1835

Am J Psychiatry 158:11, November 2001 1835

Article

Clinical Outcome Following Neuroleptic Discontinuation in Patients With Remitted Recent-Onset Schizophrenia

Michael Gitlin, M.D.

Keith Nuechterlein, Ph.D.

Kenneth L. Subotnik, Ph.D.

Joseph Ventura, Ph.D.

Jim Mintz, Ph.D.

David L. Fogelson, M.D.

George Bartzokis, M.D.

Manickam Aravagiri, Ph.D.

Objective: The goal of this report was to

examine the clinical course following

neuroleptic discontinuation of patients

with recent-onset schizophrenia who had

been receiving maintenance antipsy-

chotic treatment for at least 1 year.

Method: Fifty-three volunteer patients

with recent-onset schizophrenia who had

been clinically stabilized on a mainte-

nance regimen of fluphenazine decanoate

for a mean of 16.7 months had their anti-

psychotic medications withdrawn under

clinical supervision. Participants initially

entered a 24-week, double-blind crossover

trial in which fluphenazine and placebo

were administered for 12 weeks each. For

those who did not experience symptom

exacerbation or relapse during this period,

fluphenazine was openly withdrawn; par-

ticipants were then followed for up to 18

additional months.

Results: When a low threshold for defin-ing symptom reemergence was used, 78%(N=39 of 50) of the patients experiencedan exacerbation or relapse within 1 year;96% (N=48 of 50) did so within 2 years.Mean time to exacerbation or relapse was235 days. When hospitalization was usedas a relapse criterion, only six of 45 of in-dividuals (13%) experiencing an exacerba-tion or relapse who continued in treat-ment in the clinic were hospitalized,demonstrating the sensitivity of the psy-chotic exacerbation criterion.

Conclusions: The vast majority of clini-cally stable individuals with recent-onsetschizophrenia will experience an exacer-bation or relapse after antipsychotic dis-continuation, even after more than a yearof maintenance medication. However,clinical monitoring and a low thresholdfor reinstating medications can preventhospitalization for the majority of thesepatients.

(Am J Psychiatry 2001; 158:1835–1842)

Consistent evidence shows that neuroleptics, admin-istered as a maintenance treatment, reduce relapse ratesin schizophrenic patients. A comprehensive review thatanalyzed 66 studies found a mean cumulative relapse rateof 53% in patients withdrawn from neuroleptic therapycompared to 16% for those maintained on a regimen ofneuroleptic therapy over a mean follow-up period of 9.7months (1). Despite this conclusion, many questions re-main regarding the optimal use of antipsychotics as amaintenance treatment.

A central question is how long to continue maintenanceantipsychotic treatment for patients after their first epi-sode of schizophrenia. Patients in the early course ofschizophrenia frequently request a decrease or discon-tinuance of their antipsychotic medications, and manyhave poor adherence to treatment (2). After successful an-tipsychotic treatment, many patients believe that they willno longer need medication. Given that the early course ofthe disorder is highly variable across patients and is gener-ally not well characterized in the literature, clinicians arehard put to insist on indefinite neuroleptic treatment.Among the 66 studies reviewed in the article by Gilbert etal. (1), only two examined relapse rates in first-break orrecent-onset patients (3, 4). In the first of the two studies,

seven of 17 patients (41%) with remitted first-episodepsychosis who received placebo experienced a relapse,whereas none of the 11 patients who continued takingfluphenazine over a 1-year period relapsed (3). In contrast,Crow et al. (4) randomly assigned 120 first-break schizo-phrenia patients to continued treatment with antipsy-chotic medication (five different agents were used) or pla-cebo following acute treatment. Relapse rates over a 2-year period were 62% for those given placebo versus 46%for those receiving active medication. In these two initialstudies, random assignment to possible placebo treat-ment occurred shortly after resolution of psychotic symp-toms. Since the Gilbert et al. review (1) was published, weknow of one other study that has addressed the risk of re-lapse after medication discontinuation in first-breakschizophrenia patients. Robinson et al. (5) found that pa-tients who discontinued antipsychotic medications (notrandomly assigned but self-selected) following at least 1year of treatment relapsed at a rate almost five times thatof those who continued taking medications over a 5-yearperiod. Specific data on relapse rates for patients who dis-continued medications were not provided.

