Evidence-Based Reviews

Psychotic prodrome: Are antipsychotics effective? Ethical?

Current Psychiatry. 2005 March;4(3):32-46

Evidence is mixed but risk is high when abnormal cognition falls short of schizophrenia

References

1. Corcoran C, Walker E, Huot R, et al. The stress cascade and schizophrenia: etiology and onset. Schizophr Bull 2003;29(4):671-92.

2. Klosterkotter J. Diagnosing schizophrenia in the initial prodromal phase. Arch Gen Psychiatry 2001;58:158-64.

3. Yung AR. The initial prodrome in psychosis: the prodromal phase of first-episode psychosis: past and current conceptualizations. Schizophr Bull 1996;30:587-99.

4. Perkins DO. Evaluating and treating the prodromal stage of schizophrenia. Current Psychiatry Reports 2004;6:289-95.

5. Wood S W, Miller TJ, McGlashan TH. The “prodromal” patient: both symptomatic and at risk. CNS Spectrums 2001;6(3):223-32.

6. Keshavan MS, Haas G, Miewald J, et al. Prolonged untreated illness duration from prodromal onset predicts outcome in first episode psychosis. Schizoph Bull 2003;29(4):757-69.

7. Loebel AD, Lieberman JA, Alvir JM, et al. Duration of psychosis and outcome in first-episode schizophrenia. Am J Psychiatry 1992;149:1183-8.

8. Wyatt RJ, Green MF, Tuma AH. Long-term morbidity associated with delayed treatment of first admission schizophrenic patients: a re-analysis of the Camarillo State Hospital data. Psychol Med 1997;27:261-8.

9. Cornblatt BA, Lencz T, Smith CW, et al. The schizophrenia prodrome revisited: a neuro developmental perspective. Schizophr Bull 2003;29(4):633-51.

10. McGorry PD, Yung AR, Phillips LJ. The “close-in” or ultra high-risk model: a safe and effective strategy for research and clinical intervention in prepsychotic mental disorder. Schizophr Bull 2003;29(4):771-90.

11. Johnstone EC, Lawrie SM, Cosway R. What does the Edinburgh high-risk study tell us about schizophrenia? Am J Med Genet 2002;114(8):906-12.

12. Miller TJ, Clashing TH, Rosen JL, et al. Prodromal assessment with the Structured Interview for Prodromal Syndromes and the Scale of Prodromal Syndromes: predictive validity, interrater reliability, and training to reliability. Schizophr Bull 2003;29(4):703-15.

13. Cannon TD, Huttunen MO, Dahlstrom M, et al. Antipsychotic drug treatment in the prodromal phase in schizophrenia. Am J Psychiatry 2002;159:1230-2.

14. Tsuang MT, Stone WS, Faraone SV. Treatment of nonpsychotic relatives of patients with schizophrenia: four case studies. Biol 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 symptoms. Arch Gen Psychiatry 2002;59:921-8.

16. McGlashan TH, Zipursky R, Perkins DO, et al. The PRIME North America randomized double-blind clinical trial of olanzapine versus placebo in patients at risk of being prodromally symptomatic for psychosis. I. Study rationale and design. Schizophr Res 2003;61:7-18.

17. Cornblatt B, Lencz T, Correll C, et al. Treating the prodrome: naturalistic findings from the RAP program. Acta Psychiatr Scand 2002;106(suppl):44.-

18. Morrison AO, French P, Walford L, et al. Cognitive therapy for the prevention of psychosis in people at ultra-high risk: randomized controlled trial. Br J Psychiatry 2004;185:291-7.

19. Wentzell B. This family experience in a supportive first episode program (abstract S-25-03). Davos, Switzerland: Schizophrenia Research 67(1) 11th Biennial Winter Workshop on Schizophrenia. Feb. 7-13, 2004.

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Because 40% of individuals with a psychotic prodrome develop schizophrenia, detecting and preventing this transition could improve many patients’ lives. Unfortunately:

psychotic prodrome lacks clear-cut symptoms 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 psychosis to the risk of psychotropics’ side effects.

How, then, can psychiatrists help patients who present with possible prodromal symptoms? Based on research and our experience, this article describes the psychotic prodrome and offers a pragmatic, evidence-based approach to diagnosis and treatment.

WHAT CAUSES PSYCHOTIC CONVERSION?

