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BRITISH JOURNAL OF (2007), 191 (suppl. 51), s96^s96^s101. s101. doi: 10.1192/bjp.191.51.s96

Aripiprazole in the treatment of the past 3 months; (e) use of medication in the previous 3 months; (f) prodromeprodrome change in dosage of any within 6 weeks, stimulant medication with- in 4 weeks, or stabiliser within 4 An open-label pilot study weeks.weeks. The Criteria of Prodromal SCOTT W.WOODS, ELIZABETH M. TULLY, BARBARA C. WALSH, (COPS; Woods et aletal, 2001) were used to KEITH A. HAWKINS, JENNIFER L. CALLAHAN, SHUKI J. COHEN, identify those possibly prodromal. The DANIEL H. MATHALON, TANDY J. MILLERand THOMAS H. McMcGLASHANGLASHAN COPS are based on sub-threshold levels of positive symptoms and operationally de- fine three prodromal syndromes (Yung etet Background Research studies for the The prodromal phase of schizophrenic dis- alal, 1998): attenuated positive symptom treatmentofthe putative prodromal orders has been recognised since the 19th , brief intermittent psychotic century (Bleuler, 1911) and the possibility syndrome, and genetic risk and recent phase of psychotic disorders have begunto of treatment during the prodromal phase functional decline syndrome. The COPS appear.appear. has a history almost as long (Sullivan, and the three syndromes are described in 1927). Although some studies have begun detail elsewhere (Woods et aletal, 2001; Miller Aims To obtain preliminary evidence of to investigate methods to prevent progres- et aletal, 2003,2003aa). Individuals were assessed to the short-term efficacy and safetyof sion from the putatively identified pro- determine whether the COPS were met by aripiprazole treatment in people with the dromal phase to frank psychosis (Falloon, using the Structured Interview for Prodro- psychosis prodrome. 1992; McGorry et aletal, 2002; Morrison etet mal Syndromes (SIPS; Miller et aletal, 1999).,1999). alal, 2004; McGlashan et aletal, 2006), fewer Reliability of the COPS diagnosis of pos- MethodMethod Fifteen participants meeting have focused on the acute treatment effects sible prodrome has been excellent when prodrome criteria (mean age17.1years, on current symptoms (Woods et aletal, 2003).,2003). using the SIPS (Miller et aletal, 2002, 2003aa),), Aripiprazole is a relatively new anti- and patients thus diagnosed are symptom- s.d.s.d.¼5.5) enrolledin an open-label, single- psychotic medication with limited liability atic (Milleratic(Miller et aletal, 2003,2003bb), functionally im- site trialwith fixed-flexible dosing of for weight gain (Marder et aletal, 2003), whose paired (Miller et aletal, 2003,2003bb), cognitively aripiprazole (5^30 mg/day) for 8 weeks. mechanism of action differs from other impaired (Hawkins et aletal, 2004,2004aa) and)and in that it is a partial agonist treatment-seeking (Preda et aletal, 2002).,2002). ResultsResults Inthe mixed-effects repeated- rather than a full antagonist at dopamine

measures analysis, improvementfromimprovement from DD22 receptors (Burris et aletal, 2002). The Study design overall goal of the present pilot study was baseline on the Scale of Prodromal Participants were enrolled between October to obtain preliminary information about Symptoms total score was statistically 2004 and February 2006. The Yale Human the efficacy and safety of aripiprazole in significant by the first week.No Investigation Committee Institutional relieving symptoms that may be prodromal Review Board approved the protocol. The participantconvertedparticipantconvertedto to psychosis and for . trial is registered with ClinicalTrials.gov 13 completed treatment.Neuro- (NCT00237874). This was an open-label psychologicalmeasures showed no study at one site for 8 weeks, followed by consistent improvement; mean weight METHOD an open-label extension phase with gain waswas1.2 1.2 kg. Akathisia emerged in 8 SampleSample monthly follow-up visits to 52 weeks. Findings from the extension phase will be participants, butthe mean Barnes Adult participants gave written informed reported subsequently. Akathisia Scale score fell to baseline levels consent and minors gave written informed by the finalfinalvisit. visit. Adverse events were assent with consent from a parent or guar- dian. Participants were included if they Procedure otherwise minimal. were treatment-seeking out-patients of 13– During the 1–2 weeks prior to beginning Conclusions Aripiprazole shows a 40 years of age who met diagnostic criteria study medication, participants underwent for a possible prodromal syndrome. People eligibility and neuropsychological examina- promising efficacy and safety profile for were excluded for any of the following tions. After beginning study medication, the psychosis prodrome.Placebo- reasons: (a) past or current DSM–IV criter- participants were scheduled for eight controlled studies are indicated. ia (American Psychiatric Association, 1994) weekly visits. for any lifetime psychotic disorder; (b) they Dosing followed a fixed-flexible sched- Declaration of interest S.S.W.W.W.has W. h a s were judged clinically to have a psychiatric ule. Initial doses were 5 mg/day aripipra- received grants from Bristol-Myers disorder (e.g. , , attention- zole; after 1 week, the dose was scheduled Squibb,Janssen, and Eli Lilly. deficit hyperactivity disorder) which could for increase to 10 mg/day and after 2 weeks account for the symptoms; (c) they pre- to 15 mg/day, unless adverse effects dic- sented with symptoms occurring primarily tated a slower titration schedule. After the as sequelae to drug or alcohol use; (d) alco- third week, the dose could be increased hol or drug misuse or dependence in the further to 20 mg/day and if needed to