In addition to the scarcity of studies involving first-break schizophrenia patients and the discrepant results

1836 Am J Psychiatry 158:11, November 2001

OUTCOME FOLLOWING NEUROLEPTIC WITHDRAWAL

in these three studies (clear benefit of continued treat-ment [3, 5] versus a less robust effect [4]), many questionsremain. For example, the Kane et al. study (3), with a totalof 28 subjects, included patients with diagnoses of maniawith schizotypal features (N=1), depression with schizo-typal features (N=1), unspecified functional psychosis(N=3), and other psychiatric disorders (N=4), leaving only19 schizophrenic patients within the study group. Fur-thermore, as has been described in detail elsewhere (1, 6,7), definitions of “relapse” differ markedly across studies.Relapse rates are likely to differ across studies when thedefinition of the term ranges from return of active medi-cation to a specified change in symptom rating scales orhospitalization. Consistent with this definitional disarray,the rate of relapse during neuroleptic withdrawal acrossall studies included in the review (1) ranged from 0% to100%!

Studies with more sensitive, symptom-based defini-tions of relapse will likely show higher rates of relapse butlower rates of hospitalization, since reinstitution of treat-ment will occur more quickly. The Kane et al. study (3)used the criteria of “substantial clinical deterioration witha potential for marked social impairment,” whereas Crowet al. (4) defined relapse as a point at which the responsi-ble clinician considered rehospitalization to be necessaryor resumption of active antipsychotic medication essen-tial. In the Robinson et al. study (5), relapse was defined asat least “moderately ill” on the CGI severity scale (8),“much worse” or “very much worse” on the CGI improve-ment scale, and a rating of “moderate” for at least 1 weekon one or more psychotic symptom items from the Sched-ule for Affective Disorders and Schizophrenia—ChangeVersion With Psychosis and Disorganization Items (9).

Current consensus suggests approximately 1 year of an-tipsychotic treatment for a first episode of schizophreniafollowed by consideration of medication discontinuationfor stable patients. In 1991, Johnson (10) recommendedcontinuing medication for 12–24 months depending onthe patient’s stability, followed by a gradual discontinua-tion of medication. Similar recommendations have beenmade elsewhere in 1997 and 1998 (11, 12). The APA Prac-tice Guideline for the Treatment of Patients With Schizo-phrenia (13), published in 1997, states that “a patient whohas had only one episode of positive symptoms and hashad no symptoms during the following year of mainte-nance therapy may be considered for a trial period with-out medication.”

Despite these consistent recommendations, the naturalhistory of clinically stable patients with recent-onset (i.e.,nonchronic) schizophrenia who discontinue antipsy-chotic medication remains relatively unexplored by sys-tematic clinical study, leading to a lack of empirical basisfor decisions about continuing maintenance antipsy-chotic medication after an initial year. Therefore, to helpclarify this issue, as one phase of a longitudinal study, weexamined the clinical course of a cohort of patients with

recent-onset schizophrenia who gave permission to havetheir antipsychotic medication withdrawn while continu-ing to receive ongoing psychosocial treatment and pro-spective clinical management. The design of this study(conducted between 1982 and 1993) parallels fairly closelythe schizophrenia treatment recommendations publishedbefore, during, and after the current study.

In essence, this study may be viewed as an attempt toapply a targeted medication approach to a recent-onsetschizophrenia cohort (14–16), in that patients were fol-lowed regularly when not receiving medication, and treat-ment was again recommended as soon as symptom exac-erbation occurred. As has been noted elsewhere (16),targeted medication approaches might be most applica-ble for clinically stable patients in the early phases ofschizophrenia. At this point, patients are frequently un-willing to commit to long-term maintenance medicationand voice concerns about avoiding adverse side effects.

