Methods | Statistics | Clinical | Educational | Industrial | Professional items | World psychology |
The concept of the schizophrenia prodrome has generated considerable interest during the last few years because it suggests that it may be possible to alter the natural course of schizophrenia by intervening early in the disease process to reduce the progression to psychosis, relapse rate, or symptom severity (Kane, 2003). Several studies of prodromal schizophrenia, using a variety of rating scales to assess early signs of psychosis, have demonstrated that approximately 30% to 50% of patients with prodromal symptoms progress to schizophrenia within the first few years after presentation (Correll, 2004). One long-term, prospective study examined the transition to schizophrenia among 160 patients who were seeking help for psychiatric symptoms, but who did not meet diagnostic criteria for schizophrenia or other delusional or psychotic disorders at baseline (Klosterkotter, 2001). The relationship between prodromal symptoms, in this case so-called "basic symptoms" (ie, alterations in thinking and perceptions of self and the environment), at the time of first examination and the long-term transition to schizophrenia is shown in Table 1 (Klosterkotter, 2001). During a mean follow-up period of nearly 10 years, 77 of 110 patients (70%) with prodromal symptoms at first examination transitioned to schizophrenia, whereas only 2 of 50 patients (4%) without prodromal symptoms had transitioned to schizophrenia (correct prediction in 78%).
Patients may evolve through several specific phases of the schizophrenia prodrome (Correll, 2004; Cornblatt, 2003). The early prodromal period is characterized primarily by subtle, self-experienced deficits (eg, self-perception, stress tolerance, thought organization, and social and nonverbal interactions), as well as attenuated negative symptoms of schizophrenia (eg, social isolation, decreased expression of emotion, rigid or simplistic thinking, odd behavior or appearance, and impairments of personal hygiene). The later prodromal period is characterized to a greater extent by attenuated positive symptoms of schizophrenia (eg, unusual thought content, suspiciousness, grandiosity, perceptual abnormalities, and cognitive disorganization). The early, attenuated negative symptoms may also persist during this period.
Children with schizophrenia exhibit a range of neuropsychological impairments, including deficits of fine motor control, attention, short-term memory, executive function, and intellectual function (Biswas, 2006). A recent study compared the neuropsychological impairments associated with schizophrenia first occurring in childhood, adolescence, or adulthood (Biswas, 2006). Patients were matched for total duration of schizophrenia (approximately 5 to 6 years for each group), and patients in all 3 groups had been treated with antipsychotic medications for a mean of approximately 2 years. Patients with onset in childhood exhibited significantly greater scores than the other groups on rating scales of positive symptoms, negative symptoms, and total psychotic symptom severity. Mean Positive and Negative Symptom Scale (PANSS) positive symptom scores were 12.13, 9.40, and 8.15 for the child-onset, adolescent-onset, and adult-onset groups, respectively (P < .001); negative symptom scores were 18.86, 12.95, and 10.15, respectively (P < .001). Patients with child-onset schizophrenia also performed significantly worse than individuals with adolescent- or adult-onset schizophrenia on a range of neuropsychological tests, including verbal IQ and performance IQ. The scores of adolescent-onset patients were intermediate between child- and adult-onset patients for most outcome measures.
Early intervention may help to delay or prevent the progression to psychosis in pediatric patients with prodromal schizophrenia (Correll, 2004). One option for early intervention for prodromal schizophrenia is the use of an atypical antipsychotic. These agents have largely displaced the older antipsychotics, such as haloperidol, because they are at least as effective for the control of psychotic symptoms, are less likely to cause acute and chronic neuromotor side effects, and are associated with improved treatment adherence (Correll, 2004). The atypical antipsychotics may therefore be especially well suited for the treatment of pediatric patients with prodromal schizophrenia. The efficacy of low-dose risperidone (in combination with cognitive behavioral therapy [CBT]) for the prevention of psychosis was compared with usual care (eg, supportive therapy and benzodiazepine or antidepressant treatment, if needed) to manage symptoms in 59 patients aged 14 to 28 years who were considered to be at ultra-high risk for psychosis (McGorry, 2002). At the end of 6 months of treatment, progression to psychosis was noted for 10 of 28 patients (36%) receiving usual care vs 3 of 31 patients (10%) receiving risperidone and CBT (P = .03). After another 6 months, during which all of the patients received needs-based therapy focused on their particular symptoms, the difference between the 2 groups was no longer statistically significant. The incidence of psychosis tended to be lower for patients in the risperidone group who were fully adherent to therapy than for patients who received usual care, or who were assigned to risperidone but were not fully adherent. However, the number of patients in the adherent and nonadherent subgroups was small, and these differences were not statistically significant. A second study compared olanzapine vs placebo for 1 year in 60 patients with prodromal psychotic symptoms (McGlashan, 2006). Although the conversion to psychosis was less common in the olanzapine group (16 %) than in the placebo group (38%), this difference was not statistically significant (P = 0.08), perhaps due to the small sample size.