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30 mg/day should the person not be re- forms for verbal memory; and the Wiscon- there are a dearth of age-specific normative sponding. Aripiprazole was prescribed as sin Card Sort Test (WCST; Heaton et aletal,, data (our sample with test–retest data has a a single daily dose unless there was a reason 1993), semantic (category) fluency, and mean age of 15.5 years, s.d.¼1.3), baseline to divide the dose. The number of milli- Controlled Oral Word Association (FAS; data (Table 3) suggest mild neuropsycho- grams prescribed and the number taken Spreen & Benton, 1969) test of phonemic logical impairment similar to that observed were recorded each day; these data were fluency for executive functioning. in our previous prodromal sample (Hawkins used to calculate the percentage adherence Abnormal involuntary movements and et aletal, 2004,2004aa). A higher mean AVLT total since the previous visit. Drowsiness was EPS were assessed by observation and ad- score was reported for a younger sample managed initially by switching the timing ministration of the Simpson–Angus Scale by Spreen & Strauss (1998) and substan- of the daily dose to bedtime or by dividing (SAS; Simpson & Angus, 1970), the Barnes tially better Trail-Making Part A and Part the dose. was managed initially Akathisia Scale (BAS; Barnes, 1989), and B performances were reported for a healthy by switching the timing of the daily dose the Abnormal Involuntary Movement Scale sample aged 15–17 years by Fromm-Auch to early morning. Lorazepam was used to (AIMS; Branch, 1975). Safety was also & Yeudall (1983). treat insomnia or agitation. Lorazepam or assessed by analysing treatment-emergent Thirteen participants completed the 8- the anticholinergic benztropine was per- adverse events (Systematic Assessment For week study (87%). Of the two drop-outs, mitted for extrapyramidal symptoms Treatment-Emergent Events, SAFTEE, spe- one completed 48 days on aripiprazole (EPS). Participants continued doses of anti- cific inquiry method; Levine & Schooler, and dropped out because of improvement, depressant, mood stabiliser, or stimulant 1986), vital signs and weight. Treatment- feeling medication was no longer needed. medication prescribed before consent but emergent adverse events were defined as The other completed only 8 days on medi- were not permitted to begin or increase do- those first occurring or worsening after cation and left the study primarily because sage of these medications after consent. baseline. All of the above measures were of sedation after the first 10 mg dose, after Individual and family psychosocial inter- assessed at baseline and weekly thereafter. having concluded that 5 mg was ineffective ventions with supportive and psychoeduca- after the first week. tional components were available to each Statistical analyses participant. Medication For the present report, the time frame was the first 8 weeks after beginning study Prescribed mean (s.d.) aripiprazole doses at Assessments medication, and the principal outcome weeks 1, 2, 3, 4, 5, 6, 7 and 8 were 5 (0), 9 (2), 11 (5), 11 (7), 11 (6), 13 (6), 14 (8), and The primary efficacy measure for the analy- measure was the SOPS total score. Analyses 15 (7) mg/day, respectively. Final pre- sis of acute treatment was change over time were based on the intent-to-treat (ITT) scribed doses were 5 mg/day (nn¼1 parti-1parti- in the total score of the Scale of Prodromal principle. All participants were included in cipant), 10 mg/day (nn¼3), 15 mg/day Symptoms (SOPS; Miller et aletal, 1999), a 19- the analysis. The principal outcome mea- (s.d.(s.d.¼7) (7)(nn¼6), 20 mg/day (nn¼4) and4)and item scale with items scored 0–6. The inter- sure was addressed using a mixed-effects 30 mg/day (nn¼1). Reported mean (s.d.) per- rater reliability has been excellent (Miller etet likelihood-based repeated measures linear centage adherence with prescribed aripipra- alal, 2003,2003aa). Factor analysis supports the val- model (MMRM, as implemented in SAS zole doses was 94 (13), 92 (22), 98 (4), 96 idity of the SOPS sub-scales (Hawkins etet PROC MIXED) on post-baseline change (8), 97 (7), 95 (10), 98 (5), and 94 (9) at alal, 2004,2004bb). Treatment response was defined scores, using baseline scores as a covariate. weeks 1, 2, 3, 4, 5, 6, 7 and 8 respectively. as all five SOPS positive symptom items For other measures we used tt-test end-point New concomitant medication used after being rated below the prodromal range models at 8 weeks, carrying forward the (i.e.(i.e. 442).2). last observation (LOCF). Secondary efficacy assessments in- cluded the Calgary Depression Scale for RESULTSRESULTS Schizophrenia (CDSS; Addington et aletal,, 1990), the Participants (YMRS; Young et aletal, 1978), the Beck Anxi- A total of 15 participants were enrolled. ety Inventory (BAI; Beck et aletal, 1988), the Demographic and treatment characteristics Global Assessment of Functioning Scale at baseline are shown in Table 1. All were (GAF; Hall, 1995), the Heinrichs–Carpenter diagnosed with the common attenuated Quality of Life role functioning sub-scale positive symptom syndrome putative pro- (HCRF; Heinrichs et aletal, 1984), and the drome subtype according to the COPS Social Functioning Scale (SFS; Birchwood etet and none also qualified for either of the alal, 1990).,1990). other two less common COPS prodromal Neuropsychological assessments in- syndromes. All but two had never received cluded tests of attention and working mem- antipsychotic medication prior to partici- ory: the Continuous Performance Task pating. One participantt had received anti- (CPT; Cornblatt et aletal, 1988), identical pairs psychotic for 5 weeks 5 years earlier, and Fig. 11Fig. Change in Scale of Prodromal Symptoms version, letter number sequencing, N-back, the other for 6 months ending 17 months (SOPS) total score rom baseline with aripiprazole Trails A and B; Stroop Color Word Test for before baseline, both for indications other treatment. Mixed-effect repeated-measures model- processing speed; Auditory Verbal Learning than psychosis. Scores for severity of illness derived mean and standard error are shown for each Task (AVLT; Rey, 1964), using alternate at baseline are shown in Table 2. Although time point. *PP550.05, ****0.05, PP550.001.0.001.