Method

The 53 participants in this study were drawn from a larger co-hort of patients (N=104) followed as part of a three-phase longi-tudinal study evaluating the roles of vulnerability factors andstressors in recent-onset schizophrenia patients—the Develop-mental Processes in Schizophrenic Disorders Project (17, 18). En-try criteria required all subjects to have had their first onset of apsychotic episode no more than 2 years before study entry. Sev-enty-nine percent (N=42 of 53) of participants were in their firstpsychotic episode at the time of study entry. All subjects met Re-search Diagnostic Criteria (19) for schizophrenia or schizoaffec-tive disorder, mainly schizophrenic subtype. Full inclusion andexclusion criteria are presented elsewhere (17, 18). Briefly, sub-jects were 18–45 years of age (mean=25.0 years, SD=4.3) and hadno evidence of a neurological disorder (e.g., epilepsy, encephali-tis). Additionally, patients with a history of significant and habit-ual drug use in the 6 months before study entry and those forwhom there was substantive evidence that drug use triggered thepsychotic episode were excluded from the study. All subjectswere treated every 2 weeks with fluphenazine decanoate admin-istered intramuscularly with an initial target dose of 12.5 mg.Doses were increased to a higher maintenance level during thecourse of the first outpatient year if the subject’s symptoms werenot adequately controlled. Doses were decreased if intolerableside effects could not be adequately controlled by antiparkinso-nian medications.

To be considered for inclusion in the neuroleptic discontinu-ation protocol that is the subject of this report, individuals wererequired to have their antipsychotic regimen stabilized and tobe clinically stable. Specific inclusion criteria were 1) fluphena-zine decanoate treatment for at least 1 year with clinical evalua-tions every 2 weeks, and 2) no notable psychotic symptoms forat least the last 3 months. The mean length of fluphenazinetreatment before entry into this protocol was 16.7 months (SD=5.5). An exclusion criterion was the treating psychiatrist’s clini-cal judgment that the patient was too unstable to be consideredfor medication withdrawal (even if rating scale criteria for clini-cal stability were met). With these criteria, 54 of the original co-hort of 104 patients were eligible for the study. The 54 subjectsdid not differ in age, gender, ethnicity, educational background,socioeconomic status, length of illness before study entry, or ageat onset from the other 50 individuals who were ineligible for theprotocol. Of the 51 subjects who did not enter this study, 28 had


GITLIN, NUECHTERLEIN, SUBOTNICK, ET AL.

dropped out of the clinic, 21 were excluded because of insuffi-cient clinical stability, one subject was excluded per the psy-chiatrist’s clinical judgment, and one eligible subject declined toenter the study because of fear of a potential return of symptoms.

Table 1 presents the demographic data for the 53 individualsincluded in the study.

Treatment Protocol

During the first 24 weeks of the study, patients were randomlyassigned to treatment in a double-blind fashion to 12 weeks oftheir usual fluphenazine decanoate regimen or 12 weeks of pla-cebo treatment, administered by a research nurse or physician. Asshown in Figure 1, those assigned to condition A were given pla-cebo followed by active drug, while those in condition B weregiven their usual dose of fluphenazine decanoate followed by pla-cebo. For patients who did not experience symptom exacerbationor psychotic relapse during these 24 weeks, intramuscular medi-cation shots were openly discontinued, and the patient was fol-lowed for up to 18 months. Thus, the entire time of observation inthis study was 102 weeks, or just under 2 years.

During the first 24 weeks of the study (the double-blind cross-over phase), patients were seen every 2 weeks and were evaluatedwith the expanded Brief Psychiatric Rating Scale (BPRS) (20) bytheir case managers. Each rater achieved a median intraclass cor-relation coefficient of 0.80 or higher across all BPRS items com-pared with the criterion ratings (21). During the open withdrawalphase, patients were evaluated with the BPRS every 2 weeks forthe first 6 months and then every 4 weeks thereafter. If dictated byclinical need, the frequency of clinical evaluations was increased.Aside from the scheduled BPRS evaluation, if a patient called witha possible change in symptoms, a BPRS rating was done at thatpoint.

