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Arch Gen Psychiatry 2005 Apr; 62 (4): 361-70. 24. Lieberman JA, Phillips M, Gu H, et al. Atypical and conventional antipsychotic drugs in treatment-naive first-.
CNS Drugs 2009; 23 (10): 837-855 1172-7047/09/0010-0837/$49.95/0

REVIEW ARTICLE

ª 2009 Adis Data Information BV. All rights reserved.

Antipsychotic Drugs for First-Episode Schizophrenia A Comparative Review Kayvon Salimi,1 L. Fredrik Jarskog2,3 and Jeffrey A. Lieberman2,3 1 Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA 2 Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, New York, USA 3 New York State Psychiatric Institute, New York, New York, USA

Contents Abstract. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. Early Stages of Schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Efficacy of Antipsychotic Drugs in First-Episode Schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1 Antipsychotic Drug Dosing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2 Efficacy of Typical Versus Atypical Antipsychotic Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3 Comparative Efficacy of Atypical Antipsychotic Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4 Efficacy of Antipsychotic Drugs for Negative Symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5 Summary of Efficacy of Antipsychotic Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Safety of Antipsychotic Drugs in First-Episode Schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1 Neurological Adverse Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.1 Tardive Dyskinesia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2 Metabolic Adverse Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3 Prolactin Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4 Summary of Safety of Antipsychotic Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Cognitive Function in First-Episode Schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1 Cognitive Function and Antipsychotic Drug Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5. Brain Structure and Antipsychotic Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1 Brain Morphology in the Early Stages of Schizophrenia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2 Subcortical Effects of Antipsychotic Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3 Cortical Effects of Antipsychotic Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Abstract

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Increasingly, it is recognized that first-episode schizophrenia represents a critical stage of illness during which the effectiveness of therapeutic interventions can affect long-term outcome. In this regard, the advent of clozapine and subsequent atypical antipsychotic drugs held promise for improved outcomes in patients with first-episode schizophrenia, given the expectation of improved therapeutic efficacy and a more benign side effect burden compared with typical antipsychotic drugs. A growing number of large clinical trials have evaluated the merits of atypical antipsychotic drugs in the early stages of psychosis. A number of conclusions can be drawn from studies

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completed to date, with the caveat that data are either limited or unavailable for the antipsychotic drugs most recently approved by the US FDA. Studies of atypical antipsychotic drugs support data obtained with typical agents indicating that positive symptoms of psychosis are very treatment responsive and generally at lower doses than in chronic illness. It also appears that first-episode patients tend to stay on atypical antipsychotic drugs longer than on typical agents when all-cause discontinuation criteria are considered as the primary outcome measure. However, there are few differential advantages of clinical efficacy among the individual atypical antipsychotic drugs and there is little evidence to support distinct therapeutic advantages for negative symptoms or cognitive symptoms for atypical agents. Furthermore, while new-onset psychosis patients are particularly susceptible to extrapyramidal symptoms, they are also prone to gain weight and related metabolic adverse effects associated with many, but not all, atypical antipsychotic drugs. Recent data indicating that certain atypical antipsychotic drugs may have a sparing effect on cortical grey matter loss in first-episode schizophrenia is intriguing, given the potential long-term benefits. In summary, atypical antipsychotic drugs represent an incremental advance for patients in first-episode schizophrenia, especially in the area of neurological tolerability. However, metabolic concerns associated with many atypical agents along with limited benefits in cognition and negative symptom domains highlight the persistent therapeutic needs of these patients.

Schizophrenia is a complex neurodevelopmental disorder that also encompasses a progressive pathophysiology and limited clinical deterioration following the onset of illness. Deterioration is most evident in the overall functional capacity of the patient, but is also found in psychopathological, neurocognitive and neuroanatomical features of schizophrenia.[1] The evidence that functional capacity deteriorates following the initial onset of psychosis provides a compelling rationale for providing effective and sustained intervention as early as possible, with the goal of reducing cumulative morbidity. In this context, the initial stage of schizophrenia, and its hallmark first psychotic episode, provides a critical and possibly singular opportunity for therapeutic intervention. For the purpose of this review, first-episode schizophrenia (FES) includes initial presentations of schizophrenia, schizoaffective disorder and schizophreniform disorder. These diagnoses have been included in a number of large FES treatment trials and this grouping may better represent the heterogeneous ‘real world’ first-episode populations than more narrowly defined samples. ª 2009 Adis Data Information BV. All rights reserved.

Treatment of the FES patient presents special opportunities but also special challenges. For example, in FES, initial antipsychotic response is associated with high remission rates, but treatment discontinuation and subsequent relapse is also common with subsequent development of functional disability.[2-4] The goal of optimizing outcome depends on early intervention with pharmacological and psychosocial treatments while paying particular attention to factors associated with poorer prognoses such as duration of untreated psychosis (DUP), medication nonadherence, psychotic relapse, negative and cognitive symptoms, substance abuse and psychosocial disability.[5] In this regard, the choice of antipsychotic drug (APD) treatment can have an important impact on many of these factors because of potential differences in efficacy and tolerability among the agents. The American Psychiatric Association (APA) Practice Guideline for the Treatment of Schizophrenia and the recently updated Texas Medication Algorithm Project (TMAP) recommendations advise clinicians to use atypical APDs as initial CNS Drugs 2009; 23 (10)

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treatment in FES.[6,7] This recommendation is based primarily on evidence that atypical APDs are less likely to produce extrapyramidal symptoms (EPS) and tardive dyskinesia (TD) than typical APDs.[8] The current article reviews the efficacy of atypical APDs in FES in psychopathological and neurocognitive domains, examines tolerability factors with a focus on neurological and metabolic adverse effects, and assesses emerging evidence that APDs differentially affect brain structure, which may impact outcome. To identify relevant studies for this review, the MEDLINE database (1950 to July 2008) was searched using combinations of the following terms: schizophrenia, first episode, new onset, psychosis, antipsychotic, typical, atypical, efficacy, negative symptoms, deficit, side effect, extrapyramidal, dyskinesia, metabolic, prolactin, cognition, neuroimaging, MRI, longitudinal, grey matter, white matter, progression. The references in the identified papers were further searched for relevant studies. Greater weight was given to data from large randomized clinical trials compared with smaller and/or non-randomized trials. 1. Early Stages of Schizophrenia FES is deserving of special attention, not only for the possibility that rapid and effective intervention may improve long-term outcome for individual patients, but also because it presents a unique opportunity for understanding disease pathophysiology and aspects of treatment that are unencumbered by the many confounding influences of chronic mental illness. Despite growing recognition of the importance of studying FES, achieving adequate study power and obtaining highly applicable and generalizable results remain considerable challenges. The FES population is relatively small and often difficult to identify, contributed to in part by an often extended delay between the onset of symptoms and the point at which patients present for initial treatment, as well as challenges associated with diagnosing new-onset schizophrenia in the setting of concurrent mood symptoms, substance abuse and the many biological and social stresses associated with adolescence and young adulthood. ª 2009 Adis Data Information BV. All rights reserved.