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Ta b l e 1 Demographic and treatment data at Ta b l e 22Tab Baseline and change from baseline in severity of illness scores of participants treated with baseline aripiprazole

Characteristic Mean

Age, years: mean (s.d.) 17.1 (5.5)(5.5)17.1 MeasureMeasure BaselineBaselineChange from baseline11 tt (14)22,, PP Male, nn (%) 8(53)8 (53) White, nn (%) 11 (73) SOPS Total 43.3 (15.0) 7729.1 (12.3) 779.2550.0010.001 Single, nn (%) 15 (100) Positive 13.6 (3.7) 7710.0 (4.1) 779.4550.001 First-degree family history, nn (%) Negative 12.9 (6.9)(6.9)12.9 778.2 (6.5) 774.94.9550.001 Psychosis 3 (20)3(20) Disorganisation 7.1 (3.8) 774.8 (3.3) 775.65.6550.001 Non-psychotic major depression6(40) 6 (40) GeneralGeneral 9.7 (4.2)(4.2)9.7 776.1 (2.6)(2.6)6.1 779.1550.001 Non-psychotic bipolar disorder1(7) 1 (7) YMRS total 4.7 (3.7) 773.9 (3.6)(3.6)3.9 774.3550.001 Medication use at baseline11,, nn (%) CDSS total 4.6 (4.5) 773.8 (4.2)(4.2)3.8 773.4 0.005 Antidepressants7(47) 7 (47) BAI total 14.9 (12.3) 7713.1 (11.2) 774.5550.0010.001 Antipsychotics 0 (0)0(0) Current GAF 41.5 (6.4)(6.4)41.5 9.2 (5.3)(5.3)9.2 6.7550.001 Benzodiazepines/hypnotics2(13) 2 (13) HCRF 14.2 (4.7)(4.7)14.2 3.2 (5.1) 2.3 0.044 Mood stabilisers 0 (0) SFS 118 (30) 772(21) 770.3 0.734 Stimulants 1(7)1 (7) SOPS, Scale of Prodromal Symptoms; YMRS,Young Mania Rating Scale; CDSS, Calgary Depression Scale for Lifetime substance Schizophrenia; BAI, Beck Inventory; GAF,Global Assessment of Functioning; HCRF, Heinrichs^Carpenter Quality of Life role functioning sub-scale; SFS, Social Functioning Scale. misuse/dependence, nn (%) 1. Last-observation-carried-forward values at 8 weeks. 2.2. nn¼14, d.f.d.f.14, ¼13 for CDSS; nn¼13, d.f.¼12 for HCRF and SFS. Marijuana 1(7)1 (7) Other (except nicotine)22 0 (0)0(0) after 8 weeks; the remaining 11 who anticholinergic medication (2), slowing 1. Patients taking , anxiolytics, mood stabilisers, or stimulants were permitted to continue completed 8 weeks elected to continue on dose titration and prescribing anticholiner- these medications. aripiprazole into the extension phase. gic medication (2), slowing dose titration 2. Includes alcohol, sedatives, opioids, cocaine, Table 3 shows the results of the neuro- and prescribing benzodiazepine (2) and pre- hallucinogens and others. psychological testing. Participants improved scribing anticholinergic medication and as a group on two tests of attention and then adding benzodiazepine (1). In the con- enrollment included benzodiazepine in working memory at the significant or trend text of these management efforts, all parti- three participants (20%) and anticholiner- level (2-digit CPT reaction time, 2-back cipants experiencing emergent akathisia gic medication in 5 participants (33%). number correct) but worsened on one other completed treatment, and the emergent (2-digit CPT performance). They