 mg/day (n = 15), haloperidol 10 mg/day (n = 15)or lithium 800 to 1200mg/day (n = 15) in a double-blind protocol. All 3 treatment groups showed sim-ilar improvement on BPRS, GAF and CGI.[41] Nosignificant difference existed in adverse effects ex-perienced between haloperidol and risperidonerecipients, but both groups of patients showed ahigher incidence of EPS as measured by the Simp-son-Angus scale than the lithium group, partly dueto the relatively high dosage of risperidone used.The results of this study were also limited by lowlithium concentrations (day 7 = 0.53 mmol/L, day21 = 0.62 mmol/L, day 28 = 0.72 mmol/L) and alack of a placebo arm.



In a second study, 158 patients with acute maniareceiving either lithium or valproic acid (sodiumvalproate) were randomised to receive add-on ther-apy with risperidone, haloperidol or placebo, forup to 3 weeks. Compared with placebo, patientsreceiving risperidone or haloperidol displayed sta-tistically significantly greater improvement at end-point evaluation as measured by YMRS and CGIscores. The risperidone versus placebo advantagein YMRS scores was apparent as early as week 1,but dropped to below significant levels at week 3(p = 0.085),[42] suggesting that combination ther-apy can produce more rapid remission of manicsymptoms than treatment with a mood stabiliseralone. Somnolence, dizziness and EPS, however,were more common in the haloperidol or risperi-done group than in the placebo group. This studyis limited in its interpretation by the use of some-what low serum mood stabiliser concentrations.Risperidone has also been reported as being ef-

fective as add-on treatment for rapid-cycling bi-polar disorder refractory to mood stabiliser treat-ment.[43] A case report[44] and a retrospective chartreview[45] suggest that the use of risperidone in ad-dition to mood stabiliser therapy is well toleratedand effective in alleviating manic symptoms in ad-olescents. Risperidone has also been reported to beeffective in the treatment of mania associated withHIV in 4 patients.[46]Thus, it appears that, as reported in controlled

studies, risperidone can be effective for the treatmentof mania. Risperidone is a well tolerated agent withminimal anticholinergic adverse effects, and min-imal potential for blood dyscrasias or liver func-tion abnormalities. This is especially advantageouswhen treating medically ill and elderly patients.Risperidone appears to be less likely to be associatedwith bodyweight gain than olanzapine or clozap-ine;[47] however, it has a higher likelihood of causingelevations in prolactin level than these agents.[48]The potential for EPS increases with dosage.

3. Olanzapine

Case reports have suggested that olanzapine iswell tolerated and effective in the treatment of bi-

polar disorder, including in patients with mania,[49]depression[50] or mixed states,[51,52] and in adoles-cents.[53,54]A prospective study was performed in which 14

consecutive patients with bipolar I disorder thatwas inadequately responsive to standard psycho-tropic agents received olanzapine in an open-label,add-on protocol at a mean dosage of 14 mg/day.Patients were followed for a mean of 101 days oftreatment. Eight patients (57%) were classified asbeing ‘much’ or ‘very much’ improved. The mostcommon adverse effects were sedation, tremor, drymouth, and appetite stimulation with bodyweightgain.[55]Asimilar trial in 9 inpatients experiencing amixed

state of bipolar disorder showed significant improve-ment in symptoms as measured by the BPRS andGAF.[56] In a retrospective chart review assessingthe response to olanzapine in 150 consecutive in-patients, moderate-to-marked response was asso-ciated with female gender and a diagnosis of bipo-lar disorder.[57] A recent report suggests that, whenused for augmentation of mood stabiliser therapy,olanzapine can be effective in up to 70% of patientswith acute episodes of psychotic and nonpsychoticmanic and mixed states, as well as for prophylaxisof further episodes.[58]Three controlled studies of the use of olanzap-

ine in mania have been reported. In the first study,olanzapine was compared with lithium in a double-blind, randomised manner. No significant outcomedifferences between the 2 groups were noted onBPRS, CGI improvement scale or Mania scale. Atweek 4, olanzapine was superior to lithium on theCGI severity scale (p = 0.02).[59] This study waslimited in its conclusions by low olanzapine (10mg/day) and low lithium (800 mg/day, mean lith-ium concentration of 0.74 mmol/L) dosages, andthe lack of a placebo arm.In a further 2 studies, the use of olanzapine in

acute mania was examined in a randomised, double-blind, placebo-controlled design.[60,61] In 1 studyof 139 patients with acute manic symptoms, signif-icantly more olanzapine-treated patients (48.6%)responded than did those assigned to placebo



(24.2%), as measured by CGI. However, only sleep,irritability and total YMRS scores were significantlydifferent from placebo, with elevated mood almostreaching significance (p = 0.06). No significant dif-ferences were noted between the olanzapine- andplacebo-treated patients with respect to measuresof parkinsonism, akathisia and dyskinesias. No dis-continuations of treatment due to adverse eventsoccurred in the olanzapine treatment group.[60]The second study involved 115 patients with

bipolar disorder who were experiencing an acutemanic episode. A higher initial olanzapine dosagewas used (15 versus 10 mg/day) than in the pre-vious study. A statistically significant improvementby week 1, in CGI, YMRS and Positive and Ne-gative Symptom Assessment Scale (PANSS) totalscores, were noted in patients receiving olanzapine.These improvements were sustained through week4. Patients presenting with depressive symptomsaccording to the 21-itemHamilton Depression Rat-ing Scale (HDRS-21; >19) demonstrated a signifi-cant improvement in scores on this scale comparedwith placebo. At study completion, a greater than50% improvement in YMRS total score was foundin 65% of patients treated with olanzapine, com-pared with in 42% of patients receiving placebo (p= 0.023).[61] Both patients with and without psy-chotic features experienced similar levels of im-provement in this study.Olanzapine appears to also be effective in the