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Diagnostic precision may be further challenged by a lack of longitudinal psychiatric history at the time of initial presentation. In distinguishing FES, most studies impose criteria that select for limited APD exposure and non-recurrent illness while allowing for greater variance in overall illness duration. FES cohorts can therefore be quite heterogeneous with regard to DUP, which is likely to result in heterogeneity in illness severity and outcome. Increased research focus on the prodromal phase of schizophrenia has aided FES research by facilitating more accurate diagnosis during a first episode of psychosis and identifying high-risk populations for longitudinal studies. The prodromal syndrome of schizophrenia is characterized by nonspecific psychiatric symptoms such as depressed mood, attenuated psychotic symptoms or brief psychotic experiences, cognitive impairment, and social withdrawal in the setting of deteriorating social, academic or occupational functioning.[9] While the best pharmacological approach to individuals with prodromal symptoms remains an unresolved and controversial issue, it is clear that supportive monitoring of such individuals has the potential to reduce DUP in those who eventually develop schizophrenia, and in so doing may mitigate disease severity and improve long-term outcome.[10-12] DUP varies from only a few weeks to many years, with a mean estimated DUP of 2 years in the general population.[13] These findings support the concept of early psychosis as a dynamic, modifiable disease process and provide the rationale for early detection programmes.[14] 2. Efficacy of Antipsychotic Drugs in First-Episode Schizophrenia Compared with the vast number of clinical trials in patients with chronic schizophrenia, few adequately powered studies have focused on the comparative effectiveness of APDs in the treatment of FES. Especially informative to this issue would be large head-to-head trials of two or more atypical APDs with a typical APD comparator, similar to the recent CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) CNS Drugs 2009; 23 (10)

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30

16,29

5,17,28

27

25,26

24

study in chronic schizophrenia in which four atypical APDs (risperidone, olanzapine, quetiapine and ziprasidone) and one typical APD (perphenazine) were compared.[15] In the recently published EUFEST (European First Episode Schizophrenia Trial) study, four atypical APDs (quetiapine, olanzapine, amisulpride and ziprasidone) and one typical APD (haloperidol) were compared in a large, randomized, open-label trial of patients with FES.[16] Similar to the CATIE study,[15] the EUFEST study used time to allcause treatment discontinuation as the primary outcome measure.[16] The only other large headto-head comparison of multiple atypical APDs in FES is the CAFE´ (Comparison of Atypicals in First-Episode psychosis) study in which three atypical APDs (olanzapine, quetiapine and risperidone) were compared.[17] Important data on the comparative effectiveness of APDs have also come from head-to-head comparisons of individual atypical and typical APDs. Reviews of these and selected studies of typical APDs in FES follow (table I).

X

X X Year of first publication of data. b

106 1991

Common acronym or code used for study, when available. a

McEvoy et al.

ª 2009 Adis Data Information BV. All rights reserved.

2.1 Antipsychotic Drug Dosing

Haloperidol

X X Haloperidol, amisulpride, olanzapine, quetiapine, ziprasidone 2008 Kahn et al. (EUFEST)

498

X X Olanzapine, risperidone, quetiapine 2007 Perkins et al./McEvoy et al./Keefe et al. (CAFE´)

400

2006 Robinson et al.

112

X X Olanzapine, risperidone

X

X X Haloperidol, risperidone 2005 Schooler et al./Harvey et al.

555

X

X

X

X X Haloperidol, olanzapine

Chlorpromazine, clozapine Lieberman et al.

263 2003

2003

Lieberman et al./Green et al./Keefe et al. (FIRST)

160

X

X

X

Risperidone 2002 Merlo et al.

49

1999 Emsley

183

X

Haloperidol, risperidone

X

cognition Outcomes clinical safety Medications N Yearb Investigators (study acronym)a

Table I. Selected randomized, clinical trials of antipsychotic drugs in first-episode schizophrenia

20-23

18 neuroimaging

19

References

840

In a landmark study, McEvoy et al.[30] demonstrated that patients with FES are both more responsive and sensitive to a given dose of a typical APD than patients with chronic schizophrenia. The results demonstrated that among first-episode antipsychotic-naı¨ ve patients, the mean dose of haloperidol eliciting EPS – the neuroleptic threshold – was half that of patients with prior antipsychotic exposure (2.1 vs 4.3 mg/day), and increasing the dose above the neuroleptic threshold did not improve the speed or magnitude of antipsychotic response. Results from subsequent studies with atypical APDs appear to confirm that for most FES patients, lower doses of APDs are needed to achieve a therapeutic response. For example, risperidone at 4 mg/day or higher did not provide greater antipsychotic benefit but was associated with more neurocognitive adverse effects in FES compared with lower doses of risperidone.[19,31-33] Merlo et al.[19] randomized 49 antipsychotic-naı¨ ve FES patients to an 8-week trial of risperidone at either 2 or 4 mg/day and found that efficacy did not CNS Drugs 2009; 23 (10)

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differ between the doses but that 4 mg/day was associated with greater fine motor impairment. Although comparative dosing strategies have not been examined for all atypical APDs, it is believed that this principle holds true for most APDs[17] (table II). 2.2 Efficacy of Typical Versus Atypical Antipsychotic Drugs

Results from large-scale randomized trials comparing an atypical versus a typical APD demonstrate that these two drug classes have similar efficacy for treating acute psychosis in FES. Atypical APDs appear to offer modest advantages on secondary outcomes such as increased time to relapse, better treatment retention and greater probability of staying in remission. In most FES studies, haloperidol has been used as the typical APD comparator. Emsley[18] randomized 183 subjects to 6 weeks of double-blind treatment with risperidone or haloperidol. Dosing was flexible for both APDs (2–16 mg/day). Mean doses at the end of the study were risperidone 6.1 mg/day and haloperidol 5.6 mg/day. The response rates were similar in the two arms, 63% for risperidone and 56% for haloperidol (p = 0.19), as defined by a 50% reduction in total Positive and Negative Syndrome Scale (PANSS) scores at the sixth week of treatment. Schooler et al.[25] randomized 555 FES patients to multi-year, double-blind, flexible dosing of risperidone (1–4 mg/day; mean dose 3.3 mg/day) or haloperidol (1–4 mg/day; mean dose 2.9 mg/day). Mean duration of treatment was 192 days for risperidone and 218 days for haloperidol, with a maximum duration of 4 years for both arms. A 12-week analysis demonstrated clinical responses in 73.6% of patients assigned to risperidone and 76.2% of patients assigned to haloperidol, with response defined by 20% reduction in PANSS scores. Similar response rates were also found at study endpoint, and 50% of patients were rated as ‘much’ or ‘very much’ improved on the Clinical Global Impression (CGI) scale. Notably, a secondary analysis found relapse prevention to be significantly better with risperidone compared with haloperidol – time to ª 2009 Adis Data Information BV. All rights reserved.