improved akathisia remitted by the final evaluation Efficacy as a group on a test of executive function- in six participants. Mean BAS total scores ing (WCST perseverative errors) but wor- consequently returned to baseline by the In the mixed-effects model, the effect of sened on another (semantic fluency). end-point evaluation (Table 5). Four parti- time for the SOPS total score change from Scores on the remaining 15 tests of atten- cipants continued to receive medication baseline was statistically significant (FF tion, working memory, executive function- for akathisia at the 8-week evaluation. (7)(7)¼9.2,9.2, PP550.001. The reduction in the ing, processing speed and verbal memory Little change from baseline to end-point SOPS total score was statistically signifi- did not change significantly. was observed for blood pressure (Table 5). cant at each time point (Fig. 1). The LOCF Pulse increased 6 beats per minute on aver- analyses revealed that improvement on the age. There were no significant differences SOPS was statistically significant at end- Safety from baseline to end-point on the SAS or point for each of the positive, negative, One participant discontinued aripiprazole AIMS scales (Table 5). Patients gained a disorganisation and general symptom sub- because of adverse events (sedation after 8 mean of 1.2 kg in weight (Table 5). scales (Table 2). The LOCF analyses also days). As determined by the SAFTEE, there revealed significant symptomatic improve- were few adverse events of more than mild ment from baseline on the YMRS, CDSS severity (Table 4). Complaints of adverse DISCUSSION and BAI scales, as well as significant func- events tended to remit over time. Other tional improvement on the GAF and HCRF than the participant who took medication The principal finding of the present study scales (Table 2). for only 8 days, at the final evaluation an was that those meeting criteria for a schizo- A total of 11 participants met response emergent SAFTEE complaint of moderate phrenic prodromal syndrome who were criteria (73%) at week 2 (nn¼1), 3 ((1),3 nn¼2), 42),4 or greater severity was present in only one treated with aripiprazole improved to a ((nn¼1), 6 ((1),6 nn¼4), 7 ((4),7 nn¼1) and 8 (nn¼2).2). participant (nasal congestion). significant degree over an 8-week period Response was sustained thereafter until During treatment, eight participants on the SOPS and other rating scales. Ad- end-point in all but one participant. No experienced emergent akathisia demon- verse effects were generally mild and participant converted to psychosis. Two strated by increases from baseline on the manageable. Important limitations, how- non-responders who completed the 8-week BAS. Emergent akathisia was managed by ever, are the small sample size and the use course elected not to continue aripiprazole slowing dose titration (1), prescribing of an uncontrolled, open-label design.