Patients were removed from the medication discontinuationtrial if any of the following three conditions were met: 1) An in-crease in psychotic symptoms assessed with the BPRS met the apriori definition for exacerbation or relapse. The definition of ex-acerbation was any 2-point change on any of the three BPRS psy-chotic items (hallucinations, unusual thought content, and con-ceptual disorganization), excluding changes in which the ratingsremained at nonpsychotic levels (i.e., ≤3). Psychotic relapse wasdefined as a rating of 6 or 7 on any of the three BPRS psychoticsymptom items. One patient had a nonpsychotic relapse (depres-sion), which was not included in the current analysis. 2) A wors-ening of clinical condition occurred that warranted a change intreatment according to the treating psychiatrist, even if the BPRS

ratings did not meet criteria for exacerbation or relapse. 3) Thepatient decided to withdraw from protocol participation. The cri-teria for removal from the medication discontinuation trial werepurposely sensitive to relatively small symptomatic changes. Ourgoal was to intervene as soon as it became clear that the patienthad a clinically significant return of symptoms in order to avoid,as much as possible, a full psychotic episode.

Information on the nature of the double-blind crossover andthe open medication withdrawal components of this protocolwas described verbally and with a written informed consent form.After complete description of the study to the potential partici-pants, written informed consent (approved by the institutionalreview board of the University of California, Los Angeles, and theNational Institute of Mental Health) was obtained before studyentry. These informed consent procedures were separate fromthe procedures that occurred at entry into the preceding protocol,which involved repeated assessment batteries during an initialyear of maintenance treatment with fluphenazine decanoate.

Blood samples for fluphenazine levels were scheduled to bedrawn every 2 weeks during the crossover portion of the studyand every 4 weeks during the first 6 months of open withdrawal.To accommodate patients’ personal schedules, occasionally pa-tients were seen and had their blood drawn 3 weeks after the priorfluphenazine injection. During the crossover phase of the proto-col, blood samples were taken before the administration of thenext intramuscular shot.

Plasma levels of fluphenazine were measured by using a spe-cific radioimmunoassay that was validated for specificity by usinggas chromatography mass spectroscopy (22, 23). The sensitivityof the assay was 0.1 ng/ml for most of the samples analyzed. Thecoefficient of variation was 3%. Some of the initial samples wereanalyzed by an earlier method with a sensitivity of 0.3 ng/ml.

Data Analysis

In calculating time to return of psychotic symptoms, we used 2weeks after the last active fluphenazine injection as day 0 of drugwithdrawal; for example, a return of psychotic symptoms de-clared at 14 days occurred 28 days after the last injection. Drugwithdrawal was considered to start during the placebo conditionfor subjects whose psychotic symptoms returned during initialassignment to placebo in the crossover phase (condition A in Fig-ure 1). Condition A subjects who did not experience a return ofpsychotic symptoms during the placebo condition and had their

TABLE 1. Demographic and Clinical Characteristics of 53Clinically Stable Patients With Recent-Onset Schizophre-niaa Who Voluntarily Entered an Antipsychotic WithdrawalProtocol

Characteristic N %Male gender 46 87Diagnosis

Research Diagnostic Criteria (19)Schizophrenia 47 89Schizoaffective disorder, mainly

schizophrenic subtype 6 11DSM-III-R schizophrenia, schizoaffective

disorder, or schizophreniform disorder 44 83Ethnicity

Caucasian 44 83Latino 5 9Asian American 2 4Mixed 2 4

a Patients had experienced their first psychotic episode no more than2 years earlier, had received fluphenazine treatment for at least 1year with clinical evaluations every 2 weeks, and had been free ofnotable psychotic symptoms for at least 3 months.