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relapse among responders was more than twice as long for risperidone (466 days) compared with haloperidol (205 days). Discontinuation rates were approximately 40% in both groups and there were no differences in reasons for discontinuation. Taken together, these studies demonstrate similar efficacy on overall psychopathology between risperidone and typical APDs. However, risperidone may have an advantage with respect to long-term outcome. Lieberman et al.[20] and Green et al.[21] compared olanzapine with haloperidol in a 2-year, randomized, double-blind study of 263 FES patients, which is also known as the FIRST (First-episode Intervention and Relapse prevention STudy) trial. Dosing was flexible: olanzapine 5–20 mg/day and haloperidol 2–20 mg/day. Mean dosages were olanzapine 9.1 mg/day and haloperidol 4.4 mg/day at 12 weeks, and olanzapine 10.2 mg/day and haloperidol 4.8 mg/day at 2 years. The agents had similar overall response rates at 12 weeks (olanzapine 55% and haloperidol 46%) and at 2 years (olanzapine 67% and haloperidol 60%) based on predefined clinical rating criteria. In secondary analyses, olanzapine showed certain advantages over haloperidol. In particular, mean time to discontinuation was longer for olanzapine versus haloperidol (322 vs 230 days), and, while attrition was high in both groups, more patients in the olanzapine group remained in the study for 2 years compared with the haloperidol group (23% vs 12%). The atypical APD clozapine is well recognized for its superior efficacy in treatment-resistant schizophrenia and there has been interest in whether clozapine is also superior for the treatment of FES.[34] Given the increased risks associated with clozapine treatment (including agranulocytosis, myocarditis and seizures), it is clear that efficacy would need to be robustly better for clozapine in order for it to have a meaningful role in FES. In the only randomized trial of clozapine conducted to date in FES, Lieberman et al.[24] evaluated 160 Chinese patients who received double-blind, flexible dose treatment for 52 weeks with either clozapine (maximum dose 400 mg/day, median effective dosage 400 mg/day at 12 weeks and 300 mg/day at 52 weeks) or CNS Drugs 2009; 23 (10)

842

ª 2009 Adis Data Information BV. All rights reserved.

Table II. Study design, medication dose ranges and mean effective dosing in first-episode schizophrenia studies Study design and dosing strategy

Medication dose range (mg/day)

Mean effective dose (mg/day)

References

Emsley

Double-blind, flexible dose

HAL and RIS (2–16)

HAL 5.6, RIS 6.1

18

Merlo et al.

Double-blind, fixed dose

RIS (2 or 4)

NA

19

Lieberman et al./Green et al./Keefe et al. (FIRST)

Double-blind, flexible dose

HAL (2–20), OLZ (5–20)

HAL 4.8, OLZ 10.2

20-23

Lieberman et al.

Double-blind, flexible dose

CPZ (max 600), CLZ (max 400)

CPZ 400, CLZ 300

24

Schooler et al./Harvey et al.

Double-blind, flexible dose

HAL and RIS (1–4)

HAL 2.9, RIS 3.3

25,26

Robinson et al.

Open-label,b flexible dose

RIS (1–6), OLZ (2.5–20)

RIS 3.9, OLZ 11.8

27

Perkins et al./McEvoy et al./Keefe et al. (CAFE´)

Double-blind, flexible dose

OLZ (2.5–20), RIS (0.5–4.0), QUE (100–800)

OLZ 11.7, RIS 2.4, QUE 506

5,17,28

Kahn et al. (EUFEST)

Open-label, flexible dose

HAL (1–4), AMI (200–800), OLZ (5–20), QUE (200–750), ZIP (40–160)

HAL 3.0, AMI 450.8, OLZ 12.6, QUE 498.6, ZIP 107.2

16,29

McEvoy et al.c

Open-label then double-blind, fixed dose

HAL at NT dose, then 2- to 10-fold dose increase or continue at NT

First-episode NT: HAL 2.1 Chronic NT: HAL 4.3

30

a

Common acronym or code used for study, when available.

b

Study used blinded raters.

c Study compared patients with first-episode and chronic schizophrenia. AMI = amisulpride; CLZ = clozapine; CPZ = chlorpromazine; QUE = quetiapine; RIS = risperidone; ZIP = ziprasidone.

HAL = haloperidol;

max = maximum;

NA = not

applicable;

NT = neuroleptic

threshold;

OLZ = olanzapine;

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Investigators (study acronym)a

Antipsychotics for First-Episode Schizophrenia

chlorpromazine (maximum dose 600 mg/day, median effective dosage 600 mg/day at 12 weeks and 400 mg/day at 52 weeks). The clinical response rates, as defined by a 50% reduction in the Brief Psychiatric Rating Scale (BPRS) total score, were approximately 80% in both treatment groups. In a secondary analysis, clozapine demonstrated an advantage of shorter median time to remission compared with chlorpromazine: 8 versus 12 weeks. However, taken together, the outcome of the clozapine study was comparable to findings from other studies of typical versus atypical APDs in FES, indicating that the risks associated with clozapine therapy appear to outweigh its potential advantages as a first-line agent in FES. 2.3 Comparative Efficacy of Atypical Antipsychotic Drugs

In 2006, Robinson et al.[27] published the findings of a 4-month interim analysis of a 3-year trial in which 112 subjects with FES were randomized to receive olanzapine or risperidone at mean modal doses of 11.8 and 3.9 mg/day, respectively. Treatment was open-label with blinded raters. Similar to other FES trials, the two APDs performed equally well with regard to clinical efficacy measures. The olanzapine and risperidone groups, respectively, were similar in study retention (11.5 vs 12.1 weeks), cumulative response rates (43.7% vs 58.6%) and mean time to response (10.9 vs 10.4 weeks). Prior to EUFEST, the CAFE´ study[17] was the largest head-to-head comparison of multiple atypical APDs in FES, and the first large randomized FES study to include a quetiapine treatment arm. CAFE´ was a 52-week, randomized, double-blind study that tested the effectiveness of flexible dosing of quetiapine 100–800 mg/day, olanzapine 2.5–20 mg/day and risperidone 0.5–4.0 mg/day in 400 FES patients. Similar to CATIE,[15] the CAFE´ study[17] used time to all-cause treatment discontinuation as the primary outcome measure. Time to all-cause treatment discontinuation is thought to better assess the overall effectiveness of a treatment than efficacy measures alone because it combines the effects of multiple factors including efficacy, tolerability and patient choice.[35] In the ª 2009 Adis Data Information BV. All rights reserved.

