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Psychotic prodrome: Are effective? Ethical? Evidence is mixed but risk is high when abnormal cognition falls short of

Meera Narasimhan, MD Director, division Associate professor of clinical Department of and behavioral sciences University of South Carolina School of Columbia

Peter F. Buckley, MD Chairman and professor Department of psychiatry and behavioral health Medical College of Georgia, Augusta

ecause 40% of individuals with a psy- B chotic prodrome develop schizophrenia, detecting and preventing this transition could improve many patients’ lives. Unfortunately: • psychotic prodrome lacks clear-cut symp- toms and is difficult to identify • little evidence exists to help clinicians select psychotropics and decide how long to use them • treating all prodromal patients would expose those who never develop to the risk of psychotropics’ side effects. How, then, can help patients who present with possible prodromal symptoms? Based on research and our experience, this article describes the psychotic prodrome and offers a © Marc Bruce / Images.com

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pragmatic, evidence-based approach to Box 1 diagnosis and treatment. detects brain changes during psychotic prodrome WHAT CAUSES PSYCHOTIC CONVERSION? Reduced gray matter volumes in certain educed gray matter volumes in certain brain brain regions may be associated with con- Rregions may be associated with conversion to version to psychosis (Box 1). Stress also may psychosis. Imaging studies have found medial play a role; elevated stress-reactive cortisol temporal lobe changes—specifically, hippocampal volume alterations—in persons with schizophrenia, levels are associated with positive symptom genetic high-risk groups, and those thought to be at 1 severity in the prodrome. Other factors risk for imminent psychosis.11 being investigated include obstetric compli- MRI imaging of patients with prodromal signs has cations at birth, maternal age >30, premor- shown less gray matter in the right medial temporal, bid schizotypal personality disorder, and lateral temporal, inferior frontal cortex, and bilateral impaired olfaction. cingulate regions in those who have developed Symptoms. Nearly 80% of patients with psychosis, compared with those who have not. schizophrenia experience a psychotic pro- In the psychotic patients, 12-month longitudinal drome that lasts a few months to several follow-up has found reduced gray matter in the left hippocampal, fusiform, orbitofrontal, cerebellar 2 years. Common features include: cortices, and cingulate gyrus.12 • gradual worsening of perceptual dis- Brain structure is related to genetic liability turbance for schizophrenia in high-risk patients, who seem to • referential thinking have smaller right and left prefrontal lobes and smaller • paranoia right and left thalami. These findings are consistent • mild cognitive deficits with the prodrome’s neurocognitive deficits, which • lability are less than those reported in schizophrenia and • impulsivity greater than those seen in healthy subjects. • suicidality • declining social function and acade- mic performance.3,4 predict outcome. A longer prodrome is thought to Patients with these symptoms may be at immi- indicate a poor prognosis,6 such as in patients nent risk; if untreated, an estimated 40% progress to who wait a year before seeking treatment.7 A schizophrenia within 1 year.5 review of 22 studies of first-episode psychosis A premorbid phase often precedes the pro- found early psychosocial and pharmacologic drome, with symptoms such as impaired atten- interventions improved long-term prognosis, and tion, soft neurologic signs, and subtle social medication discontinuation predicted more- deficits. These changes may be harbingers of the severe and chronic .8 prodrome but are too nonspecific to be diagnos- Genetic risk. Schizophrenia has a strong genetic tic. Other functional impairments—including predisposition, although not everyone in the , , drug abuse, and psychosocial genetic high-risk group develops schizophrenia. factors such as school stress—may mimic schizo- Persons with a family history of schizophrenia phrenic prodrome. have a 10% to 20% risk of psychotic conversion.9 Prognosis. Studies of patients’ first schizophrenia Pioneering work by McGorry et al10 identi- episodes suggest that prodrome duration may fied an “ultra high-risk group” with a psychotic

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Table 1 3 patient groups considered at ‘ultra high risk’ to develop schizophrenia

Patients with… Symptoms

Attenuated psychotic symptoms Overvalued ideas, perceptual disorders Present at least 1 week; not >5 years At least 1 symptom several times a week