FIGURE 1. Antipsychotic Withdrawal Protocol for 53 Clini-cally Stable Patients With Recent-Onset Schizophreniaa


Months Since StabilizationWith Fluphenazine Decanoate

No Medication

No MedicationFluphenazine

Decanoate(at least1 year)

Condition A

Condition B

Placebo(12 weeks)

Placebo(12 weeks)

Fluphen-azine

Decanoate (12 weeks)

Fluphen-azine

Decanoate (12 weeks)

Open WithdrawalPhase

StabilizationPhase

Double-BlindCrossover Phase

12 13 14 15 16 17 18 19 20 21 22 23 ... 36



medications reinstated after 12 weeks were considered to startdrug withdrawal at the time of open withdrawal. Those subjectsassigned to condition B (Figure 1) were considered to start drugwithdrawal during the placebo phase of the crossover componentof the protocol. Time to relapse was analyzed by using product-limit (Kaplan-Meier) survival analysis (24). Analysis of the effectsof fluphenazine levels on relapse risk were done by using propor-tional hazard regression, with baseline and most recent fluphena-zine level included as time-varying covariates (25). In addition tothe tests of significance for the survival parameters, estimatedhazard ratios from the proportional hazard regression are re-ported with 95% confidence intervals (CIs).

Results

Crossover Phase

During the 24-week crossover phase of the study, 10 of53 subjects (19%) experienced an exacerbation or relapse,three during the medication period and seven while re-ceiving placebo. As seen in Table 2, fluphenazine levelsslowly decreased during the placebo period of the cross-over protocol. However, even after 12 weeks of placebo,plasma levels of fluphenazine remained substantial inmany patients. As an example, at the end of the first 12weeks, the difference in mean fluphenazine levels be-tween those treated with active medication versus placebowas not significant (Table 2).

Withdrawal Phase

The three subjects who experienced an exacerbation orrelapse during the active medication phase of the cross-over protocol were not included in the withdrawal analy-sis, leaving 50 subjects. The seven subjects who experi-enced an exacerbation or relapse during the placebocondition of the crossover phase were included in the sur-vival analysis.

Only 22% of the subjects (N=11 of 50) went 1 year with-out an exacerbation or relapse following medication dis-continuation. By 2 years, 96% (N=48) of the subjects had

experienced an exacerbation (N=28) or relapse (N=20).Figure 2 shows the survival curve for the entire cohort.

The mean time to exacerbation or relapse for the 48subjects whose psychotic symptoms returned within thetime frame of the study was 235 days, or just under 8months. The median time to exacerbation or relapse was245 days. The two subjects who did not experience an ex-acerbation or relapse within the time frame of the studywere followed clinically and ultimately developed psy-chotic symptoms after drug withdrawal: one at 28 monthsand the other at 93 months (i.e., 7 years and 9 months).

Because of the possibility that subjects in condition A(placebo followed by active drug) had lower fluphenazinelevels at the beginning of open withdrawal because thewithdrawal period was preceded by the earlier 12-weekplacebo period, we compared the fluphenazine levels inthese subjects after the 12-week drug reinstatement to thelevels of subjects in condition B at the point just beforedrug withdrawal. The difference was clearly not significant(t=0.22, df=43, p=0.83). In order to further ensure that timeto exacerbation or relapse was not affected by the order ofthe double-blind crossover trial, we compared the survivalcurves for those in condition A versus those in conditionB. There was no difference between the two curves (Ka-plan-Meier log-rank χ2=0.66, df=1, p=0.42). Additionally, asimilar percentage of patients from the two groups experi-enced an exacerbation or relapse 90 days after medicationdiscontinuation (22% and 26%, respectively).

Because fluphenazine levels during decanoate treatmentmay remain measurable for months (26), we evaluated apotential relationship between fluphenazine plasma lev-els and time to exacerbation or relapse. In the followinganalysis, we excluded data from one outlier subject whosefluphenazine plasma levels were consistently four stan-dard deviations higher than mean values of all other sub-jects. We performed a time-dependent covariate analysiswith time to exacerbation or relapse as the dependent

TABLE 2. Fluphenazine Levels of 53 Clinically Stable Patients With Recent-Onset Schizophreniaa During the Double-BlindCrossover Phase of an Antipsychotic Withdrawal Protocol

Week

Patients Receiving Placebo First(Condition A)

Patients Receiving Fluphenazine First (Condition B) Analysis

N

Fluphenazine Level (ng/ml)

N

Fluphenazine Level (ng/ml)