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CAFE´ study,[17] mean modal APD doses were quetiapine 506 mg/day, risperidone 2.4 mg/day and olanzapine 11.7 mg/day. Overall, clinical response outcomes were very similar with each APD. At week 52, all-cause treatment discontinuation did not differ between the treatment arms: olanzapine 68%, risperidone 71% and quetiapine 71%. Median time to discontinuation was also similar: olanzapine 28 weeks, quetiapine 25 weeks and risperidone 25 weeks. Response rates were not significantly different among the groups (64% for olanzapine, 58% for quetiapine and 65% for risperidone). Risperidone and olanzapine showed a slight advantage over quetiapine for reduction in positive symptoms at week 12 and olanzapine retained this advantage at week 52. Inadequate therapeutic effect and unacceptable adverse effects accounted for roughly 10% of causes of discontinuation in all groups, whereas patient decision to discontinue medication against the clinician’s recommendation accounted for 40% of causes of treatment discontinuation. This suggests that the medications were more effective in the eyes of clinicians than was implied by discontinuation rates. The results of the CAFE´ study[17] corroborate the findings of Merlo et al.[19] that risperidone 2 mg/day is an effective dosage for many FES patients. Similarly, the CAFE´ study[17] supports the results of the FIRST study,[20] which indicated that olanzapine 10 mg/day is effective for many FES patients. Unlike risperidone and olanzapine, the mean quetiapine dose of 500 mg/day in the CAFE´ study[17] was roughly equivalent to that used in the CATIE study[15] for long-term patients. The CAFE´ investigators suggested that this may be related to the low affinity of quetiapine for dopamine D2 receptors.[17] Most recently, the EUFEST study[16] has provided additional data that are generally consistent with prior data for atypical APDs in FES. The EUFEST study was a 12-month, randomized, open-label, flexible dose study in 498 patients with FES comparing haloperidol (1–4 mg/day, mean dose 3.0 mg/day), amisulpride (200–800 mg/day, mean dose 450.8 mg/day), olanzapine (5–20 mg/day, mean dose 12.6 mg/day), quetiapine (200–750 mg/ day, mean dose 498.6 mg/day) and ziprasidone (40–160 mg/day, mean dose 107.2 mg/day). CNS Drugs 2009; 23 (10)

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Similar to the CATIE[15] and CAFE´[17] studies, EUFEST employed time to all-cause discontinuation as its primary outcome measure.[16] The results showed that treatment discontinuation was substantially lower in patients randomized to any of the four atypical APDs compared with the typical comparator drug haloperidol. No significant differences on this measure emerged among the individual atypical APDs. Treatment discontinuation because of insufficient efficacy was significantly lower for the atypical APDs (except for quetiapine) compared with haloperidol. CGI and Global Assessment of Functioning (GAF) scales also demonstrated an advantage for the atypical APDs. Interestingly, changes in clinical psychopathology scores as assessed by the PANSS did not differ across the agents tested, a finding that the investigators have recently suggested may reflect a type II error resulting from a lower frequency of PANSS assessments in the early stages of the treatment protocol.[29] The EUFEST investigators avoided drawing definitive conclusions regarding the comparative efficacy of haloperidol and atypical APDs in FES due to the discrepancy between psychopathology and effectiveness data and the potential influence of bias introduced by the open-label design. Indeed, haloperidol seems to have fared worse, and olanzapine better, in EUFEST compared with prior blinded FES trials. For example, olanzapine had a much lower 1-year discontinuation rate in EUFEST (33%) than in the FIRST study[21] (65%, as extrapolated by the EUFEST investigators). High rates of discontinuation due to insufficient efficacy in the haloperidol (48%) and quetiapine (40%) groups compared with olanzapine (14%) also distinguished EUFEST data from prior blinded FES trials. This measure did not distinguish haloperidol or quetiapine from olanzapine in the FIRST study[21] at 2 years (haloperidol 25% vs olanzapine 19%) or in CAFE´[17] at 1 year (olanzapine 11.3% vs quetiapine 11.9%). Furthermore, in the Schooler et al. study,[25] discontinuation due to insufficient response was only 5.8% for haloperidol compared with 9.0% for risperidone. Another distinguishing aspect of EUFEST was that the maximal haloperidol dose was limited to 4 mg/day and that exceeding the maximal dose ª 2009 Adis Data Information BV. All rights reserved.

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was defined a priori as a cause for treatment discontinuation.[16] The proportion of subjects discontinuing for this reason was not provided, although, presumably, they were included in discontinuations due to insufficient efficacy. Groups differed with regard to percentage reaching maximum or higher dose received, with this occurring most frequently in haloperidol-treated subjects (61%) compared with patients treated with amisulpride (26%), olanzapine (52%), quetiapine (38%) and ziprasidone (47%). Overall, the EUFEST findings agree with prior FES trials in that atypical APDs were associated with better treatment retention than typical APDs, but conclusions from EUFEST regarding the efficacy of haloperidol relative to atypical APDs are less clear because of the potential impact of confounders introduced by the study design. It should also be noted that the EUFEST study did not include risperidone or aripiprazole, both of which are frequently used in the FES population. 2.4 Efficacy of Antipsychotic Drugs for Negative Symptoms

Negative symptoms are correlated with worse functional outcome and poorer quality of life in schizophrenia.[36,37] Carpenter et al.[38] proposed the term ‘deficit symptoms’ to distinguish stable, enduring, negative symptoms from negative symptoms that are secondary manifestations of modifiable disease factors such as positive psychotic symptoms (e.g. active social withdrawal due to paranoia), depression and substance abuse, or of APD treatment such as affective flattening due to extrapyramidal effects or anhedonia and asociality resulting from hyperprolactinaemiarelated sexual dysfunction. Findings from studies that were designed to differentiate the effects of APDs on primary and secondary negative symptoms indicate that APDs have, at most, modest effects on primary negative symptoms.[39-41] It has been estimated that 23% of FES patients have clinically significant deficit symptoms 6 months after positive symptoms have remitted.[42] The severity of enduring negative symptoms may be unstable in the first 12 months of illness,[43] suggesting that effective intervention CNS Drugs 2009; 23 (10)

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at this time could prevent further worsening. Global negative symptoms lessen during treatment of FES with typical and atypical APDs, but published studies do not control for sources of secondary negative symptoms and therefore are not informative as to whether APDs specifically affect primary negative symptoms. The study by Emsley[18] and the larger Schooler et al.[25] study reported that risperidone and haloperidol groups had moderate mean PANSS negative symptom scores at baseline and experienced a 20–25% reduction in negative symptom scores by study endpoint. Risperidone and haloperidol were associated with equivalent positive symptom reductions in both studies and all groups had significant rates of EPS and hyperprolactinaemia that may have contributed to negative symptoms (see sections 3.1 and 3.3). Olanzapine and clozapine showed advantages over typical APD comparators for negative symptoms, but the differences may have resulted from lower EPS and/or greater antidepressant effects for the atypical APDs. In the FIRST study,[20] there was a greater reduction in mean PANSS negative symptom scores in the olanzapine group than in the haloperidol group, but the overall reduction in negative symptoms was small in both groups (roughly 16% for olanzapine and 6% for haloperidol). The small advantage for olanzapine may have resulted from reduced depression, fewer EPS, a smaller increase in prolactin level and less adjunctive medication use in the olanzapine group (see sections 3.1 and 3.3). It is also notable that duration of illness was shorter in the olanzapine group (52 vs 72 weeks) given that response of negative symptoms to APD treatment was associated with shorter DUP in a meta-analysis of FES trials.[44] Clozapine was also associated with greater improvement in negative symptoms than its typical APD comparator chlorpromazine, with greater reductions in overall negative symptoms, affective flattening and avolition at week 12.[24] These differences remained after controlling for EPS; however, this study did not control for other factors such as non-neurological adverse effects, overall psychopathology and remission of psychotic symptoms. ª 2009 Adis Data Information BV. All rights reserved.

