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General Hospital Psychiatry 26 (2004) 233–236

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Brief Reportshis section will carry communications of work in progress, preliminary research reports, or interesting and unusual vignettes. Such reportsill be considered for their practical clinical relevance or heuristic value.

Mood-stabilizer-maintained, remitted bipolar patients: taper anddiscontinuation of adjunctive antipsychotic medication

John R. Saksa, Psy.D.*, C. Bruce Baker, M.D., J.D., Scott W. Woods, M.D.Department of Psychiatry, Yale University School of Medicine, 34 Park Street, New Haven, CT 06519, USA

Received 24 December 2003; accepted 11 February 2004

bstract

The aim of this study was to determine whether bipolar patients who had been stabilized on combined antipsychotic and mood-stabilizeredications and were currently in remission benefited from continuation of the antipsychotic medication. Remitted bipolar patients were

andomly assigned to either remain on adjunctive antipsychotic medication or to taper to placebo. Antipsychotic/placebo medicationssignment was double-blind. Subjects were outpatients at a university-affiliated community mental health center. Fifteen subjects consentednd proceeded with eligibility assessments. Five subjects were never randomized. One of these was excluded when the Structured Clinicalnterview for DSM-IV interview revealed schizoaffective disorder. The remaining four subjects were not randomized for other reasons.hree randomized subjects never received study medications, or were withdrawn by the investigator within 1 week after beginning studyedications. The seven remaining subjects received study medication for more than 1 week. Five subjects were randomized to taper to

lacebo and two to antipsychotic continuation. Of the five randomized to taper to placebo, three successfully tapered and completed the yearf follow-up in continuous remission. One subject became manic 4 months after taper was completed, and one subject became psychotic,n the absence of a mood episode, during taper. Of the two subjects randomized to double-blind antipsychotic continuation, both completedhe year of follow-up in continuous remission. When adjunctive antipsychotic medications are discontinued, bipolar patients’ clinicalymptoms can remain unchanged. Others are, however, at risk for manic relapse. © 2004 Elsevier Inc. All rights reserved.

eywords: Bipolar disorder; Taper; Adjunctive antipsychotic medications

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We recently enrolled 15 bipolar subjects in a double-lind taper study that would potentially discontinue theirntipsychotic medications. Diagnosis was established bytructured Clinical Interview for DSM-IV. We conducted

his study because the long-term use of conventional anti-sychotic medications for bipolar disorder is generally dis-ouraged [1,2], but antipsychotic medications are frequentlyrescribed beyond the acute treatment phase of an episode.ne study from the early 1990s discovered that 40 of 45

onsecutively discharged bipolar inpatients were receivingntipsychotic medication at the time of discharge [3]. Ofhose 40 patients, 38 (95%) remained on antipsychotic med-cation at 6-month follow-up. Similar findings were re-orted by Keck et al. [4].

* Corresponding author. Tel.: �1-203-974-7043; fax: �1-203-974-057.

pE-mail address: john.saksa@yale.edu (J.R. Saksa).

163-8343/04/$ – see front matter © 2004 Elsevier Inc. All rights reserved.oi:10.1016/j.genhosppsych.2004.02.002

The benefits of long-term conventional antipsychoticrug use in bipolar disorder have been documented weaklyn the research literature. The uncertain benefits of mainte-ance conventional antipsychotic medication in bipolar pa-ients suggest a need for discontinuation studies. However,nly two previous articles have addressed antipsychoticedication discontinuation in bipolar patients [5,6].The risks associated with long-term antipsychotic treat-

ent in bipolar disorder patients include tardive dyskinesiaTD), neuroleptic malignant syndrome, extrapyramidal sideffects, diabetes, and weight gain [7–9]. TD risk may beliminated with the novel antipsychotic clozapine, but theisks of clozapine have reserved it for refractory cases. TDisk may be lower with the novel antipsychotic medication,lanzapine, although questions have been raised about thene published study [10].

Many patients are started concurrently on both an anti-

sychotic and mood stabilizer, and their subsequent im-

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234 J.R. Saksa et al. / General Hospital Psychiatry 26 (2004) 233–236

rovement is not clearly attributable to either medication.iven the uncertain benefits of maintenance adjunctive an-

ipsychotic medications in bipolar patients, it is possiblehat some proportion of such patients do not receive benefitrom the adjunctive antipsychotic. The importance of thisossibility is accentuated by the known risks of long-termntipsychotic medication. Therefore, we recently conductedstudy that sought to determine the relative clinical out-

omes associated with randomization to adjunctive antipsy-hotic medication continuation versus discontinuation. Pa-ients considered appropriate for the study were those whoad achieved sustained remission and in whom the moodtabilizer and adjunctive antipsychotic had been started si-ultaneously, or nearly so. In all cases no determination

ould be made about which medication was responsible forhe subjects’ remissions. Specific details about the exactymptoms being targeted by the antipsychotic medicationere not available. Antipsychotic medications were started

ither concurrent with the initiation of the mood-stabilizeredication, or when an increase or change in the mood-

able 1ssignment, medications, doses, and outcomes of subjects participating fo

aseo.

