Treating young individuals at clinical high risk for psychosis

Original Article

Treating young individuals at clinical highrisk for psychosiseip_299 60..68

Catherine Marshall,1 Jean Addington,1,3,4 Irvin Epstein,3 Lu Liu,1 Stephanie Deighton2 andRobert B. Zipursky5

1Hotchkiss Brain Institute, Department ofPsychiatry, University of Calgary,2Neuroscience Program, University ofCalgary, Calgary, Alberta and3Department of Psychiatry, University ofToronto, 4Centre for Addiction andMental Health, Toronto and 5Departmentof Psychiatry and BehaviouralNeurosciences, McMaster University,Hamilton, Ontario, Canada

Corresponding author: Dr JeanAddington, Centre for Mental HealthResearch and Education, University ofCalgary, 3280 Hospital Drive NW, Calgary,Alberta, Canada T2N 4Z6. Email:[email protected]

Received 2 February 2011; accepted 10July 2011

Abstract

Background: Typically, studies inves-tigating those at clinical high risk forpsychosis have focused on predictorsof conversion and treatments thatmight prevent conversion to full-blown psychosis. Few studies havefollowed those who do not go on todevelop a psychotic illness.

Methods: Participants were 48 youngpeople who were at risk for developingpsychosis based on the StructuredInterview for Prodromal Symptomscriteria and participated in a treat-ment programme where they wereoffered up to 6 months of psycho-social treatment and psychiatricmanagement. Attenuated psychoticsymptoms, negative symptoms,depression, anxiety, social function-ing, alcohol and drug use, and meta-cognitive beliefs were assessed atbaseline, 6, 12 and 18 months. Person-ality characteristics were assessed atbaseline. Medication use was trackedand psychiatric visits were logged overthe 18-month study period.

Results: On average, participantsattended 12 sessions of psychosocialtreatment and had one meeting withthe psychiatrist every 6 months. Only24% were ever prescribed any psy-chotropic medications, and antipsy-chotics were not used. Significantimprovements were found over timein attenuated positive symptoms,negative symptoms, depression,anxiety, meta-cognitions and socialfunctioning with most improvementoccurring in the first 6 months. Therewas no change in the level of sub-stance use. For personality assess-ment, participants generally scoredhigh on neuroticism and opennessand had low scores on extraversion,agreeableness and conscientiousness.

Conclusion: With minimal treatmentand no antipsychotics, young peoplewho present as being at risk for devel-oping a psychotic disorder demon-strate clinical improvement over time.However, a few continued to have theliability of ongoing attenuated psy-chotic symptoms.

Key words: prodrome, psychosis, treatment outcome.

INTRODUCTION

In psychosis research, there is a major focus on earlydetection and intervention, particularly in the diag-nosis of individuals who may be in the pre-psychoticor putatively prodromal phase of a psychotic illness.Well-established criteria have been developed toidentify those who may be prodromal for psy-chosis.1,2 These individuals have been described asbeing at ultra high risk or clinical high risk (CHR) fordeveloping psychosis. For the sake of consistency,

in this paper we will use the term CHR. Typically, theemphasis has been on the risk of conversion andunderstanding the evolution of the psychotic illness.Likewise, treatment studies have focused on pre-venting or reducing conversion through the use ofantipsychotic medications or with psychologicalinterventions.3,4 There has been less emphasis onimproving the outcome and/or presenting concernsof these help-seeking individuals.

These young people often present with otherconcerns in addition to complaints of attenuated

Early Intervention in Psychiatry 2012; 6: 60–68 doi:10.1111/j.1751-7893.2011.00299.x

First Impact Factor released in June 2010and now listed in MEDLINE!