Brief intermittent psychotic episodes Frank psychotic features Resolve spontaneously within 7 days Can be drug-induced

Genetic risk and recent deterioration Psychotic disorder in a first-degree relative Schizotypal personality disorder Present at least 1 month; not >5 years Significant functional decline

Source: Adapted from reference 10 conversion rate of 40% to 60%. These patients • Bonn Scale for the Assessment of Basic present with three symptom patterns: Symptoms (BSABS): captures subtle • attenuated positive symptoms changes in thinking, feeling, and perception. • brief intermittent psychotic episodes • Schizophrenia Prediction Instrument for • genetic risk and recent deterioration syn- Adults (SPI-A): defines prepsychotic drome (Table 1). deviations and rates symptoms that are Early identification of these high-risk indi- subjectively experienced by the patient. viduals with perceptual distortions, frank psy- • Comprehensive Assessment of At Risk chotic symptoms, family history of psychosis, Mental State (CAARMS): defines ultra and schizotypal personality disorder may aid in high-risk criteria and incorporates eight early recognition and treatment. dimensions of . The Edinburgh High Risk Study of 162 indi- • Scale of Prodromal Symptoms (SOPS): viduals ages 16 to 25 showed more marked psy- rates psychosis severity. When embedded chopathology in those with at least two close rel- within the Structured Interview for atives with schizophrenia, compared with con- Prodromal (SIPS), the SOPS trol groups. A direct correlation was seen determines the presence or absence of psy- between genetic liability and poor neurocogni- chosis and predicts progression to psy- tive performance.11 chopathology. • Criteria for Prodromal Symptoms PRODROME RATING SCALES (COPS): defines ultra high-risk categories. Researchers are using outcome measures to diag- • Presence of Psychosis Scale (POPS): rates nose prodromal symptoms and assess their severity. severity, intensity, and duration of positive Operational, validated assessment tools include: prodromal symptoms.12 continued on page 37

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continued from page 34 These instruments may identify pro- Table 2 dromal symptoms in psychiatric practice, Should you intervene with patients but further validation of clinical criteria in suspected psychotic prodrome? is needed before they could be recom- Arguments for: mended for routine patient assessment. • Early treatment may prevent psychosocial decline PROPHYLACTIC ANTIPSYCHOTICS? • Treatment may delay or ameliorate psychosis onset Atypical antipsychotics may be the stan- • Treatment may improve patient awareness dard of care for patients with a first psy- and acceptance of diagnosis chotic episode, but this intervention is • Antipsychotics are effective for symptoms based on few double-blind controlled trials. and may be neuroprotective Not surprisingly, only a handful of studies • Medications may improve overall outcome have examined therapy for • Neuroimaging findings may predict psychosis the prodrome’s less clear-cut symptoms. • Outcome scales have improved diagnosis Risperidone. An 8- to 12-week open-label • Treatment may reduce prodrome duration study in adolescents with first- and second- and improve prognosis degree relatives with schizophrenia13 Arguments against: included four prodromal and six first- episode psychosis patients who met criteria • Treatment would likely be given to persons for a cluster A personality disorder. who would not develop psychosis Risperidone, 1.0 mg/d and 1.8 mg/d, • Treatment would unnecessarily stigmatize individuals respectively, improved who do not have schizophrenia and attention symptoms, as measured with • Exposing patients with uncertain diagnoses the Child Behavior Checklist. Verbal to treatment risks is an ethical dilemma memory improved minimally, and no • Antipsychotics are associated with side effects medication side effects were reported. • Psychotic prodrome studies are inconclusive, An open-label observational study14 with small sample sizes and short follow-up identified four middle-aged subjects • No biological markers exist to predict psychosis with a genetic risk of schizophrenia who reported negative symptoms and neu- rocognitive deficits. Risperidone, started at 0.25 ing antipsychotics, and supportive psy- mg/d and gradually increased to a maximum of 2 chotherapy mg/d, improved negative symptoms, attention, • or a specific preventive intervention (SPI) that and working memory. Mild side effects including included risperidone, 1 to 2 mg/d, and a mod- tremors, sedation, dry mouth, and anxiety symp- ified cognitive-behavioral therapy (CBT). toms were reported. After 6 months, 10 of 28 (36%) in the NBI An open-label, randomized, comparator trial15 group had converted to a first episode of psychosis, examined psychotic transition rates in 59 subjects compared with 3 of 31 (10%) in the SPI group (P = (mean age, 20) who met ultra high-risk criteria. 0.03). At this point, risperidone was stopped, and all They received: patients were offered NBI for 6 more months. • a needs-based intervention (NBI) compris- At 12-months’ follow-up, another 3 SPI ing case management, psychotropics exclud- patients who had been partially adherent or non-