Mean SD Mean SD t df pBaseline 24 0.42 0.25 25 0.44 0.28 0.25 47 0.812 21 0.38 0.37 25 0.48 0.32 0.93 44 0.364 23 0.40 0.51 26 0.61 0.56 1.37 47 0.176 22 0.31 0.49 25 0.35 0.24 0.33 45 0.748 22 0.25 0.20 24 0.50 0.40 2.67 44 0.0110 18 0.18 0.51 25 0.42 0.28 3.15 41 <0.0112 22 0.26 0.42 22 0.45 0.37 1.61 42 0.1214b 20 0.30 0.24 25 0.39 0.23 1.20 43 0.2416 20 0.30 0.25 23 0.30 0.17 0.10 41 0.9318 20 0.38 0.30 20 0.21 0.22 –2.00 38 0.0520 20 0.46 0.51 21 0.24 0.22 –1.81 39 0.0822 21 0.39 0.38 18 0.18 0.24 –2.06 37 0.0524 16 0.47 0.31 17 0.12 0.16 –4.05 31 <0.01a Patients had experienced their first psychotic episode no more than 2 years earlier, had received fluphenazine treatment for at least 1 year

with clinical evaluations every 2 weeks, and had been free of notable psychotic symptoms for at least 3 months.b First plasma levels after crossover.



variable. Three separate survival regression models wereevaluated with different fluphenazine variables. Plasmalevel at the beginning of drug withdrawal was not associ-ated with time to relapse (relative risk=1.28, 95% CI=0.58–2.82; χ2=0.38, df=1, p=0.54) nor was the last plasma levelmeasured or the last level before exacerbation or relapse(relative risk=1.42, 95% CI=0.29–4.01; χ2=0.03, df=1, p=0.86). Finally, the slope of the plasma level from the begin-ning of drug withdrawal to the last fluphenazine levelmeasured or the last one before exacerbation or relapsealso was not associated with time to exacerbation or re-lapse (relative risk=0.67, 95% CI=0.33–4.32; χ2=1.03, df=1,p=0.31). (This last analysis excluded eight subjects whohad only one fluphenazine level measured.) Thus, exacer-bation or relapse could not be explained simply by a prox-imate decrease in fluphenazine levels.

Since our threshold for psychotic exacerbation was solow, we also examined hospitalization rates among thosewho experienced exacerbation or relapse. Of these 48 pa-tients, 45 continued to be followed regularly in the clinicafter medication withdrawal, and only six (13%) were hos-pitalized within 3 months of exacerbation (N=3) or relapse(N=3). The rest were successfully managed on an outpa-tient basis in the initial restabilization period. Of the threedropouts, two were hospitalized later, one in the context ofmethamphetamine abuse. Figure 3 shows the survivalcurve for hospitalization over the course of the study,which contrasts strikingly with the exacerbation/relapsecurve (Figure 2). There were no suicides during the courseof the study.

Discussion

There were three main findings in this study of clinicallystable patients with recent-onset schizophrenia whoseantipsychotic medications were gradually withdrawn (asis inherent in decanoate treatment) after at least a year ofmaintenance treatment. First, exacerbation or relapse wasalmost universal within 2 years, when low exacerbationthreshold criteria were used. Second, these exacerbationsor relapses were clinically managed without resorting tohospitalization in the vast majority of cases in which co-operative patients agreed to be clinically monitored.Third, the timing of exacerbation or relapse did not corre-late either with overall rate of fluphenazine decline ormost recent absolute fluphenazine level.

Our exacerbation/relapse rates were higher than thoseseen in either the Kane et al. (3) or Crow et al. (4) studies,which may be explained by use of different methodologiesas well as different methods of analysis. As an example, inthe Kane et al. study (3), dropouts were considered to havecompleted the risk period without relapse. Examiningonly patients with Research Diagnostic Criteria schizo-phrenia in that study, the relapse rate for those randomlyassigned to placebo and who continued in the study forthe entire year was 86% (N=6 of 7), which is similar to the1-year rate of exacerbation/relapse in our study (78%).The reasons for the lower relapse rate in the placebo groupof the Crow et al. study (4)—62% at 2 years—are not en-tirely apparent but may reflect either the sensitivity of ourdefinition of exacerbation or the advantage of a placebotreatment in their study, which differed from the openmedication discontinuation used in our study.