© 2011 Blackwell Publishing Asia Pty Ltd60

positive psychotic symptoms. Many have comor-bid diagnoses, in particular anxiety, depression andsubstance use disorders.5 High levels of negativesymptoms,6 significant impairments in academicperformance and occupational functioning,7 anddifficulties with interpersonal relationships areoften observed.8 Furthermore, these young peopleare help-seeking, but their concerns and difficul-ties are neither well understood nor addressedadequately in a regular mental health clinic. As aresult, many research programmes investigatingthe pre-psychotic period have been implementedin mental health clinics often integrating researchand clinical service. Internationally, the first suchresearch clinic was the Personal Assessmentand Crisis Evaluation (PACE) clinic in Melbourne,Australia.9 Other research clinics have beenestablished to further investigate the developmentof psychosis or the effectiveness of interventions toprevent conversion, as well as to provide someongoing clinical or supportive care for thosein the putatively prodromal phase of psychoticdisorders.10–12

Evidence from the literature suggests that only aminority (approximately 15–25%) of the samplesstudied go on to develop psychosis or at least within1 year following entry to the study. The short-termoutcome of those who do not develop full-blownpsychosis has only just begun to be addressed.13–15

In one study, approximately 50% of these non-converters had transient attenuated psychoticsymptoms and the rest continued to have residualattenuated positive symptoms without progressionto psychosis.13

In a recently published Canadian study, Access,Detection and Psychological Treatments (ADAPT),psychological treatments were examined in asample of individuals meeting the Criteria of Pro-dromal States (COPS) criteria for prodromal risksyndrome for psychosis based on the StructuredInterview for Prodromal Symptoms (SIPS). Thirty-six out of 51 individuals did not convert to psy-chosis over the 18-month course of the study.16

The primary goal of ADAPT was to compare theoutcome of 6 months of individual cognitive-behaviour therapy (CBT) versus 6 months of asupportive therapy (ST). There were no differencesin either symptomatic or functional outcomebetween the two therapy groups and thus boththerapies were seen as potentially effective.16

Because all participants received well-documentedtreatment, the purpose of this part of the ADAPTproject is to examine the extent to which clinicalimprovement was experienced in those who didnot convert to psychosis.

METHODS

Setting

In Toronto, the Prevention through Risk and Identi-fication Management and Education (PRIME)Clinic, was a research-based clinic for individualsbetween the ages of 14 and 30 who were at CHR fordeveloping psychosis based on the COPS criteria ofthe Scale of Prodromal Symptoms (SOPS). The goalsof PRIME were to longitudinally investigate the evo-lution of pre-psychotic symptoms and illness expe-rience and to develop targeted, comprehensive,appropriate and effective treatments aimed at eitherreducing the rate of conversion to psychotic illnessor delaying its onset.17

Sample

Recruitment and ascertainment methods have beendescribed in detail elsewhere.16 Referrals andsample outcome are described in Figure 1. After theinitial assessment, 37 individuals chose not toattend the PRIME clinic or to participate in the psy-chological treatment study. Nineteen individualspreferred to be followed in a longitudinal monitor-ing study either because they lived too far away toattend regular sessions or because they did not wantongoing therapy. Clinical data on those 19 individu-als are not available at this time.

All CHR participants met the COPS using theSIPS.1 Although COPS include three differentgroups, all participants exclusively met criteria forthe Attenuated Positive Symptom Syndrome, whichincludes the emergence or worsening over the pastyear of a non-psychotic disturbance of thoughtcontent, thought process or perceptual abnormal-ity. The Structured Clinical Interview for Diagnosticand Statistical Manual of Mental Disorders, FourthEdition (DSM-IV) (SCID-I)18 was used to determinethe presence of any axis I disorders. Participantswere excluded if they met criteria for any current orlifetime axis I psychotic disorder, prior history oftreatment with an antipsychotic, intelligence quo-tient< than 70 or past or current history of a clini-cally significant central nervous system disorderthat may confound or contribute to CHR symptoms.A comprehensive clinical assessment was con-ducted by the PRIME psychiatrist or psychologist(IE, JA) to determine if entry criteria were met.

Fifty-six CHR individuals consented post-screening to participate in the ADAPT study, detailsof which have been published elsewhere.16 Of thosewho consented, two were determined to be psy-chotic at baseline, and three did not return after the

C. Marshall et al.

© 2011 Blackwell Publishing Asia Pty Ltd 61

initial screening. In total, three participants con-verted to psychosis during the first 6 months of thestudy. The clinical sample of those participants whodid not convert consisted of 33 males and 15females. Thirteen participants dropped out of thetrial before the 6-month assessment. There was nosignificant difference between these 13 and the 35participants who completed at least one follow-upassessment with respect to demographics, depres-sion, ratings on severity of attenuated psychoticsymptoms or level of social functioning.