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Table 3 antipsychotic therapy may exceed unproven bene- Psychotic prodrome: fits in this population. Unanswered clinical questions Discussion. Little information exists on using que- tiapine, ziprasidone, or aripiprazole in prodromal • Does prodrome reflect a vulnerability patients. As cited above, preliminary studies with for progression to psychosis? risperidone and suggest that these • Can prodrome progress to psychosis agents may improve several domains of psychotic in the absence of early interventions? prodrome. The evidence does not support firm • Does duration of untreated psychosis conclusions, however, given the trials’ small sam- predict prognosis? ple sizes and brief duration. • Do treatments reduce the risk of conversion The prevalence of obesity and metabolic syn- to psychosis? drome in patients with schizophrenia and the • Do interventions alter disease severity added metabolic risks associated with atypical and prevent relapses? antipsychotics make their use during the pro- • Can early interventions prevent cognitive drome controversial. Weighing the potential and functional impairment? advantages and disadvantages (Table 2, page 37), we consider antipsychotics to be the last resort after psychosocial interventions have failed to improve adherent to antipsychotic therapy had converted to prodromal symptoms. psychosis. For adherent SPI patients, protection Low-dose atypical antipsychotics may be war- against conversion appeared to persist for 6 ranted for some patients, but their use requires months after risperidone therapy ended. All med- stringent monitoring of: ication side effects were mild and transient. • weight and waist circumference Olanzapine. One double-blind, randomized, place- • vital signs bo-controlled trial has been published using olan- • metabolic parameters such as fasting blood zapine in patients with a prodromal syndrome.16 glucose and lipid profile Sixty patients received olanzapine, 5 to 15 mg/d, or • abnormal involuntary movements placebo. The olanzapine group showed significant • prolactin elevations. reductions in positive, negative, and disorganiza- Lifestyle modification—including diet and tion subscale scores and total SOPS and Positive exercise to counteract the risk of weight gain—must and Negative Syndrome Scale scores, compared be part of the treatment plan. Because the exact risks with the placebo group. of antipsychotics are unknown—particularly their In the first year, 11 of 29 placebo-group weight-gain potential among children and adoles- patients and 5 of 31 receiving olanzapine convert- cents—we recommend specialist consultation (see ed to psychosis. Among patients receiving no treat- Related resources, page 46) and careful documenta- ment in the second year, 2 of 8 former placebo tion of all treatment decisions and discussions. patients and 3 of 9 former olanzapine patients con- verted to psychosis. OTHER THERAPIES Discontinuation rates were 35% and 28%, . Researchers are also exploring respectively. Compared with the placebo group, the efficacy of using antidepressants and anxiolyt- patients taking olanzapine experienced greater ics in the prodromal phase. The only published weight gain, suggesting that risks associated with naturalistic study of adolescents found antide- continued on page 45