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Head-to-head trials comparing atypical APDs did not find significant differences among agents with regard to overall negative symptom reduction in FES. In the Robinson et al. study,[27] olanzapine and risperidone groups were each associated with moderate baseline avolition and apathy, and minimal-to-mild asociality and anhedonia as measured by the Scale for the Assessment of Negative Symptoms (SANS) and overall reductions in these measures during the study. As with the overall symptom response rate, there was no differential efficacy between olanzapine and risperidone on negative symptoms. In the CAFE´ study, subjects entered with moderate negative symptoms and all treatments were associated with 10–15% reductions in PANSS negative subscale scores at weeks 12 and 52.[17] The EUFEST trial also reported moderate baseline PANSS negative symptom subscale scores but did not provide data on change at endpoint.[16] 2.5 Summary of Efficacy of Antipsychotic Drugs

A number of practical conclusions can be drawn concerning the comparative efficacy of APDs from available studies:  APD treatment (typical and atypical) is associated with high rates of response and remission of positive symptoms of psychosis.  Depending on the agent, mean effective APD doses are up to 50% lower in FES than in chronic schizophrenia (table II).  Atypical APDs (including olanzapine, quetiapine, risperidone, ziprasidone and amisulpride) appear to have similar effectiveness as measured by time to all-cause treatment discontinuation and these agents, as a group, appear to have modest superiority over haloperidol, a high potency typical APD.  Compared with haloperidol, olanzapine may be associated with improved treatment retention while risperidone may provide reduced risk of relapse and better stability of response.  Treatment with typical or atypical APDs is associated with reductions in overall negative symptoms in FES, but published trials do not CNS Drugs 2009; 23 (10)

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distinguish between effects that are secondary to reductions in other symptom domains and those representing effects on primary negative symptoms.  Information on the clinical utility of aripiprazole and paliperidone in FES is not yet available from large randomized studies. Likewise, data from large controlled trials comparing oral with long-acting antipsychotics are currently lacking and would be useful given the important problem of treatment non-adherence in FES. 3. Safety of Antipsychotic Drugs in First-Episode Schizophrenia 3.1 Neurological Adverse Effects

Neurological adverse effects of APDs can cause distress and functional impairment, and may contribute to treatment non-adherence. Parkinsonian adverse effects can increase the probability that patients with FES discontinue maintenance treatment following their first psychotic relapse.[45] In the 12-week analysis of the FIRST study,[20] EPS were a reason for discontinuation in about 10% of FES subjects in the haloperidol group but in no patients in the olanzapine group. While the use of adjunctive anticholinergic medications can improve the tolerability of EPS, these agents are often associated with adverse cognitive effects and peripheral anticholinergic effects.[46] In the 6-week risperidone versus haloperidol study in FES, Emsley[18] found that haloperidol was associated with more severe EPS and akathisia. Furthermore, a greater percentage of haloperidoltreated subjects received antiparkinsonian medications compared with risperidone-treated subjects (75% vs 50%). The high rates of EPS likely reflected the somewhat higher APD doses used in this study – approximately 6 mg/day for each drug. In the Schooler et al. trial,[25] lower doses of risperidone (mean dose 3.3 mg/day) and haloperidol (mean dose 2.9 mg/day) were used. Risperidone treatment was associated with lower rates of EPS and akathisia and less adjunctive medication use in comparison with haloperidol treatment. Similarly, ª 2009 Adis Data Information BV. All rights reserved.

in the FIRST study,[20] haloperidol was associated with higher rates of EPS and akathisia and more frequent use of adjunctive anticholinergics, benzodiazepines and b-adrenoceptor antagonists (b-blockers) at the 12-week and 2-year assessments compared with olanzapine. The haloperidol group also had higher scores on the Abnormal Involuntary Movement Scale (AIMS) at weeks 24, 52 and 104. In the FES clozapine versus chlorpromazine study, the chlorpromazine group had significantly more EPS at week 12 but not week 52, and a greater incidence of dystonia and akathisia.[24] In the comparison of olanzapine (mean dose 11.8 mg/day) with risperidone (mean dose 3.9 mg/day) in FES, Robinson et al.[27] found that risperidone was associated with a trend toward higher rates of EPS and with more frequent use of adjunctive medication without which, it is speculated, the difference in EPS between the two groups may have reached significance. However, the CAFE´ study[17] suggested that a lower dose of risperidone (2.4 mg/day) compares well with olanzapine (11.7 mg/day) with regard to efficacy and neurological adverse effects in FES. In fact, the majority of patients in all groups did not experience more than mild parkinsonism or akathisia. In the CAFE´ study, there were no group differences in the frequency of EPS, but the olanzapine group received adjunctive medication for parkinsonism and akathisia more frequently than the quetiapine group (11% vs 4%). In the EUFEST study,[16] parkinsonism was more common with haloperidol (34%) than with atypical APDs: amisulpride (17%), olanzapine (6%), quetiapine (11%) or ziprasidone (16%). Akathisia was more prevalent with haloperidol (26%) or ziprasidone (28%) than with amisulpride (16%), olanzapine (10%) or quetiapine (13%). Anticholinergic use was higher among patients taking haloperidol (45%) or amisulpride (34%) than among patients taking olanzapine (22%), quetiapine (19%) or ziprasidone (22%). These differences likely contributed to the higher rate of discontinuation of haloperidol due to adverse effects (20%) compared with olanzapine (6%) and quetiapine (3%). Haloperidol was also associated with a higher rate of discontinuation due to nonadherence (30% vs 13–19% among atypical APDs), CNS Drugs 2009; 23 (10)

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although differences across groups were not statistically significant on this measure. It is possible that patient bias contributed to higher nonadherence rates in the haloperidol group in the open-label EUFEST study than was reported in the blinded Schooler et al.[25] study (2.9%) and FIRST (10 mg/day) may have contributed to the elevated TD risk. Indeed, among five long-term studies using risperidone, mean risperidone dosage ranged from 1 to 4.9 mg/day and, similarly, TD rates in risperidone-treated subjects varied from 0% to 13.4%.[8] Age and APD dose positively correlated with risk for TD. In a prospective study of 57 patients treated with low-dose haloperidol, Oosthuizen et al.[49] reported that subjects who developed TD had a mean age of 37 years and received a mean haloperidol dosage of 2.8 mg/day compared with a mean age of 27 years ª 2009 Adis Data Information BV. All rights reserved.