FIGURE 2. Reemergence of Psychotic Symptoms Among 50Clinically Stable Patients With Recent-Onset Schizophre-niaa Who Voluntarily Entered an Antipsychotic WithdrawalProtocol


b Patients were removed from the trial if their BPRS ratings for hallu-cinations, unusual thought content, or cognitive disorganizationchanged by 2 points (exacerbation) or reached a level of 6 or 7(relapse).

0 12 24 36 48 60 72Week

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FIGURE 3. Reemergence of Psychotic Symptoms RequiringHospitalization Among 45 Clinically Stable Patients WithRecent-Onset Schizophreniaa Who Voluntarily Entered anAntipsychotic Withdrawal Protocol


b Patients were removed from the trial if their BPRS ratings for hallu-cinations, unusual thought content, or cognitive disorganizationchanged by 2 points (exacerbation) or reached a level of 6 or 7(relapse).

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Although the results of this and other studies indicatethe very high rate of exacerbation or relapse following an-tipsychotic discontinuation in stable patients with first-episode schizophrenia, we still do not automatically rec-ommend long-term maintenance treatment after a firstepisode for every patient. Individuals with schizophreniatake into consideration the considerable costs of neuro-leptic treatment (e.g., side effects, social stigma), barriersto treatment (e.g., financial, geographical), their assess-ment of whether they are ill and in need of treatment, andtheir belief in the efficacy of the treatment (27). Quite fre-quently, individuals with recent-onset schizophrenia whorespond well to neuroleptic treatment will no longer be-lieve that their need for treatment outweighs the per-ceived costs of treatment. The prospect of a monitoredtrial without medication might help the clinician to nego-tiate a longer period of treatment adherence and preventcovert noncompliance. Many patients included in thisstudy expressed their intention not to continue their anti-psychotic medication regimen indefinitely without atleast having a chance to be medication free. Medicationwithdrawal while continuing in ongoing clinical man-agement made it possible to monitor the patients in acontrolled setting and to intervene when symptoms re-emerged as long as patient treatment adherence waspossible. We believe this resulted in the low hospitaliza-tion rate that we observed (13%) in contrast with the 2-year rate of exacerbation or relapse (96%). The hospital-ization rate would very likely have been higher had morepatients dropped out of treatment entirely and then dis-continued medication unilaterally and without clinicalsupervision. The success of early reinstatement of anti-psychotic treatment—as evidenced by the low hospitaliza-tion rate—is consistent with the results of previous studies(28, 29).

Some authors have voiced concern about the potentialfor untreated psychosis to produce lasting harm and aworse long-term prognosis in schizophrenic patients (4,30). Both theoretical objections and other interpretationsof the data upon which these concerns are based makethis concern less plausible (31, 32). Additionally, a recentstudy found no evidence that the duration of untreatedpsychosis was associated with clinical outcome 2 yearslater (33). Furthermore, the potential outcome of monthsof an untreated full psychosis is not relevant to the impactof quick resumption of antipsychotic medications whenpsychotic symptoms appear, as was done in the currentstudy.

Another concern regarding targeting medications as wedid in the current study is whether even more sensitive cri-teria for medication reinstatement would decrease overalldisease morbidity. However, in a study that examined theuse of adjunctive antipsychotic treatment at the time ofprodromal symptoms, 48% of the prodromes treated withplacebo resolved without progression to exacerbation(34). Thus, we believe that the ability of existing defini-

tions of prodromal (not psychotic) symptoms to heraldfurther clinical worsening is currently poor, limiting theutility of this approach.

We did not find any temporal relationship betweendecreases in fluphenazine levels after drug discontinua-tion and timing of exacerbation or relapse. To our knowl-edge, no previous study has examined this relationship. Ofcourse, since neuroleptic drugs are consistently associatedwith lower relapse rates (1), this negative result may reflectlimited sensitivity for evaluating changes in fluphenazinelevels. Alternatively, this result may reflect slower changesin brain fluphenazine levels, other factors related to intrin-sic disease processes, or environmental stressors as proxi-mate causes of schizophrenic exacerbation or relapse. It isclear, however, that the timing of exacerbations and re-lapses could not be easily explained by a decreasing level ofan antipsychotic that had been suppressing a continuouspsychosis. The presence of substantial amounts of flu-phenazine (and marked interindividual variability inplasma levels) even after 12 weeks of placebo treatment isconsistent with other studies, including our own (26, 35).