Measures

The SIPS was used as described earlier to identifyoperationally the presence of prodromal symptomsand to measure severity over time. The SCID-I18 wasused to determine diagnoses at baseline. Depres-sion and anxiety were assessed with the CalgaryDepression Scale for Schizophrenia (CDSS),19 theself-report Social Anxiety Scale (SAS)20 and the self-report Social Interaction Anxiety Scale (SIAS).20

Current alcohol and drug use were assessed with the

Alcohol and Drug Use Scale (AUS/DUS).21 Function-ing was assessed using the Global Assessment ofFunctioning (GAF),22 the Social Functioning Scale(SFS)23 and the self-report Goldberg Health Ques-tionnaire (GHQ).24

Personality characteristics were assessed at base-line using the NEO Five Factor Inventory (NEO-FFI).25 The NEO-FFI consists of 65 items on aLikert-type scale ranging from 1 (strongly disagree)to 5 (strongly agree). Five major domains ofpersonality are assessed including neuroticism,extraversion, openness, agreeableness and consci-entiousness. Neuroticism assesses affective adjust-ment versus emotional instability. The extraversiondomain represents the quantity and intensity ofinterpersonal interaction, the need for stimulationand the capacity for joy. Openness to experience isdefined as the proactive seeking and appreciationof experience for its own sake and as toleration forexploration of the unfamiliar. Agreeableness exam-ines the attitudes an individual holds towards otherpeople. The domain of conscientiousness assessesindividuals’ degree of organization, persistence and

FIGURE 1. Description of referrals andfollow-up. COPS, Criteria of ProdromalStates; CBT, cognitive-behaviouraltherapy; ST, supportive therapy.

Treating clinical high risk

62 © 2011 Blackwell Publishing Asia Pty Ltd

motivation in goal-directed behaviour. Normalscores are found within the range 45–55.

Meta-cognitions were assessed using the meta-cognitions questionnaire.26 The meta-cognitionsquestionnaire is a measure of positive and negativebeliefs about mental events. Positive beliefs mayinclude the idea that worrying helps the person tocope, whereas negative beliefs may be expressed byideas such as the person being unable to controlhis/her worry. High scores on both positive andnegative beliefs, indicate maladaptive thinking,which has been characterized as a potential featureof the CHR population.27

Medications used and the number of visits with apsychiatrist were logged over the 18-month period.

Procedures

Raters were experienced research clinicians whodemonstrated adequate reliability at routine reli-ability checks. Gold standard post-training agree-ment on the distinction between high risk andpsychotic levels of intensity on the positivesymptom items (i.e. the critical threshold for deter-mining initial eligibility and subsequent conver-sion status) was excellent (kappa = 0.90). TheDSM-IV diagnoses were made using the SCID-I.Interrater reliability was determined at the start ofthe study and annually by 100% agreement on thediagnosis and at least 80% agreement for symptompresence.

Treatment received

All participants had an assigned psychiatrist withwhom they could see on an as-needed basis. Casemanagement was also available where required andall participants had monthly symptom monitoringin the first 6 months. All participants were offeredpsychological treatment through the ADAPT studyin which participants received either ST or CBT.16

Both therapies consisted of up to 20 sessions to becompleted within 6 months. For the purpose of thispaper, we merged the two treatment groups as bothtreatments were found to be acceptable and therewas no difference in number of sessions received ordropouts between the two treatment groups.16 Intotal, 13 participants dropped out of treatmentbefore 6 months because they had moved away,started to feel better or had lost contact. An addi-tional four participants dropped out before12 months and three more prior to the 18-monthassessment for similar reasons.

Analysis

Descriptive statistics, including the mean, median,standard deviation (SD) and range, were com-pleted for all measures. To accommodate missingdata and account for intra-participant correlationover time, generalized linear mixed model forrepeated measures was used to examine changesover time (baseline, 6, 12 and 18 months) forratings on the SOPS, CDSS, SAS, SIAS, AUS/DUS,GAF, SFS, GHQ and the meta-cognitions question-naire. Adjustment for multiple comparisons wasconducted using Tukey–Kramer’s method. Theanalyses included exploratory data analysis prior tobuilding a mixed effects model, mixed effectsmodel development and interpretation, and modelassessment. Pearson’s correlation was used toexamine the relationship between the five dimen-sions on the NEO-FFI and the clinical measures(i.e. ratings on the positive and negative symptomsubscales of the SOPS, CDSS, SAS, SAIS andSFS).