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and a mean haloperidol dosage of 1.4 mg/day in subjects who did not develop TD. Recent FES studies using lower APD doses have observed low rates of TD. In the Schooler et al. study,[25,50] 2 of 229 risperidone-treated patients and 5 of 215 haloperidol-treated patients developed TD, with estimated annualized rates of new-onset TD of 0.72% in the risperidone group and 1.87% in the haloperidol group. These differences were not significant. In the FIRST study,[21] haloperidol treatment was associated with a higher rate of abnormal involuntary movements at weeks 24, 52 and 104. In the CAFE´ study,[17] only 1% of subjects had more than mild abnormal involuntary movements and there were no differences among treatment groups. In the EUFEST study,[16] rates of dyskinesia were low; three subjects had dyskinesia at baseline (one each in the haloperidol, amisulpride and ziprasidone arms) and three subjects had dyskinesia at study endpoint (two in the haloperidol arm, one in the amisulpride arm). In sum, the incidence of new-onset TD appears to be low in the first year of treatment with low-dose typical or atypical APDs. Although cumulative evidence suggests that atypical APDs may pose a lower risk of TD than haloperidol, studies are too heterogeneous and underpowered to draw definitive conclusions. Meta-analyses of long-term data could help resolve this issue. 3.2 Metabolic Adverse Effects

APDs vary in their tendency to cause weight gain, dyslipidaemia and glucose dysregulation, which elevate risk of diabetes mellitus and cardiovascular disease and shorten life expectancy.[51,52] Both typical and atypical APDs have been associated with weight gain in FES. In the Schooler et al. study,[25] risperidone was associated with greater mean weight gain at 3 months compared with haloperidol (4.6 vs 3.5 kg) but this difference was no longer significant by the study endpoint (7.5 vs 6.5 kg). In the FIRST study,[53] olanzapine was associated with greater mean weight gain than haloperidol at week 12 (observed case analysis 9.2 vs 3.7 kg) and after 2 years of treatment (observed case analysis 15.4 vs 7.5 kg). Also, more patients who received olanzapine compared with CNS Drugs 2009; 23 (10)

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haloperidol gained >7% of their baseline weight (72% vs 42%). Lieberman et al.[24] found that after 52 weeks of treatment, clozapine was associated with a 9.9 kg mean weight gain compared with 6.5 kg for chlorpromazine, but the differences did not achieve statistical significance. In patients with chronic schizophrenia, among atypical APDs, clozapine and olanzapine are associated with the greatest average weight gain followed by risperidone and quetiapine, which have intermediate risk, and ziprasidone and aripiprazole, which have low risk of associated weight gain.[51] With the exception of aripiprazole for which there is insufficient evidence to date, these risk strata are arranged similarly in FES, but a greater magnitude and rate of weight gain are observed in FES than in chronic schizophrenia. Robinson et al.[27] reported that among FES patients treated with olanzapine or risperidone for 4 months, the olanzapine group gained 17.3% of their baseline weight compared with an 11.3% weight gain in the risperidone group. While the mean body mass index of both groups moved from normal to overweight within the 4 months, a mixed models approach to repeated measures ANCOVA demonstrated that the olanzapine group gained more weight. In the CAFE´ study,[17] all three treatment groups had substantial weight gain with more robust increases in the first 12 weeks of the study, but the olanzapine group gained nearly twice as much weight as the quetiapine and risperidone groups. At week 12, mean weight gain was 7.1 kg for olanzapine, 3.7 kg for quetiapine and 4.0 kg for risperidone. At week 52, mean weight gain was 11.1 kg for olanzapine, 5.7 kg for quetiapine and 6.6 kg for risperidone. Metabolic-related laboratory measures worsened in all groups, but risperidone was associated with less change in serum triglycerides and highdensity lipoprotein cholesterol levels than olanzapine and quetiapine. In the EUFEST study,[16] olanzapine-treated patients had the highest mean weight gain (13.9 kg), followed by quetiapine (10.5 kg), amisulpride (9.7 kg), haloperidol (7.3 kg) and ziprasidone (4.8 kg). All groups demonstrated worsening lipid and fasting glucose status, but significant differences among agents did not emerge. ª 2009 Adis Data Information BV. All rights reserved.

3.3 Prolactin Effects

Prolactin level elevation is associated with sexual and menstrual dysfunction, gynaecomastia/ galactorrhoea and increased risk of osteoporosis. As with other adverse effects, atypical APDs vary with regard to their effects on prolactin levels. Consistent with the experience in chronic schizophrenia, risperidone has demonstrated a higher propensity to induce prolactin level elevation and related adverse effects than other APDs in FES. In the Schooler et al. study,[25] risperidone was associated with a higher incidence of hyperprolactinaemia than haloperidol (73.8% vs 49.8%) and a greater incidence of prolactin-related adverse effects (14% vs 1%). In contrast, the FIRST study[20] found that olanzapine was associated with less prolactin level elevation than haloperidol. In the CAFE´ study,[17] risperidone was associated with higher prolactin levels than olanzapine and quetiapine. Furthermore, the risperidone group had a higher incidence of gynaecomastia (9.8%) than the quetiapine group (2.2%), while the incidence of gynaecomastia in the olanzapine group (6.8%) did not differ from the other two groups. Among female subjects, moderate to severe menstrual irregularities were associated with risperidone (47.1%), olanzapine (31.3%) and quetiapine (23.8%), although these differences did not reach significance. In the EUFEST study,[16] 89% of patients taking amisulpride had hyperprolactinaemia compared with 40–50% of subjects in the other treatment arms. The incidence of sexual dysfunction did not differ among agents. 3.4 Summary of Safety of Antipsychotic Drugs

A number of practical conclusions can be drawn from the safety literature of APDs in FES:  Overall, clozapine, risperidone, olanzapine, quetiapine, amisulpride and ziprasidone appear to have lower risk of EPS – especially parkinsonism and akathisia – and are associated with lower use of adjunctive medications to treat these adverse effects than typical APDs.  With less certainty, the incidence of abnormal involuntary movements appears to be lower with atypical compared with typical APDs. CNS Drugs 2009; 23 (10)

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 Olanzapine, quetiapine and risperidone are all associated with rapid weight gain in the first 3 months of treatment – sustained during the first year of treatment – but olanzapine is associated with up to twice as much weight gain as quetiapine and risperidone. Ziprasidone and haloperidol are associated with more modest weight gain.  Treatment with olanzapine, quetiapine and risperidone is associated with increased fasting triglycerides, glucose, total cholesterol and decreased high-density lipoprotein cholesterol.  Risperidone is associated with higher prolactin levels and prolactin-related effects than olanzapine, quetiapine, ziprasidone and lowdose haloperidol.  Information on the comparative adverse effects of aripiprazole and paliperidone in FES is unavailable but could be useful, given the limited options for patients who need to switch antipsychotics, especially in regard to weight gain and related metabolic concerns. 4. Cognitive Function in First-Episode Schizophrenia Given the evidence for functional[54] and neuroanatomical[55] progression in FES,[56] it is tempting to posit a concomitant progressive decline in cognitive function. However, studies indicate that considerable impairment may already be present at the onset of psychosis and that there is little evidence to support further decline. For example, in a study of 94 patients with FES, mean generalized neurocognitive scores were 1.5 standard deviations below the control group and up to 2 standard deviations below control in memory and executive function domains.[4] In another study, 111 patients with FES and 76 patients with chronic schizophrenia demonstrated similar cognitive deficits, both in cross-section and longitudinally, suggesting that cognitive decline following the onset of psychosis is not a prominent feature of schizophrenia.[57] Other data, however, support the hypothesis that progressive cognitive decline pre-dates the onset of psychosis. Studies show more limited cognitive, motor and social abnormalities in individuals in the pre-morbid[58-60] and ª 2009 Adis Data Information BV. All rights reserved.