maintenance phase of bipolar disorder. When 113patients were treated in an open-label fashion witholanzapine for 49 weeks, significant improvementwas found in cognitive and manic symptoms, aswell as a reduction of hostility.[62] A limitation ofthis study, in addition to the open-label design, wasthat adjunctive lithium was used in 35 (31%) pa-tients, while 36 (32%) received adjunctive fluoxet-ine. It is also important to mention that inductionor worsening of mania has been associated witholanzapine treatment in some case reports.[63-66]Olanzapine is usually a well tolerated agent. Its

main adverse effects include somnolence, sedation,dry mouth and constipation. EPS, including akathi-sia, are more common at the higher end of the dos-

age range. Bodyweight gain is also significantlyassociated with the use of olanzapine.

4. Quetiapine

Quetiapine is the most recent atypical antipsy-chotic approved by the US Food and Drug Admin-istration (FDA) for the treatment of schizophrenia.It is also available for this indication in a numberof other countries, including the UK, Germany andCanada, and is being assessed for approval in var-ious others.To date, experience with quetiapine in bipolar

disorder is limited. Ghaemi and Katzow[67] descri-bed 2 (of 6) patients with symptoms that were re-fractory to standard treatment who responded toquetiapine after open-label treatment. Another pa-tient who also had symptoms resistant to standardtreatment was reported to respond to the additionof quetiapine to lithium.[68] A case series reportedon 9 patients with bipolar disorder and 7 with schizo-affective disorder who required both mood stabilis-ing and antipsychotic medication. They receivedadd-on quetiapine (mean dosage 155 mg/day) in anopen label protocol while standard antipsychotictherapy was withdrawn. Patients were prospectivelyevaluated and found to display significant improve-ment in BPRS, YMRS and HDRS rating scales af-ter a mean of 11 weeks of treatment.[69]Another case series reported on the adjunctive

use of quetiapine in 6 patients with acute mania andthe use of quetiapine monotherapy in another pa-tient with mania. Moderate to marked improvementwas retrospectively observed in 5 patients as mea-sured by CGI, and no worsening of manic symptomswas evidenced (Dunayevich et al., unpublished ob-servations). However, in addition to its retrospec-tive design, this study was also limited by the con-current initiation of mood stabiliser and quetiapinetherapy in 5 patients.Unlike risperidone and olanzapine, and similarly

to clozapine, quetiapine appears to induce little tono EPS as the dosage is increased. However, its useis commonly associated with sedation, lighthead-edness, hypotension and mild anticholinergic ad-verse effects. It has also been recommended that



ocular exams be performed on a regular basis tomonitor for potential opacification of the crystal-line lens.So far, quetiapine appears to be a promising agent

in the treatment of bipolar disorder, but controlledtrials are required.

5. Ziprasidone

Ziprasidone is currently under review by the FDAfor the treatment of schizophrenia. It has been eval-uated in 1 placebo-controlled, double-blind studyin patients with DSM-IV–diagnosed bipolar manicor mixed episodes. The results of this study arecurrently being analysed.

6. Atypical Antipsychotics and Tardive Dyskinesia

Clinical experience with atypical antipsychot-ics indicates that the prevalence of acute and tard-ive EPS is significantly lower than with conven-tional agents.[2,3,36,60,62] However, most of the dataavailable regarding long term use of atypical anti-psychotics have been on patients with schizophreniaand schizoaffective disorder, rather than patientswith bipolar disorder. Patients with bipolar disor-der may be at risk for more frequent or more severetardive dyskinesia, as compared with patients withschizophrenia.[70] Case reports have suggested that,like conventional antipsychotics, atypical agentsincluding risperidone,[71-76] quetiapine,[77] olanza-pine[78,79] and clozapine[80] can be associated withtardive dyskinesia and tardive dystonia. However,controlled studies suggest that this occurs at a lowerfrequency than with conventional agents.[3] An im-portant caveat is that clozapine in particular,[81-83]but also risperidone[84,85] and olanzapine,[86-88] havebeen reported to be effective in the treatment oftardive movement disorders.

7. Conclusions

Atypical antipsychotics are commonly being usedin the treatment of bipolar disorder, most often foracute manic and psychotic symptoms. These drugsappear to be well tolerated and effective, and re-

cently the FDA released an approvable letter forolanzapine in the treatment of acute mania. Thereare emerging data suggesting these agentsmay alsobe useful in the treatment of the depressed phaseof bipolar disorder.[10,57,89,90]However, antipsychotic treatment can be asso-

ciated with the emergence of potentially seriousendocrinological (bodyweight gain, hyperprolac-tinaemia, abnormalities of thermoregulation) andneurological (parkinsonism and tardive movementdisorders) adverse effects. Thus, caution should beexercised in the prescription of these agents, espe-cially for extended periods. Patients should beclosely monitored for the emergence of adverseeffects, and alternative treatments that could re-place antipsychotic therapy should be consideredand discussed with the patients on a regular basis.

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Correspondence and offprints: Dr Eduardo Dunayevich,Clinical Psychobiology Program, Department of Psychia-try, University of Cincinnati, PO Box 670559, Cincinnati,OH 45267-0559, USA.E-mail: [email protected]



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