Antidepressant treatment may also prevent the transition to psychosis in patients with prodromal schizophrenia. A recent prospective naturalistic treatment study examined the efficacy of antidepressant therapy for 48 adolescent patients who were considered to be in the prodromal phase of schizophrenia (Cornblatt, 2007). The patients were treated naturalistically with either antidepressants or atypical antipsychotics for at least 8 weeks, and were followed up for a mean of 30 months. The incidence of new psychotic disorders was significantly lower for patients in the antidepressant group (0%) than for patients receiving second-generation antipsychotics (43%; P = .007). However, treatment nonadherence was also much higher in the group of patients who received antipsychotics (61% vs 20%; P = .005). Due to the nonrandom assignment of treatment, a prescriber bias cannot be excluded (ie, assignment of antidepressants to patients not truly prodromal for schizophrenia). However, the neuroprotective properties of antidepressants and their ability to reduce depression, anxiety, and the impact of stress make this well-tolerated and accepted treatment option an important strategy that should be investigated further.
Together, these studies suggest that antipsychotic agents may reduce the transition to schizophrenia in patients with prodromal psychosis, but that the effectiveness of this approach may be limited by difficulties with adherence. Antidepressant therapy is a reasonable alternative for the prevention of new psychotic disorders in younger patients who are thought to have prodromal psychosis.
Finally, in patients amenable to group and individual therapy, these modalities have also been shown to reduce the transition from a prodromal state to overt psychosis. In 1 study, 58 patients considered prodromal for schizophrenia were randomly assigned to receive either 26 sessions of CBT over 6 months or "monitoring" only (Morrison, 2004). After 6 months, all patients were only monitored. At the end of 12 months, patients who had received CBT were significantly less likely to require clinician-driven antipsychotic treatment (5.7% vs 30.4%, P = .014) or fulfill criteria for a DSM-IV psychotic disorder (5.7% vs 26.1%, P = .019) than those who underwent monitoring only.
The efficacy of olanzapine for adolescent patients with schizophrenia was evaluated in a randomized, double-blind, placebo-controlled, 6-week clinical trial (Kryzhanovskaya, 2005). Patients received flexible olanzapine dosages, beginning at 2.5 to 5.0 mg/d, which could be increased to 20 mg/d or to the maximum-tolerated dose. Treatment with olanzapine was associated with significant improvement from baseline on a number of outcome measures, including scores on the positive symptom subscale of the PANSS (improvement of 6.5 points vs 2.7 points for the olanzapine and placebo groups, respectively; P = .002), the PANSS total score (21.3 vs 8.6; P = .005); and the Clinician Global Impression of Severity (CGI-S; 1.1 vs 0.5; P =.004). Negative symptoms tended to improve more with olanzapine than with placebo, but the difference between groups was not statistically significant.
A double-blind, randomized clinical trial examined risperidone for the treatment of adolescents with acute exacerbation of schizophrenia symptoms (Haas, 2007). A total of 160 patients were randomized to 1 of 2 doses of risperidone (1-3 or 4-6 mg/d) or placebo for 6 weeks. Total score on the PANSS improved by a mean of approximately 8 points for patients in the placebo group, 20 points for patients receiving low-dose risperidone, and 21 points for patients receiving high-dose risperidone (P <.001 for comparisons between placebo and both risperidone dosages). Significant differences between risperidone and placebo groups were noted after 8 days for patients in the high-dose risperidone group and after 15 days for those in the low-dose group. Compared with placebo, risperidone also produced significant improvements in individual positive and negative symptom subscales, the proportion of patients who were considered to have responded to treatment, and clinician global ratings of disease severity.