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Ta b l e 3 Baseline and change from baseline in neuropsychological functioning measures (nn¼10)10)11 Ta b l e 4 Treatment-emergent adverse events in participants with prodromal symptoms treated with aripiprazolearipiprazole BaselineBaseline11 Change from baseline1,2

DomainDomain Mean (s.d.) tt (9)(9)11 PP SAFTEE items11 nn (%)(%)

Attention and working memory Irritability5(33) 5 (33) CPT^IP D-prime (2 digit)3.5 (0.7) 770.3 (0.4)(0.4)0.3 772.5 0.0400.0402.5 Increased appetite 4 (27) CPT^IP D-prime (3 digit) 2.3 (0.7) 770.2 (0.8) 770.5 0.5980.5980.5 Sedation 3 (20)3(20) CPT^IP D-prime (4 digit) 1.2 (0.5) 770.2 (0.6) 770.8 0.452 Insomnia 2(13)2 (13) CPT^IP reaction time (2 digit)33 454 (39)454(39) 31 (40)(40)31 2.2 0.066 Nervousness 2(13)2 (13) CPT^IP reaction time (3 digit)33 477 (79)(79)477 27 (60)27(60) 1.3 0.249 Memory impaired 2(13)2 (13) CPT^IP reaction time (4 digit)33 469 (48) 7714 (64) 770.6 0.547 Sensory perception impaired 2(13)2 (13) Letter number sequencing12.9 (4.3) 770.3 (1.7)(1.7)0.3 770.6 0.5630.5630.6 Saliva increased 2(13)2 (13) 1-back number correct 47.5 (17.9) 770.8 (15.7) 770.1 0.8960.8960.1 Libido decreased 2(13)2 (13) 2-back number correct 26.8 (16.1) 9.1 (10.5)(10.5)9.1 2.5 0.0440.0442.5 Excessive sweating 2(13)2 (13) Trails AATrails 33 31.9 (11.3) 0.3 (7.0) 0.1 0.890 SAFTEE, Systematic Assessment forTreatment- Trails BBTrails 33 95.9 (54.2)2.3 (37.9) 0.2 0.8580.8580.2 Emergent Events. 1. Proportion of participants endorsing adverse events Processing speed as determined by the SAFTEE at the moderate level or Stroop colours 59.9 (15.2) 770.8 (11.4) 770.2 0.829 higher at any time point and representing an increase over baseline. Adverse events endorsed by only one Stroop words 82.0 (21.0) 772.1 (14.1) 770.5 0.648 participant are not shown. Stroop colour-word 35.5 (8.5) 0.0 (3.5) 0.0 1.0000.01.000 Verbal memory sample demography were similar. Improve- AVLT immediate trials sum 47.7 (11.7) 0.4 (13.5)(13.5)0.4 0.1 0.927 ment on GAF, as well as on mania and de- AVLT delay trial 10.5 (2.6) 770.3 (2.4) 770.4 0.7030.7030.4 pression measures, was also more robust in Executive functioning the open-label study of aripiprazole than WCST perseverative errors33 10.9 (6.4) 3.6 (5.2)(5.2)3.6 2.1 0.0720.0722.1 we had previously observed in a marked WCST categories completed 4.0(0.9)4.0 (0.9) 0.00.0(0.7) (0.7) 0.0 1.000 study of . Semantic fluency 36.9 (10.1) 774.3 (4.0) 773.4 0.0080.0083.4 Weight gain with aripiprazole also Phonemic fluency 30.6 (8.9) 771.1 (5.1) 770.7 0.5130.5130.7 compared favourably with our previous experience with olanzapine. Participants CPT^IP,Continuous PerformanceTask Identical Pairs version; AVLT,ReyAVLT, Rey Auditory Verbal LearningTest; WCST, WisconsinCardSortTest. treated with olanzapine gained a mean of 1.1. nn¼9andd.f.¼8 for letter number sequencing,Trails A and B, and WCST; nn¼8andd.f.8andd.f.