RESULTS

The participants (33 males, 15 females) had anaverage age of 21.1 years. The majority were white,single and were students. Demographic details arepresented in Table 1. At baseline 52% (n = 25) had amood disorder diagnosis, 33% (n = 16) an anxietydisorder, 19% (n = 9) cannabis use disorder and 8%(n = 4) alcohol use disorder.

TABLE 1. Baseline characteristics

Variable N = 48

Mean age in years, n (SD) 21.1 (4.2)Gender, n (%)

Male 33 (31.1)Female 15 (68.8)

Racial background, n (%)White 27 (56.2)Black 3 (6.2)Asian 9 (18.8)Other 9 (18.8)

Marital status, n (%)Single, never married 44 (91.7)Cohabiting with significant other 4 (8.3)

Currently working, n (%) 24 (50.0)Years of education, n (SD) 12.8 (3.1)Current student, n (%) 33 (68.8)

SD, standard deviation.

C. Marshall et al.


Treatment exposure

Psychosocial

The average number of sessions of CBT or ST in thetreatment phase of the study, the first 1–6 monthswas 12 (SD = 6.2, range 1–26). The study partici-pants had individual meetings with the PRIME psy-chiatrist as needed throughout the course of thestudy. The number of sessions attended with thepsychiatrist between baseline and 6 months aver-aged 1.3 (SD = 1.5, range 0–6), 0.8 sessions (SD = 1.5,range 0–5) between 6 and 12 months, and 0.7sessions (SD = 1.2, range 0–4) between 12 and18 months.

Psychotropic medication

Prior medication history was available for 48 par-ticipants. Seventy-three percent (n = 35) had nevertaken any psychotropic medications prior to thetime of the baseline assessment. Of the remaining27% (n = 13), only one participant had taken anantipsychotic but for less than 14 days total life-time exposure, and one had taken a combinationof an antipsychotic (for less than 14 days), antide-pressant and anxiolytic. Eleven participants hadtaken only an antidepressant medication previ-ously. At each assessment, the majority were notprescribed any medications. Antidepressant usewas present in 24% (n = 11) at baseline, 26%(n = 9), 19% (n = 6) and 21% (n = 6) at 6, 12 and18 months, respectively. Anxiolytic use wasminimal at 3% (n = 1), 7% (n = 2) and 4% (n = 1) at6, 12 and 18 months respectively. The combineduse of antidepressants and anxiolytics, was presentin 6% (n = 2), 7% (n = 2) and 7% (n = 2) at 6, 12 and18 months, respectively.

Changes in symptoms and functioning

Symptoms

Overall, there were significant improvements inattenuated positive and negative symptoms at eachfollow-up time point compared with baseline.Although most of the clinical improvement occurredin the first 6 months, there was still significantcontinued improvement occurring between 6 and18 months for attenuated positive symptoms andbetween 6 and 12 months for amelioration of nega-tive symptoms. Twenty-three (48%) individuals con-tinued to have at least one attenuated positivesymptom at the time of their final assessment(Fig. 2a).

There were significant improvements over timein the level of depression and anxiety as assessedby the CDSS, SAS and SIAS at each assessmentcompared with baseline. Most improvementoccurred in the first 6 months. There was no statis-tically significant change in the AUS/DUS scaleover time with respect to the use/abuse of tobacco,alcohol or marijuana. These results are presentedin Table 2.

Functioning

There was significant improvement of GAF scores at6 and 12 months compared with baseline. A signifi-cant improvement on the SFS was found over timebut did not reach statistical significance until12 months. There were significant improvements inGHQ at each follow-up assessment compared withbaseline (Fig. 2b).

FIGURE 2. (a) Total positive and negative Scale of ProdromalSymptoms (SOPS) scores at baseline, 6, 12 and 18 months.(b) Total Global Assessment of Functioning (GAF) and SocialFunctioning Scale (SFS) scores at baseline, 6, 12, and 18months.



TABL

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mon

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mon

ths

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mon

ths

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28)

Rang

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valu

es

Mea

n(S

D)

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n(S

D)

Mea

n(S

D)

Mea

n(S

D)

Med

ian

SOPS

Posi

tive

Scor

e11

.21

(4.3

9)6.