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prodromal[61,62] phases of illness. Studies that assessed cognitive function longitudinally generally demonstrated a progression of cognitive decline as individuals approached the formal onset of psychosis.[59,61,62]

4.1 Cognitive Function and Antipsychotic Drug Treatment

The evidence for prominent and enduring cognitive symptoms in FES suggests that cognitive domains are relatively refractory to treatment intervention. These data are consistent with the growing body of literature demonstrating the limitations of currently available APDs in treating cognitive deficits in schizophrenia. Reviews of studies that have assessed the cognitive effects of typical APDs in patients with chronic schizophrenia have demonstrated little, if any, benefit.[63] With the advent of atypical APDs, there was initial optimism that these agents would possess improved therapeutic potential across many illness domains, including cognition. In fact, a number of studies and meta-analyses have suggested that atypical APDs do offer some efficacy for cognitive deficits.[64-66] However, even the presence of modest benefits has been called into question based on factors such as use of an inadequate sample size, insufficient duration of treatment, excessively dosed comparator drugs (usually typical APDs) and the failure to account for associated factors such as EPS and the use of anticholinergic medications.[67-69] Interestingly, in the CATIE study,[67] 817 patients completed neuropsychological testing at baseline and at 2 months. Mean cognitive function improved with each APD, but gains were small and there were no differences between any pair of agents, including the typical APD perphenazine. In fact, at the 18-month mark, 303 remaining patients were also tested and perphenazine showed a small advantage over olanzapine and risperidone in neurocognitive performance. These findings demonstrate the complexity of assessing the neurocognitive efficacy of APDs in patients with schizophrenia and the fact that all available APDs have considerable limitations in addressing the substantial cognitive deficits in this population. CNS Drugs 2009; 23 (10)

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Only a few studies have assessed the effects of atypical APDs on cognition in FES and incorporated most of the aforementioned study design features required for meaningful data interpretation. In the CAFE´ study,[28] 224 patients completed baseline and 12-week neurocognitive testing, and 81 patients also completed testing at 52 weeks. At 12 weeks there was modest cognitive improvement with all treatments, but no significant overall differences between treatments on the primary outcome measure, the composite score of the neurocognitive battery (the same as that used in the CATIE study[15]). The significance of within-group improvements seen at 12 weeks was lost by 52 weeks, even though the pattern of change remained the same. Furthermore, even though cognitive improvements were small, these changes correlated with functional improvement at both 12 and 52 weeks, suggesting that the effects may have been clinically meaningful. Several other large double-blind studies in FES have compared neurocognitive function in patients taking a low-dose typical APD compared with those taking an atypical APD. In the FIRST study,[22] neurocognitive assessments were administered at baseline and at regular intervals during the 2-year treatment period. Both treatment groups experienced neurocognitive improvement on the composite neurocognitive score and a small advantage emerged for olanzapine at the 12- and 24-week intervals compared with haloperidol. In the Harvey et al. study,[26] 359 patients completed baseline and 3-month neurocognitive assessments, demonstrating improvements in cognition for both haloperidol and risperidone, with a small differential advantage for risperidone. Taken together, these data indicate that in FES, treatment with both typical and atypical APDs is associated with modest cognitive gains. There may be a small advantage for atypical over typical APDs, but this advantage is of unclear clinical significance. Moreover, it is unclear whether this benefit is due to a direct therapeutic effect in cognitive enhancement or is secondary to some other effect on psychosis or to adverse effects. There is currently no evidence of a significant advantage for one atypical APD over another in terms of effects on cognitive function. ª 2009 Adis Data Information BV. All rights reserved.

5. Brain Structure and Antipsychotic Drugs While the efficacy of APDs has traditionally been limited to domains of psychopathology, it is increasingly apparent that these drugs can affect both brain structure and function. Furthermore, recent data indicate that neuroanatomical changes that occur in the early stages of schizophrenia can influence long-term functional outcome. These observations suggest that the efficacy of APDs may need to be considered more broadly to encompass effects at the levels of brain structure. Evidence for altered brain morphology in FES is reviewed below, followed by an evaluation of studies that have measured the effects of APDs on cortical and subcortical structures. 5.1 Brain Morphology in the Early Stages of Schizophrenia

Structural neuroimaging studies have detected volume changes in different brain regions in schizophrenia.[70] The most prominent and replicated finding is lateral and third ventricle enlargement, but consistent changes include reduced cortical grey matter, reduced hippocampal volume and increased basal ganglia volume.[71,72] While earlier studies were generally performed in patients with chronic schizophrenia, more recent studies have found that neuroanatomical deficits are present even at the first onset of psychosis. Furthermore, longitudinal imaging studies have revealed that some cortical volume reductions are progressive. For example, in prodromal patients judged ‘ultra-high risk’ for the development of psychosis, progressive grey matter loss has been identified in multiple cortical regions in those patients who eventually converted to psychosis.[73,74] Progressive cortical volume loss in FES has also been reported in cerebral hemispheres,[75] total cerebral grey matter,[76] whole frontal cortex[77,78] and superior temporal gyrus grey matter.[79] Recognizing that neuroanatomical changes may be progressive early in the course of psychosis is important not only for understanding the pathophysiology of the illness but also because it offers the possibility that long-term outcome may CNS Drugs 2009; 23 (10)

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be improved if the rate of neuroanatomical change can be attenuated. 5.2 Subcortical Effects of Antipsychotic Drugs

The observation that caudate volume was enlarged in schizophrenia led to some of the earliest longitudinal neuroimaging studies demonstrating a relationship between APD treatment and brain structure. In two longitudinal studies in FES, long-term treatment with typical APDs led to increased caudate volume ranging from 5.7%[80] to 15%.[81] A study of major depressive disorder with psychotic features found a similar enlargement in caudate volume with typical APDs,[82] indicating that the effect was more likely a consequence of treatment rather than a disease-specific pathophysiological process. Subsequent studies found that replacing the typical APD with an atypical APD (including clozapine, olanzapine and risperidone) tended to normalize caudate volume.[83-86] These data are supported by the results of several[87,88] but not all[89] preclinical studies that have found chronic haloperidol treatment in rodents to be associated with caudate enlargement. Also in rodents, chronic treatment with clozapine,[90] olanzapine[88,89] and risperidone[88] caused either no change or a small reduction in caudate volume using post-mortem volume assessment. While the long-term functional consequences remain uncertain, worse neuropsychological test performance,[91] deficit state[92] and more severe clinical symptomatology[93] have been associated with larger caudate volumes in patients treated with typical APDs. This could be because more severely affected patients receive more antipsychotic medication. Nevertheless, these data on subcortical structures provide a limited neuroanatomical rationale for choosing atypical over typical APDs. 5.3 Cortical Effects of Antipsychotic Drugs

Until recently, the impact of extended APD treatment on cortical structures, including frontal cortical grey matter, had not been examined. In the FIRST study,[23] patients underwent structural MRI scans at baseline, 12, 24, 52 and 104 weeks. By week 12, patients receiving haloperidol ª 2009 Adis Data Information BV. All rights reserved.