¼7 for CPTand N-back. 4.5 kg over 8 weeks in LOCF analyses, 2. Positive change score and positive tt valuevalueindicateimprovement. indicate improvement. whereas the aripiprazole mean weight gain 3. Lower scores are better on these measures.The signs for the change scores and tt values have therefore been reversed so that positive change scores and positive tt values still indicate improvement. in this study was 1.2 kg (Table 5) despite being exposed to drug for a higher propor- tion of the 8 weeks. This degree of weight Improvements observed could have been a prodromal for schizophrenia. Our findings gain was comparable to that observed in result of placebo effects or simply the pas- can be compared with those from the acute previous short-term studies of aripiprazole sage of time. phase of our previous placebo-controlled (mean 0.71 kg v.v. no change for placebo; trial of olanzapine (Woods et aletal, 2003),,2003), MarderMarder et aletal, 2003).,2003). but again one must allow for the different Akathisia, on the other hand, was more Other studies study designs. Participants with established problematic with aripiprazole than it had No participants converted to psychosis schizophrenia improved less from baseline been with olanzapine, leading to higher during the 8-week trial. We would have to end-point on active medication when rates of benztropine prescription. However, expected two or three conversions without placebo-controlled designs were used benztropine, or in some cases slowing of treatment, based on the placebo group in (Woods(Woods et aletal, 2005). It is not known dose titration or benzodiazepine prescrip- our previous study (McGlashan et aletal,, whether this same effect of design occurs tion, was effective in managing this adverse 2006). Caution is indicated in comparing with putatively prodromal subjects. effect, so that by the final evaluation the net our current findings with our historical However, improvement in prodromal effect of treatment on akathisia ratings was placebo group, however, because it is symptoms and treatment completion rates similar to what we had observed with possible that people volunteering for an in participants assigned to aripiprazole olanzapine.olanzapine. open-label trial could differ from those compared favorably with these indices in Adherence with prescribed doses was volunteering for a placebo-controlled study participants randomised to olanzapine in relatively high in this short-term analysis (Woods(Woods et aletal, 2005).,2005). our previous study. Participants were as measured by participant report at each This is the second report to our know- slightly more severely ill at baseline in the visit. Adherence was similar to or higher ledge to focus on an acute pharmacological current sample according to the SOPS total than with olanzapine in our masked study, treatment of symptoms that can be score, although GAF scores at baseline and although the latter used a somewhat more