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continued from page 38 pressants alone or in combination with mood sta- Box 2 bilizers or anxiolytics to be as effective as atypical Early interventions when 17 antipsychotics in treating prodromal symptoms. you suspect psychotic prodrome A more substantial study is ongoing. . For patients with a suspected psy- • Provide patients and families information chotic prodrome, nondrug strategies may help and emotional support; a strong therapeutic minimize functional and cognitive impairments, alliance may help keep the patient ease distress, and improve coping skills. in treatment if schizophrenia develops CBT has been shown to reduce psychotic • Offer early psychosocial interventions progression over 12 months.18 Use CBT to help such as vocational training, relapse patients cope with the illness while focusing on: prevention, substance abuse treatment, , supportive and CBT • symptom monitoring • premorbid and present functioning • Explore using low-dose atypical antipsychotics as a last resort for patients • establishing a therapeutic alliance with pronounced prodromal symptoms; • assessing the patient’s experience of psy- explain risks of weight gain and other chosis and any thought distortions. metabolic changes, obtain consent, and Also assess and treat co-occurring condi- document need for such interventions tions such as alcohol and drug abuse. Involving • Consider referral, if feasible, to a center the family in early intervention has been shown specializing in psychotic prodrome to improve prognosis.19 diagnosis, treatment, and research

‘REAL WORLD’ EARLY INTERVENTION Patients with prodromal symptoms are often referred to psychiatrists by family members, pri- be developing (Box 2). Psychosocial and pharma- mary care physicians, or other mental health pro- cologic treatment options are based on presenting fessionals. They tend to be young adults, and a symptoms and other patient-specific variables. few may present in their teens. Most are experi- Psychotherapy should emphasize coping encing behavioral changes such as social isola- strategies, education about warning signals of tion, feeling suspicious, perceptual disturbances, psychotic conversion, establishing a therapeutic depression, and/or anxiety symptoms that seem alliance, assessing thought distortions, and mon- abnormal but fall short of DSM-IV criteria for itoring premorbid and present functioning. schizophrenia diagnosis. Consider atypical antipsychotics for patients Many clinical questions about schizophre- with distressing psychotic symptoms, rapidly dete- nia’s prodromal phase remain unanswered (Table riorating function, increased agitation, and safety 3, page 38). Our primary aim is to adequately risks. Consider and/or anxiolytic assess these patients and provide treatment and therapy for depression and anxiety, respectively. follow-up, taking into account: Discuss at length with patients and families • the individual’s presentation the risks and benefits of pharmacologic treat- • risks and benefits of available interventions. ments. When clinically appropriate, cautiously Begin by educating patients and their fami- discontinue or taper any medication with lies and providing social and emotional support patients’ consent, while monitoring for side to alleviate their distress that a mental illness may effects and symptoms. continued