Reduced gray matter volumes in certain brain regions may be associated with conversion to psychosis (Box 1). Stress also may play a role; elevated stress-reactive cortisol levels are associated with positive symptom severity in the prodrome.¹ Other factors being investigated include obstetric complications at birth, maternal age >30, premorbid schizotypal personality disorder, and impaired olfaction.

Symptoms. Nearly 80% of patients with schizophrenia experience a psychotic prodrome that lasts a few months to several years.² Common features include:

gradual worsening of perceptual disturbance
referential thinking
paranoia
mild cognitive deficits
mood lability
impulsivity
suicidality
declining social function and academic performance.^3,4

Patients with these symptoms may be at imminent risk; if untreated, an estimated 40% progress to schizophrenia within 1 year.⁵

A premorbid phase often precedes the prodrome, with symptoms such as impaired attention, soft neurologic signs, and subtle social deficits. These changes may be harbingers of the prodrome but are too nonspecific to be diagnostic. Other functional impairments—including anxiety, depression, drug abuse, and psychosocial factors such as school stress—may mimic schizophrenic prodrome.

Prognosis. Studies of patients’ first schizophrenia episodes suggest that prodrome duration may predict outcome. A longer prodrome is thought to indicate a poor prognosis,⁶ such as in patients who wait a year before seeking treatment.⁷ A review of 22 studies of first-episode psychosis found early psychosocial and pharmacologic interventions improved long-term prognosis, and medication discontinuation predicted more-severe and chronic disease.⁸

Box 1

Neuroimaging detects brain changes during psychotic prodrome

Reduced gray matter volumes in certain brain regions may be associated with conversion to psychosis. Imaging studies have found medial temporal lobe changes—specifically, hippocampal volume alterations—in persons with schizophrenia, genetic high-risk groups, and those thought to be at risk for imminent psychosis.¹¹

MRI imaging of patients with prodromal signs has shown less gray matter in the right medial temporal, lateral temporal, inferior frontal cortex, and bilateral cingulate regions in those who have developed psychosis, compared with those who have not. In the psychotic patients, 12-month longitudinal follow-up has found reduced gray matter in the left hippocampal, fusiform, orbitofrontal, cerebellar cortices, and cingulate gyrus.¹²

Brain structure is related to genetic liability for schizophrenia in high-risk patients, who seem to have smaller right and left prefrontal lobes and smaller right and left thalami. These findings are consistent with the prodrome’s neurocognitive deficits, which are less than those reported in schizophrenia and greater than those seen in healthy subjects.

Genetic risk. Schizophrenia has a strong genetic predisposition, although not everyone in the genetic high-risk group develops schizophrenia. Persons with a family history of schizophrenia have a 10% to 20% risk of psychotic conversion.⁹

Pioneering work by McGorry et al¹⁰ identified an “ultra high-risk group” with a psychotic conversion rate of 40% to 60%. These patients present with three symptom patterns:

attenuated positive symptoms
brief intermittent psychotic episodes
genetic risk and recent deterioration syndrome (Table 1).

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 syndrome	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

Early identification of these high-risk individuals with perceptual distortions, frank psychotic symptoms, family history of psychosis, and schizotypal personality disorder may aid in early recognition and treatment.

The Edinburgh High Risk Study of 162 individuals ages 16 to 25 showed more marked psychopathology in those with at least two close relatives with schizophrenia, compared with control groups. A direct correlation was seen between genetic liability and poor neurocognitive performance.¹¹

PRODROME RATING SCALES

Researchers are using outcome measures to diagnose prodromal symptoms and assess their severity. Operational, validated assessment tools include:

Bonn Scale for the Assessment of Basic Symptoms (BSABS): captures subtle changes in thinking, feeling, and perception.
Schizophrenia Prediction Instrument for Adults (SPI-A): defines prepsychotic deviations and rates symptoms that are subjectively experienced by the patient.
Comprehensive Assessment of At Risk Mental State (CAARMS): defines ultra high-risk criteria and incorporates eight dimensions of psychopathology.
Scale of Prodromal Symptoms (SOPS): rates psychosis severity. When embedded within the Structured Interview for Prodromal Syndromes (SIPS), the SOPS determines the presence or absence of psychosis and predicts progression to psychopathology.
Criteria for Prodromal Symptoms (COPS): defines ultra high-risk categories.
Presence of Psychosis Scale (POPS): rates severity, intensity, and duration of positive prodromal symptoms.¹²