Our study has limitations. First, all patients were treatedwith a decanoate form of an antipsychotic medication.This limits the generalizability of the results to patientstreated with oral agents who might become psychoticmore quickly after medication discontinuation. Second,there was no parallel group with which to compare exacer-bation/relapse rates during medication discontinuation.Third, the lack of relationship between fluphenazine levelsand exacerbation or relapse may not apply to oral agents.Fourth, the stringent criteria for entry into our protocol—compliance with injectable medications for greater than 1year—suggest that our patient group may have been se-lected for medication adherence and clinical stabilitybefore medication discontinuation. The time to exacerba-tion or relapse might be shorter in less selected popu-lations. The fact that 22 of 50 subjects (44%) initially con-sidered for the study were excluded because of insufficientclinical stability is consistent with this notion. Finally, thisstudy was conceived and executed (1982–1993) before theavailability of the novel antipsychotics (other than cloza-pine). The risk/benefit ratio of ongoing treatment versusdrug discontinuation may differ with the newer agents.Since these data were collected, financial considerationsaffecting hospitalization rates have generally becomemore prominent. It is possible that hospitalization ratesmight be even lower now given the current financialclimate.

Although the risk/benefit ratio with the novel antipsy-chotics differs from that of the antipsychotic used in thisstudy, fluphenazine, the results of this study are relevantfor today’s clinical practice. Even though rates of extrapy-ramidal symptoms and tardive dyskinesia are lower withthe novel antipsychotics, rates of these symptoms (withthe possible exception of clozapine) are not zero (36). Ad-ditionally, the novel antipsychotics confer risks of signifi-



cant weight gain, sexual dysfunction, and new-onset dia-betes mellitus (37). Given these concerns and the frequentresistance to long-term maintenance antipsychotic treat-ment early in the course of schizophrenia, at least somerecent-onset schizophrenic patients should be consideredfor a trial of drug discontinuation, but only if careful clini-cal monitoring is available for rapid resumption of medi-cation should psychotic symptoms emerge. Because novalidated predictors of outcome in the early course ofschizophrenia currently exist, reasonable clinical recom-mendations would be to consider a medication discontin-uation trial in patients who are clinically stable with veryfew or no psychotic symptoms for at least many monthsand who agree to participate in ongoing clinical monitor-ing. If possible (and with the patient’s permission), the pa-tient’s family members should be involved in the monitor-ing process. There should be chart documentation of adiscussion of the potential for a return of psychotic symp-toms and a plan for ongoing monitoring should medica-tion be discontinued.

Despite these caveats, our data suggest persuasivelythat the vast majority of patients with recent-onset schizo-phrenia who voluntarily have their antipsychotic treat-ment withdrawn will experience an exacerbation or re-lapse within the first 2 years, even after more than 1 year ofmaintenance treatment. In the context of clinical moni-toring, these symptoms can be handled on an outpatientbasis in the majority of cases. These findings can be usedto help both schizophrenic patients and their families de-velop informed treatment plans during the first few yearsof illness.

Received Dec. 18, 2000; revision received June 15, 2001; acceptedJune 20, 2001. From the UCLA Department of Psychiatry and Biobe-havioral Sciences. Address reprint requests to Dr. Gitlin, UCLA Depart-ment of Psychiatry and Biobehavioral Sciences, 300 UCLA MedicalPlaza, Suite 2200, Los Angeles, CA 90095.

Supported by NIMH grants MH-37705 and MH-30911. Fluphena-zine decanoate provided by Bristol Myers Squibb.

The authors thank Rosemary Collier, Sally Friedlob, Debbie Gioia-Hasick, Sandi Rappe, and Margie Stratton for providing psychosocialtreatment during this research protocol. The authors also thank thepatients who served as participants in this project.

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