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showed a significant reduction in whole brain cortical grey matter (-0.85%), while patients receiving olanzapine showed no change in cortical grey matter volume. This difference in grey matter volume between typical and atypical APDs progressed over the course of the first year of treatment (-1.7% in the haloperidol arm) and was also seen in several cortical subregions, including frontal and parietal cortices. This was the first evidence that cortical grey matter loss may be related to APD treatment. Since a placebo arm could not ethically be included in this study, it remains unclear whether grey matter loss in the haloperidol arm was pathophysiological, treatment-induced, or a combination of both. Nevertheless, these findings suggest a neuroanatomical advantage for olanzapine that may represent a neuroprotective effect in FES.[94] The potential for a neuroprotective process associated with atypical APD treatment is supported by findings from a recent longitudinal MRI study that performed baseline and 5-year follow-up MRI scans of 96 patients with schizophrenia and 113 healthy controls.[95] While treatment was not controlled, a significant correlation emerged between those patients treated with olanzapine (37 patients received olanzapine during at least part of the study) and less cortical grey matter loss over the 5-year interval. Furthermore, since neurocognitive function has been identified as the strongest predictor of long-term functional outcome in schizophrenia,[96] an association between neuroanatomical change and neurocognitive function would lend support to the clinical relevance of treatment-related neuroanatomical changes. Neurocognitive assessments were performed in parallel with the MRI scans in the FIRST study.[23] Less improvement in neurocognitive function was found to correlate with greater cortical grey matter loss in the haloperidol-treated patients. Interestingly, a recent 5-year longitudinal study of 34 patients with FES reported that progressive change in cortical grey matter volume during the first year of psychosis was associated with clinical and functional outcomes 5 years later.[97] Outcomes associated with greater grey matter volume loss ranged from higher positive and negative symptom scores to CNS Drugs 2009; 23 (10)

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lower GAF scores and a lesser likelihood of living independently. Thus, an emerging body of research supports the clinical and functional importance of considering the impact of treatment on progressive neuroanatomical changes in FES. Limited data support the use of atypical over typical APDs on the basis of the tendency of the latter to cause caudate volume enlargement. More convincing functional data support the use of olanzapine over haloperidol based on the association between haloperidol and cortical grey matter loss. It is not known whether the putative neuroprotective advantage of olanzapine extends to other atypical APDs in FES. This remains an important area for future research. 6. Conclusion This article reviews the current knowledge base of therapeutic advances and limitations associated with the use of APDs in FES. In general, it appears that FES patients respond in high rates to both typical and atypical APDs at doses roughly half of those required in chronic patient populations. FES patients appear more likely to continue treatment with atypical compared with typical APDs. The reason for this advantage is likely to be multifactorial, with contributions in the areas of tolerability, efficacy and adherence. While the neurological adverse effect burden is generally lower for atypical compared with typical APDs, it is also clear that judicious choice and dosing of typical APDs is compatible with lower EPS and reduced need for adjunctive anticholinergic medication. Weight gain and metabolic issues associated with many atypical agents present particular concerns in the FES population, given the need for ongoing treatment, frequently across the lifespan. Furthermore, the substantial cognitive deficits and primary negative symptoms of schizophrenia are not effectively addressed by typical or atypical APDs. Nevertheless, recent evidence suggesting that atypical APDs may help slow the progressive neuroanatomical changes and functional decline that accompany new-onset psychosis offers hope that long-term outcome can be improved. These ª 2009 Adis Data Information BV. All rights reserved.

early data are encouraging but replication studies are required. Ultimately, novel therapies that move beyond the dopamine receptor antagonist paradigm will likely be needed to address the full range of clinical and functional deficits associated with schizophrenia. Acknowledgements This work was supported in part by the Foundation of Hope, Raleigh, NC, USA (KS, LFJ), NARSAD Independent Investigator Award (LFJ) and the Lieber Center for Schizophrenia Research and Treatment of the New York State Psychiatric Institute (LFJ, JAL). KS reports no potential conflicts of interest. LFJ has served as a consultant for AstraZeneca and has received grant support from AstraZeneca, Eli Lilly and Forest Laboratories. JAL serves as a consultant and/or advisor to AstraZeneca, Eli Lilly, Forest Laboratories, GlaxoSmithKline, Pfizer and Wyeth; and as a member of the Data Safety Management Board for Solvay and Wyeth. He does not receive financial compensation or salary support for his participation as a consultant or as a member of a board. He receives grant support from AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Janssen, Merck, Pfizer and Wyeth; and he holds a patent from Repligen.

References 1. Jarskog LF, Gilmore JH. Neuroprogressive theories. In: Lieberman JA, Stroup TS, Perkins DO, editors. Textbook of schizophrenia. Washington, DC: American Psychiatric Publishing Inc., 2006: 137-50 2. Tohen M, Strakowski SM, Zarate Jr C, et al. The McLeanHarvard first-episode project: 6-month symptomatic and functional outcome in affective and nonaffective psychosis. Biol Psychiatry 2000 Sep 15; 48 (6): 467-76 3. Robinson DG, Woerner MG, McMeniman M, et al. Symptomatic and functional recovery from a first episode of schizophrenia or schizoaffective disorder. Am J Psychiatry 2004 Mar; 161 (3): 473-9 4. Bilder RM, Goldman RS, Robinson D, et al. Neuropsychology of first-episode schizophrenia: initial characterization and clinical correlates. Am J Psychiatry 2000 Apr; 157 (4): 549-59 5. Perkins DO, Gu H, Weiden PJ, et al. Predictors of treatment discontinuation and medication nonadherence in patients recovering from a first episode of schizophrenia, schizophreniform disorder, or schizoaffective disorder: a randomized, double-blind, flexible-dose, multicenter study. J Clin Psychiatry 2008 Jan; 69 (1): 106-13 6. Moore TA, Buchanan RW, Buckley PF, et al. The Texas Medication Algorithm Project antipsychotic algorithm for schizophrenia: 2006 update. J Clin Psychiatry 2007 Nov; 68 (11): 1751-62 7. Lehman AF, Lieberman JA, Dixon LB, et al. Practice guideline for the treatment of patients with schizophrenia, second edition. Am J Psychiatry 2004 Feb; 161 (2 Suppl.): 1-56

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Correspondence: L. Fredrik Jarskog, NYSPI/Columbia University, 1051 Riverside Drive – Unit 42, New York, NY 10032, USA. E-mail: [email protected]

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