94(5

.01)

a5.

74(5

.09)

a4.

68(4

.29)

a,b

0–30

(F3,

47=

31.6

5)**

**11

.50

6.00

4.00

3.50

SOPS

Neg

ativ

eSc

ore

7.60

(4.8

8)5.

13(5

.30)

a4.

07(5

.21)

a,b

4.79

(4.6

9)a

0–36

(F3,

47=

6.30

)**

8.00

3.00

2.00

4.50

CD

SS4.

81(4

.63)

2.50

(3.6

3)a

2.83

(4.0

2)a

2.33

(3.7

2)a

0–27

(F3,

47=

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4.00

1.00

1.50

1.00

SIA

S35

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(15.

58)

27.3

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5.94

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.86

(18.

06)a

27.7

3(1

16.8

6)a

0–80

(F3,

47=

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)***

*35

.00

24.0

026

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26.0

0SA

S41

.19

(9.7

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.27

(8.9

0)a

35.1

3(1

1.36

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.52

(9.0

6)a

20–8

0(F

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=7.

65)*

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1.00

1.00

1.00

1.00

Alc

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1.67

(0.6

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61(0

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1.70

(0.4

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71(0

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10.2

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3.93

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(7.1

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0–28

(F3,

45=

7.97

)***

8.00

1.00

3.00

2.00

GA

F53

.96

(8.0

9)62

.96

(12.

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62.6

8(1

0.93

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.63

(15.

04)

0–10

0(F

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=11

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****

53.0

060

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63.0

060

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SFS

119.

11(1

8.86

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0.90

(20.

10)

128.

85(1

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1.50

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32.9

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C. Marshall et al.


Meta-cognitive Beliefs

Significant improvements were found over time onfour of the five meta-cognitive factors. There wasno improvement on positive beliefs about worry.Improvement for beliefs about cognitive compe-tence was statistically significant at 18 months.Improvement was statistically significant for uncon-trollability and danger, general negative beliefs andcognitive self-consciousness at all assessmentscompared with baseline; for each measure, statisti-cally significant improvement was evident by6 months.

NEO-FFI

The range for normal scores is 45–55. On average,participants scored high on neuroticism (78.83) andopenness (64.78), and had low scores on extraver-sion (39.20), agreeableness (37.48) and conscien-tiousness (25.08). High ratings on neuroticism wassignificantly related to high ratings on SOPS positivesymptoms (r = 0.32, P < 0.05), CDSS (r = 0.48,P < 0.01), SAS (r = 5.25, P < 0.001) and SAIS (r = 0.54,P < 0.0001). Low ratings on extraversion was signifi-cantly associated with high ratings on CDSS(r = -0.37, P < 0.05), SAS (r = -0.42, P < 0.01) andSAIS (r = -0.55, P < 0.0001). Low ratings on agree-ableness was significantly associated with highratings on CDSS (r = -0.34, P < 0.5), SAS (r = -0.39,P < 0.05) and SAIS (r = -0.44, P < 0.01). There wereno significant associations between NEO ratingsand change over time in the clinical ratings.

DISCUSSION

A number of recent studies have noted the onset ofsignificant impairment in both symptomatic andfunctional difficulties in CHR populations. In ourstudy population, over the 6–18-month follow-upperiod, significant improvements were noted inattenuated positive symptoms, negative symptoms,depressive symptoms, anxiety and psychosocialfunctioning. Although ratings continued to improveover time, most of the significant changes generallyoccurred in the first 6 months. Similar improve-ments have been reported elsewhere.28 We havedemonstrated in this sample where we offered,minimal use of psychotropic medications andavoided exposure to antipsychotics, that weobserved significant symptomatic relief and func-tional outcome. Although ratings on some mea-sures, for example the GHQ returned to normalranges,24 many of the participants still continued to

experience attenuated symptoms and symptoms ofdepression and anxiety, albeit at reduced levelscompared with baseline. Likewise, ratings on socialfunctioning are typically lower than normally seenin non-psychiatric individuals of similar age.7 Sub-stance misuse measures were virtually unchangedfrom the low level of use experienced on enteringthe study.