Aripiprazole is the first of a new family of antipsychotic agents -- the dopamine partial agonists -- to enter clinical practice. A recent randomized, double-blind clinical trial compared 2 fixed aripiprazole doses (10 mg or 30 mg) with placebo for 6 weeks in 302 adolescent patients with schizophrenia (Robb, 2007). Both aripiprazole doses produced greater improvement from baseline for the PANSS total score than placebo after 6 weeks (21.2, 26.7, and 28.6 for patients in the placebo, aripiprazole 10-mg, and aripiprazole 30-mg groups, respectively; P < .05). Both aripiprazole doses also produced significantly greater improvement than placebo on the PANSS positive symptom subscale and the Clinicians Global Impression of Improvement (CGI-I) scale; the 10-mg dose also significantly improved the PANSS negative symptom score. Significant improvement compared with placebo was noted as early as the first week after the beginning of double-blind treatment for patients in the aripiprazole 30 mg/d group.
Long term prevention and treatmentEdit
There are a number of strategies that may help to reduce the impact of adverse effects in adolescent patients with schizophrenia.
- Initial selection of an antipsychotic medication. As noted previously, the atypical agents vary considerably in the risk of adverse effects that may interfere with adherence. Careful selection of a medication may therefore help to reduce the risk of adverse effects and increase the likelihood that patients will benefit from therapy.
- Dose reduction to allow the patient time to acclimate to the effects. However, there is no indication that dose reduction would reduce the risk of weight gain.
- Identification and elimination of medications used for comorbid conditions that produce similar or overlapping toxicities.
- Adding medications to help manage adverse effects (eg, anticholinergics for movement disorders, beta-blocker for akathisia, metformin for diabetes or weight gain).
- Adopt a healthy lifestyle that focuses on a healthy diet and reduced caloric intake in patients consuming large quantities of food, as well as increased activity/exercise (Table 6).
- Switching from 1 agent to another that does not share the same type and/or level of side-effect burden. Patients who discontinue 1 medication, whether due to lack of efficacy or adverse effects, can reverse previously accrued weight gain and metabolic adverse effects by switching to a lower risk-agent (De Hert, 2007; Weiden, 2007; Stroup, 2006; McEvoy, 2006).
Healthy Lifestyle Behaviors for the Prevention and Management of Weight Gain and Metabolic Abnormalities in Patients Receiving Psychotropic Medications 1. Replace all drinks containing sugar (soda, punch, juice), diet drinks, and whole milk with at least 2 L of water and moderate amounts of unsweetened tea or low-fat milk
2. Eat every 3 to 4 hours, with no more than 2 meals in the evening or at night
3. Eat small portions at meals
4. Eat breakfast every morning
5. Eat slowly, drink an ample amount of water between bites, and take second helpings only after a delay
6. Eat no more than 1 fast food meal per week
7. Replace refined white flour and processed sugar products with whole-grain and other food items that have a low glycemic index (ie, ≤ 55; http://www.glycemicindex.com)
8. Do not snack when full and replace high-fat, high-calorie snacks with ample amounts of fruits or vegetables
9. Limit saturated fat intake, but avoid extensive consumption of processed fat-free food items
10. Eat at least 25 to 30 g/d of soluble fiber from fruits, vegetables, and/or whole grains
11. Limit watching television or playing computer/video games to < 2 hr/d
12. Perform moderate-to-vigorous physical activity for at least 30 to 60 min/d
1. Armenteros JL, Davies M. Antipsychotics in early onset schizophrenia: systematic review and meta-analysis. Eur Child Adolesc Psychiatry. 2006;15:141-148.
2. Arseneault L, Cannon M, Poulton R, Murray R, Caspi A, Moffitt TE. Cannabis use in adolescence and risk for adult psychosis: longitudinal prospective study. BMJ. 2002;325:1212-1213.
3. Asarnow RF, Nuechterlein KH, Fogelson D, et al. Schizophrenia and schizophrenia-spectrum personality disorders in the first-degree relatives of children with schizophrenia: the UCLA family study. Arch Gen Psychiatry. 2001;58:581-588.
4. Biswas P, Malhotra S, Malhotra A, Gupta N. Comparative study of neuropsychological correlates in schizophrenia with onset in childhood, adolescence and adulthood. Eur Child Adolesc Psychiatry. 2006;15:360-366.
5. Borgmann-Winter K, Calkins ME, Kniele K, Gur RE. Assessment of adolescents at risk for psychosis. Curr Psychiatry Rep. 2006;8:313-321.