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Ta b l e 5 Baseline and change from baseline in vital signs, weight, extrapyramidal symptoms and abnormal doses were 5 mg/day, in keeping with involuntary movements guidelines for initiation of aripiprazole in adolescents/children who weigh 50–70 kg (Findling(Findling et aletal, 2004).,2004). BaselineBaselineChange from baseline11

MeasureMeasure Mean (s.d.) tt (14)(14)22 PP Implications Our current findings are relevant to discus- Blood pressure, mmHg sions of the ethics of intervention research Systolic120 (12)3 (12) 1.0 0.338 in people who appear prodromal. Pro- Diastolic BPBPDiastolic 65 (10)65(10) 1 (9) 0.5 0.635 drome research studies thus far have Pulse, beats/min 69 (11) 6 (14) 1.4 0.181 primarily focused on preventing the devel- Weight, kg 67.4 (18.1) 1.2 (2.0)(2.0)1.2 2.2 0.049 opment of psychosis. Although this is SAS total score 0.6 (0.9) 770.3 (0.8)(0.8)0.3 771.5 0.136 certainly an important goal, ethical issues BAS total score 1.2 (1.3) 770.7 (1.6)(1.6)0.7 771.6 0.136 are raised because some participants will AIMS total score 0.1 (0.5) 770.1 (0.5) 771.0 0.335 be false-positives who have no personal op- portunity to benefit if benefit is defined so- SAS,Simpson^AngusScale;BAS,BarnesAkathisiaScale;AIMS,AbnormalInvoluntaryMovementScale. 1. Last-observation-carried-forward values at 8 weeks. lely as prevention. The current data suggest 2.2. nn¼13 (d.f.¼12) for weight and nn¼14 (d.f.14(d.f.¼13) for blood pressure and pulse. that people carrying a risk of progression to psychosis can receive not only the possi- bility of a preventive benefit but also a rigorous pill-count method of monitoring memory could relate to the small sample, treatment benefit ‘on average’ from inter- adherence (Woods et aletal, 2003). As for most studying prodromal v.v. chronic illness, or, vention. The prospect of treatment benefit studies, surreptitious non-adherence cannot our use of a counterbalanced alternate form on average is generally considered sufficient be excluded. Future studies should continue for the repeat verbal learning list, which to justify exposure to some treatment risk to assess adherence in this population. may have prevented the confounding of in other illnesses. Thus the current data Our neuropsychological findings show measurement of new verbal learning by fa- strengthen the argument that intervention little consistent effect of aripiprazole over miliarity with the word list carried over studies can be ethical with people who 8 weeks. Among the 20 results reported, a from the baseline testing (practice effect; appear prodromal. few tests did show improvement, but others Hawkins & Wexler, 1999; Hawkins et aletal,, Although our findings suggest that showed a decline, with most suggesting lit- 20042004cc). In the previous study (Kern et aletal,, people who meet prodrome criteria benefit tle change. Considering tests that did 2006) aripiprazole-treated participants im- when prescribed aripiprazole, the present change, within domain of function there proved but not significantly on an executive results contribute to what is only the begin- appeared to be little consistency in direc- functioning factor on which loaded our ning of the process of establishing a stand- tion. Certainly the limited sample size WCST tasks. These findings were similar ard of care for such people. The sample would have predisposed our study to low to ours with WCST perseverative errors. size in our study was small and we had no power to detect possible real effects; on control group, placebo or otherwise. Future the other hand, some gains would be ex- placebo-controlled studies with more parti- pected on the basis of prior test exposure. Dosing cipants are needed before recommendations In the only previous study, to our know- We paid close attention to the dosing of can responsibly be made regarding routine ledge, on neuropsychological effects of aripiprazole in the current study. Although treatment. The present findings suggest that aripiprazole (Kern et aletal, 2006), 169 some investigators have emphasised that aripiprazole is a promising candidate for participants with chronic schizophrenic patients meeting prodrome criteria can be such studies. psychosis underwent neuropsychological managed with antipsychotic doses which examinations before and 8 weeks after ran- are lower than those used in chronic schizo- dom assignment to aripiprazole or olanza- phrenia (Falloon, 1992; McGorry et aletal,, ACKNOWLEDGEMENTS pine. Aripiprazole-treated participants 2002), there had been some evidence in This study was supported by an investigator-initiated improved significantly over 8 weeks on a our previous study that olanzapine had grant (S.W.(S.grant W.W.)W.) from Bristol-Myers Squibb. general cognitive factor on which loaded been used at too low a dose, especially in our letter number sequencing, verbal the first month (McGlashan et aletal, 2006).,2006). REFERENCES fluency and trail-making tasks. Our failure In the present study we employed a recom-

to find consistent improvement on these mended fixed dose titration by the end of Addington, D., Addington, J. & Schissel, B. (1990) AA measures could relate to our small sample the second week to 15 mg/day, the minimal depression rating scale for schizophrenics. Schizophrenia or to our participants being less impaired consistently effective aripiprazole dose for Research,, 33,247^251., 247^251.

and having less room to improve. Aripipra- patients with chronic schizophrenia American Psychiatric Association (1994) Diagnostic zole-treated participants improved signifi- (Woods, 2003), unless the prescriber had and Statistical Manual of Mental Disorderes (4th edn) cantly in the previous study (Kern et aletal,, a specific reason to deviate from this (DSM^IV). APA. 2006) on a verbal learning factor on which schedule. The 15 mg/day dose was also that Barnes, T. R. (1989) A rating scale for drug-induced loaded a test similar to our AVLT but with- most commonly employed in a recent pilot akathisia. British Journal of Psychiatry,, 154,,672^676. 672^676.

out use of alternative forms. Our failure to study of aripiprazole in first-episode Beck, A.T., Epstein, N. Brown, G., et aletal (19 8 8) An find consistent improvement on verbal schizophrenia (Brown et aletal, 2003). Initial inventory for measuring clinical anxiety: psychometric

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