To our knowledge, this is one of the first studiesthat has presented findings on the NEO-FFI in theCHR population, although the NEO has been usedto explore personality profiles in patients withschizophrenia.29 Findings demonstrated that as agroup, CHR individuals characteristically appearedto have profiles that reflect an individual who isexperiencing significant psychological distress andhas poor coping strategies. CHR individuals aretypically more reserved, less socially competent andare more easily distractible, which are all patternsthat have been reported in individuals with a morechronic course of schizophrenia.29 In our sample,scoring high on neuroticism and low on extraver-sion and agreeableness were associated with higherratings on positive symptoms, and increasedanxiety and depression. Although these results runthe risk of type B error because of multiple correla-tions, these findings have been reported elsewherein individuals with an established diagnosis of a psy-chotic illness.30 It is possible that certain premorbidpersonality profiles may predispose or play a role asa possible risk for developing subthreshold psy-chotic experiences.

On average, participants received 12 sessions oftherapy and one session with the psychiatrist every6 months. Thus, improvement occurred despitelimited therapeutic contact. It is possible that,because participants present with a problem that istypically at its worst, change was more related totime than to the impact of intervention and thusreflects spontaneous improvement. Approximately,one-quarter had been prescribed psychotropicmedication at any one point in time. However, com-pared with previously published clinical studies,this study was unique in scope in that individuals inthis cohort were not offered antipsychotic treat-ments.31 Improvement occurred without substantialuse of medications and no use of antipsychoticmedications suggesting that substantial improve-ment may occur without the use of antipsychoticmedications. However, it is not possible to rule outthe possibility that more improvement or morerapid improvement might have occurred withantipsychotics.

Data from most CHR studies32 indicate that largenumbers of young people (at times as high as 25% of



the samples) are receiving treatment with antipsy-chotics prior to presenting to a ‘clinical high risk’clinic, suggesting that these young people arereceiving these medications ‘off-label’, which skewsthe data and makes interpretation difficult. Accord-ing to Yung,32 this trend seems to be on the increaseover time. Typically, these young people are help-seeking and symptomatic with measurable levels ofattenuated psychotic symptom. This can be dis-tressing to the young person, their families, and thetreating clinician. Historically, prescribing an antip-sychotic may have seemed rational as a means toprevent psychosis and possibly result in a furtherincrease in symptoms and functioning. However,according to our current knowledge regarding tran-sition to psychosis during the prodromal phase,Yung suggests that ‘existing clinical guidelines donot recommend antipsychotics outside clinicaltrials unless rapid deterioration and stigmatizingbehaviours occur in conjunction with attenuatedpsychotic symptoms’, (p. 197).32

There are limitations to this study. First, thesample was small and less than 60% completed thefinal follow-up. The absence of follow-up data onthe NEO-FFI is a limitation as this could potentiallyestablish whether the NEO-FFI is measuring astable personality structure that would be predis-posing at risk mental states rather than reflectingstate changes. Without a comparable controlgroup, it is possible that these young people wouldhave improved on their own. However, unlike othersamples with more established illnesses, in thisCHR population, there are no established clinicalguidelines, and ‘treatment as usual’ is not well-defined.

Thus, in conclusion, we have demonstrated thatin a CHR population of young people who areassessed and diagnosed at a specialized clinic asbeing at risk for developing a psychotic disorder,when offered brief psychosocial treatment, limitedaccess to psychiatric appointments, minimal expo-sure to other psychotropics and no antipsychoticsdo improve over time with respect to attenuatedsymptoms, and levels of depression, anxiety andsocial functioning. Although some individuals docontinue to experience reduced levels of attenuatedpsychotic symptoms, more than 50% have completeremission of their attenuated positive symptoms.This calls into question the appropriateness of pre-scribing antipsychotics to individuals at risk for psy-chosis as symptoms may improve to a comparableextent with nonmedical interventions or perhapswith time alone. Further studies need to address thelongitudinal outcome of these high risk individualsusing a range of treatment options.

ACKNOWLEDGEMENTS

This work was supported by a grant to Jean Adding-ton from Ontario Mental Health Research Founda-tion, Ontario Canada. We would like to thank thefollowing people for their work on this project:I. Furimsky, M. Haarmans, D. Kirsopp, E. Mancuso,A. McCleery, S. McMillan, R. Rabin, H. Saeedi andL. Tran.

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Treating young individuals at clinical high risk for psychosis

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