6. Chwastiak LA, Rosenheck RA, McEvoy JP, Keefe RS, Swartz MS, Lieberman JA. Interrelationships of psychiatric symptom severity, medical comorbidity, and functioning in schizophrenia. Psychiatr Serv. 2006;57:1102-1109.
7. Cornblatt BA, Lencz T, Smith CW, et al. Can antidepressants be used to treat the schizophrenia prodrome? Results of a prospective, naturalistic treatment study of adolescents. J Clin Psychiatry. 2007;68:546-557.
8. Cornblatt BA, Lencz T, Smith CW, Correll CU, Auther AM, Nakayama E. The schizophrenia prodrome revisited: a neurodevelopmental perspective. Schizophr Bull. 2003;29:633-651.
9. Correll CU. Weight gain and metabolic effects of mood stabilizers and antipsychotics in pediatric bipolar disorder: a systematic review and pooled analysis of short-term trials. J Am Acad Child Adolesc Psychiatry. 2007;46:687-700.
10. Correll CU, Carlson HE. Endocrine and metabolic adverse effects of psychotropic medications in children and adolescents. J Am Acad Child Adolesc Psychiatry. 2006a;45:771-791.
11. Correll CU, Kane JM. The psychotic prodrome: How effective are early interventions? Adv Schizophr Clin Psychiatry. 2004;1:2-10.
12. Correll CU, Penzner JB, Parikh UH, et al. Recognizing and monitoring adverse events of second-generation antipsychotics in children and adolescents. Child Adolesc Psychiatr Clin N Am. 2006b;15:177-206.
13. Correll CU, Malhotra AK, Saurabh K, McMeniman M, Kane JM. Early prediction of antipsychotic response in schizophrenia. Am J Psychiatry. 2003;160:2063-2065.
14. De Hert M, Hanssens L, van Winkel R, et al. A case series: evaluation of the metabolic safety of aripiprazole. Schizophr Bull. 2007;33:823-830.
15. Findling RL. Atypical antipsychotics in the treatment of children and adolescents. J Clin Psychiatry. 2004;65(Suppl 6):3-4.
16. Findling RL. Tolerability of aripiprazole in the treatment of adolescents with schizophrenia. Presented at the 159th Annual Meeting of the American Psychiatric Association; San Diego, Calif; May 19-23, 2007.
17. Findling RL, Steiner H, Weller EB. Use of antipsychotics in children and adolescents. J Clin Psychiatry. 2005;66(Suppl 7):29-40.
18. Haas M. Efficacy and safety of risperidone in adolescents with schizophrenia. Presented at the 159th Annual Meeting of the American Psychiatric Association; San Diego, Califor; May 19-23, 2007.
19. Henquet C, Krabbendam L, Spauwen J, et al. Prospective cohort study of cannabis use, predisposition for psychosis, and psychotic symptoms in young people. BMJ. 2005;330:11.
20. Kane JM, Krystal J, Correll CU. Treatment models and designs for intervention research during the psychotic prodrome. Schizophr Bull. 2003;29:747-756.
21. Kim E. Efficacy of aripiprazole versus haloperidol in early episode schizophrenia. Presented at the 159th Annual Meeting of the American Psychiatric Association; San Diego, Calif; May 19-23, 2007.
22. Klosterkotter J, Hellmich M, Steinmeyer EM, Schultze-Lutter F. Diagnosing schizophrenia in the initial prodromal phase. Arch Gen Psychiatry. 2001;58:158-164.
23. Kryzhanovskaya L, Schulz C, McDougle CJ, et al. Efficacy and safety of olanzapine in adolescents with schizophrenia: results from a double-blind, placebo-controlled trial. Presented at the 44th American College of Neuropsychopharmacology; Waikoloa, Hawaii; December 11-15, 2005.
24. Kumra S, Kranzler H, Gerbino-Rosen G, et al. Clozapine and "high-dose" olanzapine in refractory early-onset schizophrenia: a 12-week randomized and double-blind comparison. Biol Psychiatry. 2007 Jul 23; (epub ahead of print).
25. Kumra S, Frazier JA, Jacobsen LK, et al. Childhood-onset schizophrenia. A double-blind clozapine-haloperidol comparison. Arch Gen Psychiatry. 1996;53:1090-1097.