Randomizationassignmenta

Medications and dose

Antipsychotic Mood stabilizer(level)

Other

C Perphenezine Divalproex Imipramin40 mg 2000 mg (69) 100 mg

Benztropin4 mgSertraline200 mg

C Haloperidol Divalproex Benztropin0.5 mg 1000 mg (68) 1 mg

T Perphenezine Divalproex Benztropin32 mg 1500 mg (74) 2 mg

Trazadone50 mg

T Thioridazine Carbamazepine –100 mg 600 mg (6.4)

T Haloperidol20 mg

Divalproex500 mg (62)

Benztropin4 mg

1 T Thiothixene30 mg

Divalproex1500 mg (57)

Benztropin1 mg

3 T Risperidone6 mg

Lithium900 mg (.31)Divalproex2500 mg (56)

Benztropin1 mg

a T � taper; C � control.

tabilizer medication was being made. Subjects were seen t

eekly by research staff to monitor their clinical condition.rimary assessments included the Young Mania Ratingcale (MRS) and the Depression Symptom Scale (DSS).hese were also used to operationally define relapse andtudy-exit. An MRS score of 16 or higher or a DSS score of5 or higher would result in the subject being exited fromhe study.

Three subjects were successfully tapered and completedyear of follow-up in continuous remission (see Table 1).wo subjects were controls and sustained their remissionithout any medication reduction. One subject becameanic 4 months after taper was completed, and one subject

ecame psychotic during taper. Additionally, eight otherubjects were initially enrolled, but were never randomizedr were administratively withdrawn within 1 week of studyarticipation due to either new information indicating ex-lusion criteria or subjects’ withdrawal of consent. Limita-ions of this study are that the sample size is very small andhat we are unable to report valid quantitative data. As aesult, it was not possible to predict what factors contribute

than 1 week

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Index diagnosis Detail

Bipolar I, MRE manic Completed studyRemission sustained

Bipolar I, MRE depressed Completed studyRemission sustained

Bipolar I, MRE depressed Completed studyRemission sustained

Bipolar I, MRE mixed Completed studyRemission sustained

Bipolar I, MRE mixed Completed studyRemission sustained

Bipolar I, single manic episode Became manic at week 28,which is 16 weeks aftertaper was completed

Withdrawn from studyBipolar I, MRE manic Became psychotic in

absence of moodcomponent at week 12,which was the time pointat which the taper wasabout to be completed. Atweek 12 patient wouldhave been taking 25% ofher prestudy dose.Withdrawn from study.

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235J.R. Saksa et al. / General Hospital Psychiatry 26 (2004) 233–236

inuation in bipolar disorder. In addition, these remittedipolar patients from our community mental health centerractice may not be representative of remitted patients seenn other practices. The seven subjects all remained on dis-bility or other form of assistance and were either unem-loyed or significantly underemployed in part-time or tem-orary positions despite their current maintained-in-emission status for a minimum of 3 months.

The strengths of the current study are that taper as-ignment was randomized and double-blind. Additionally,oth the investigator and subject were blind regardinghen the taper was initiated. Many bipolar patients are

tarted concurrently on both antipsychotic and mood-tabilizing medications and their improvement is not clearlyttributable to either. It is those cases for whom this studyas intended. Our findings suggest that, on the one hand,

ome stable bipolar patients may be successful in discon-inuing adjunctive antipsychotic medications and experi-nce no change in clinical condition. On the other hand,his study suggests there is a risk associated with suchiscontinuation. The adjunctive antipsychotic medicationpparently contributes to the stabilization of some mood-tabilizer–maintained bipolar patients, such as in theubject who became manic, who may have been an un-ecognized nonresponder to the primary mood stabilizer.ther patients who are completely asymptomatic mightevertheless be schizoaffective rather than bipolar and re-uire the antipsychotic medication, such as in the subjectho became psychotic.The question of whether to continue or discontinue

ntipsychotic medications in mood-stabilizer–main-ained, remitted bipolar patients remains an importantne to current practice. Recently revised practice guide-ines continue to support acute treatment of severe bipo-ar patients with adjunctive antipsychotic medications,hile advising mood-stabilizer monotherapy for less se-ere patients [11]. These guidelines also acknowledge noefinitive evidence in support of maintenance antipsy-hotic medications, advising their discontinuation unlessequired for persistent psychotic symptoms or preventionf recurrence of the mood episode.

The risk/benefit for long-term combination treatmentith both antipsychotic and mood-stabilizing medicationsas shifted somewhat with the atypicals. The guidelinesecommend the atypical antipsychotics as preferable to theonventional antipsychotics because of a more benign sideffect profile [11]. Like the conventional antipsychotics, thetypicals have demonstrated acute efficacy for mania [12–5]. Also similar to the conventionals, atypicals have dem-nstrated augmentation benefit to patients otherwise non-esponsive to lithium or valproate [16]. Randomizedaintenance data, however, are still lacking although some

pen-label studies are available [17–19]. Moreover, the rel-tive safety of the atypicals versus conventionals has be-ome a more complicated issue in recent years. The newer

rugs clearly have an improved side effect profile with

egard to extrapyramidal side effects. Concerns are grow-ng, however, about the risk of weight gain and diabetesith the atypicals [7–9]. Although some data suggest TD

isks are low with atypicals, the number of published studiess still relatively small, leaving this issue not fully resolved10].

There continues to be no easy answer to the questionf antipsychotic medication discontinuation in mood-tabilizer–maintained, remitted bipolar patients. The pa-ient and prescriber are in a difficult situation, not know-ng which medication is responsible for the current re-ission [20]. Given the risks inherent in continuing or

iscontinuing adjunctive antipsychotic medications, itay be better to initiate mood-stabilizer treatment during

he acute episode without adjunctive antipsychotic med-cation when feasible.

cknowledgments

Supported by a grant from the National Alliance foresearch on Schizophrenia and Depression, award number01356.

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