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3. Yung AR. The initial prodrome in psychosis: the prodromal phase Related resources of first-episode psychosis: past and current conceptualizations. Schizophr Bull 1996;30:587-99. Issue devoted to early prodrome research. Schizophr Bull 4. Perkins DO. Evaluating and treating the prodromal stage of schizo- 2003;29(4):621-879. phrenia. Current Psychiatry Reports 2004;6:289-95. Diagnostic and therapeutic intervention during psychotic prodrome. 5. Wood S W, Miller TJ, McGlashan TH. The “prodromal” patient: CNS Spectrums 2004;9(8):578-606. both symptomatic and at risk. CNS Spectrums 2001;6(3):223-32. PRIME (Prevention through Risk Identification, Management & 6. Keshavan MS, Haas G, Miewald J, et al. Prolonged untreated ill- Education) Research Clinic. Department of Psychiatry, ness duration from prodromal onset predicts outcome in first Yale University. http://info.med.yale.edu/psych/prime/pintro.html. episode psychosis. Schizoph Bull 2003;29(4):757-69. Youth Mental Health Update. Schizophrenia: New strategies for early 7. Loebel AD, Lieberman JA, Alvir JM, et al. Duration of psychosis detection and treatment. RAPP Clinic, Zucker Hillside Hospital, and outcome in first-episode schizophrenia. Am J Psychiatry Glen Oaks, NY. http://schoolnet.lij.edu/eshare/files/rapp.html 1992;149:1183-8. 8. Wyatt RJ, Green MF, Tuma AH. Long-term morbidity associated DRUG BRAND NAMES with delayed treatment of first admission schizophrenic patients: a Aripiprazole • Abilify Risperidone • Risperdal re-analysis of the Camarillo State Hospital data. Psychol Med Olanzapine • Zyprexa Ziprasidone • Geodon 1997;27:261-8. Quetiapine • Seroquel 9. Cornblatt BA, Lencz T, Smith CW, et al. The schizophrenia pro- drome revisited: a neurodevelopmental perspective. Schizophr Bull DISCLOSURES 2003;29(4):633-51. Dr. Narasimhan receives research support from Eli Lilly and Co. and 10. McGorry PD, Yung AR, Phillips LJ. The “close-in” or ultra high- Janssen Pharmaceutica and is a speaker or consultant for Eli Lilly and Co., risk model: a safe and effective strategy for research and clinical Pfizer Inc., and Abbott Laboratories. intervention in prepsychotic mental disorder. Schizophr Bull 2003; Dr. Buckley receives research support from AstraZeneca Pharmaceuticals, 29(4):771-90. Bristol-Myers Squibb Co., Eli Lilly and Co., Janssen Pharmaceutica, 11. Johnstone EC, Lawrie SM, Cosway R. What does the Edinburgh Novartis Pharmaceuticals Corp., Pfizer Inc., and Solvay Pharmaceuticals. high-risk study tell us about schizophrenia? Am J Med Genet He is a consultant to and/or speaker for Abbott Laboratories, Alamo 2002;114(8):906-12. Pharmaceuticals, AstraZeneca Pharmaceuticals, Bristol-Myers Squibb Co., Eli Lilly and Co., Janssen Pharmaceutica, Novartis Pharmaceuticals Corp., 12. Miller TJ, Clashing TH, Rosen JL, et al. Prodromal assessment Pfizer Inc., and Pharmstar. with the Structured Interview for Prodromal Syndromes and the Scale of Prodromal Syndromes: predictive validity, interrater relia- bility, and training to reliability. Schizophr Bull 2003;29(4):703-15. References 13. Cannon TD, Huttunen MO, Dahlstrom M, et al. Antipsychotic drug treatment in the prodromal phase in schizophrenia. Am J 1. Corcoran C, Walker E, Huot R, et al. The stress cascade and schiz- Psychiatry 2002;159:1230-2. ophrenia: etiology and onset. Schizophr Bull 2003;29(4):671-92. 14. Tsuang MT, Stone WS, Faraone SV. Treatment of nonpsychotic 2. Klosterkotter J. Diagnosing schizophrenia in the initial prodromal relatives of patients with schizophrenia: four case studies. Biol phase. Arch Gen Psychiatry 2001;58:158-64. Psychiatry 1999;45:1412-18. 15. McGorry PD, Yung AR, Phillips LJ, et al. Randomized controlled trial of intervention designed to reduce the risk of progression to first-episode psychosis in a clinical sample with subthreshold symp- toms. Arch Gen Psychiatry 2002;59:921-8. Schizophrenia’s prodrome is not quite 16. McGlashan TH, Zipursky R, Perkins DO, et al. The PRIME North ready for clinical prime time. In the America randomized double-blind clinical trial of olanzapine ver- sus placebo in patients at risk of being prodromally symptomatic for absence of guidelines, psychotherapy psychosis. I. Study rationale and design. Schizophr Res 2003;61:7-18. is preferred for high-risk patients along 17. Cornblatt B, Lencz T, Correll C, et al. Treating the prodrome: naturalistic findings from the RAP program. Acta Psychiatr Scand with screening and symptom monitoring. 2002:106(suppl):44. Atypical antipsychotics may protect 18. Morrison AO, French P, Walford L, et al. Cognitive therapy for the prevention of psychosis in people at ultra-high risk: randomized against psychotic conversion, but limited controlled trial. Br J Psychiatry 2004;185:291-7. data and side effect risks make them a 19. Wentzell B. This family experience in a supportive first episode pro- treatment of last resort. gram (abstract S-25-03). Davos, Switzerland: Schizophrenia Research 67(1) 11th Biennial Winter Workshop on Schizophrenia. Feb. 7-13, 2004. 20. Stahl SM. Prophylactic antipsychotics: do they keep you from catching schizophrenia? J Clin Psychiatry 2004;65(11):1445-6. Bottom Line

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