26. Leucht S, Busch R, Kissling W, Kane JM. Early prediction of antipsychotic nonresponse among patients with schizophrenia. J Clin Psychiatry. 2007;68:352-360.
27. Leucht S, Barnes TR, Kissling W, Engel RR, Correll C, Kane JM. Relapse prevention in schizophrenia with new-generation antipsychotics: a systematic review and exploratory meta-analysis of randomized, controlled trials. Am J Psychiatry. 2003;160:1209-1222.
28. Marder SR, Glynn SM, Wirshing WC, et al. Maintenance treatment of schizophrenia with risperidone or haloperidol: 2-year outcomes. Am J Psychiatry. 2003;160:1405-1412.
29. McEvoy JP, Lieberman JA, Stroup TS, et al. Effectiveness of clozapine versus olanzapine, quetiapine, and risperidone in patients with chronic schizophrenia who did not respond to prior atypical antipsychotic treatment. Am J Psychiatry. 2006;163:600-610.
30. McClellan J, Sikich L, Findling RL, et al. Treatment of early-onset schizophrenia spectrum disorders (TEOSS): rationale, design, and methods. J Am Acad Child Adolesc Psychiatry. 2007;46:969-978.
31. McGlashan TH, Zipursky RB, Perkins D, et al. Randomized, double-blind trial of olanzapine versus placebo in patients prodromally symptomatic for psychosis. Am J Psychiatry. 2006;163:790-799.
32. McGorry PD, Yung AR, Phillips LJ, et al. Randomized controlled trial of interventions designed to reduce the risk of progression to first-episode psychosis in a clinical sample with subthreshold symptoms. Arch Gen Psychiatry. 2002;59:921-928.
33. Morrison AP, French P, Walford L, et al. Cognitive therapy for the prevention of psychosis in people at ultra-high risk: randomised controlled trial. Br J Psychiatry. 2004;185:291-297.
34. Robb AS. Efficacy of aripiprazole in the treatment of adolescents with schizophrenia. Presented at the 159th Annual Meeting of the American Psychiatric Association; San Diego, Calif; May 19-23, 2007.
35. Rosen JL, Miller TJ, D'Andrea JT, McGlashan TH, Woods SW. Comorbid diagnoses in patients meeting criteria for the schizophrenia prodrome. Schizophr Res. 2006;85:124-131.
36. Ross RG, Heinlein S, Tregellas H. High rates of comorbidity are found in childhood-onset schizophrenia. Schizophr Res. 2006;88:90-95.
37. Said Q. Real world impact of second-generation antipsychotics on weight gain in an adolescent population. Presented at the 159th Annual Meeting of the American Psychiatric Association; San Diego, Calif; May 19-23, 2007.
38. Schooler N, Rabinowitz J, Davidson M, et al. Risperidone and haloperidol in first-episode psychosis: a long-term randomized trial. Am J Psychiatry. 2005;162:947-953.
39. Shaw P, Sporn A, Gogtay N, et al. Childhood-onset schizophrenia: A double-blind, randomized clozapine-olanzapine comparison. Arch Gen Psychiatry. 2006;63:721-730.
40. Sikich L. Treatment of early onset schizophrenia spectrum disorders (TEOSS): Effectiveness outcomes. Presented at the 47th Annual Meeting of the New Drug Clinical Evaluation Unit, National Institute of Mental Health; Boca Raton, Fla; June 11-14, 2007.
41. Sikich L, Hamer RM, Bashford RA, Sheitman BB, Lieberman JA. A pilot study of risperidone, olanzapine, and haloperidol in psychotic youth: a double-blind, randomized, 8-week trial. Neuropsychopharmacology. 2004;29:133-145.
42. Stroup TS, Lieberman JA, McEvoy JP, et al. Effectiveness of olanzapine, quetiapine, risperidone, and ziprasidone in patients with chronic schizophrenia following discontinuation of a previous atypical antipsychotic. Am J Psychiatry. 2006;163:611-622.
43. Weiden PJ, Newcomer JW, Loebel AD, Yang R, Lebovitz HE. Long-term changes in weight and plasma lipids during maintenance treatment with ziprasidone. Neuropsychopharmacology. 2007 Jul 18; (epub ahead of print).
44. Yung AR, Phillips LJ, Yuen HP, McGorry PD. Risk factors for psychosis in an ultra high-risk group: psychopathology and clinical features. Schizophr Res. 2004;67:131-142.