The nature of relapse in schizophrenia

BMC Psychiatry

Brian H Harvey¹  Laila Asmal²  Bonginkosi Chiliza²  Robin Emsley² 

[1] Center of Excellence for Pharmaceutical Sciences, School of Pharmacy (Pharmacology), North West University, Potchefstroom, South Africa;Department of Psychiatry, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, Cape Town, 7505, South Africa

关键词: Dopamine;    First-episode;    Discontinuation;    Antipsychotics;    Relapse;    Schizophrenia;   

Others  :  1124143
DOI  :  10.1186/1471-244X-13-50

 received in 2012-06-15, accepted in 2013-01-25,  发布年份 2013

【 摘 要 】

Background

Multiple relapses characterise the course of illness in most patients with schizophrenia, yet the nature of these episodes has not been extensively researched and clinicians may not always be aware of important implications.

Methods

We critically review selected literature regarding the nature and underlying neurobiology of relapse.

Results

Relapse rates are very high when treatment is discontinued, even after a single psychotic episode; a longer treatment period prior to discontinuation does not reduce the risk of relapse; many patients relapse soon after treatment reduction and discontinuation; transition from remission to relapse may be abrupt and with few or no early warning signs; once illness recurrence occurs symptoms rapidly return to levels similar to the initial psychotic episode; while most patients respond promptly to re-introduction of antipsychotic treatment after relapse, the response time is variable and notably, treatment failure appears to emerge in about 1 in 6 patients. These observations are consistent with contemporary thinking on the dopamine hypothesis, including the aberrant salience hypothesis.

Conclusions

Given the difficulties in identifying those at risk of relapse, the ineffectiveness of rescue medications in preventing full-blown psychotic recurrence and the potentially serious consequences, adherence and other factors predisposing to relapse should be a major focus of attention in managing schizophrenia. The place of antipsychotic treatment discontinuation in clinical practice and in placebo-controlled clinical trials needs to be carefully reconsidered.

【 授权许可】

   
2013 Emsley et al.; licensee BioMed Central Ltd.

【 参考文献 】

• [1]Robinson D, Woerner MG, Alvir JM, Bilder R, Goldman R, Geisler S, et al.: Predictors of relapse following response from a first episode of schizophrenia or schizoaffective disorder. Arch Gen Psychiatry 1999, 56:241-247.
• [2]Kane JM: Treatment strategies to prevent relapse and encourage remission. J Clin Psychiatry 2007, 68(Suppl 14):27-30.
• [3]Wyatt RJ: Research in schizophrenia and the discontinuation of antipsychotic medications. Schizophr Bull 1997, 23:3-9.
• [4]Lieberman JA, Alvir JM, Koreen A, Geisler S, Chakos M, Sheitman B, et al.: Psychobiologic correlates of treatment response in schizophrenia. Neuropsychopharmacology 1996, 14:13S-21S.
• [5]Alvarez-Jimenez M, Priede A, Hetrick SE, Bendall S, Killackey E, Parker AG, et al.: Risk factors for relapse following treatment for first episode psychosis: a systematic review and meta-analysis of longitudinal studies. Schizophr Res 2012, 139:116-128.
• [6]Coldham EL, Addington J, Addington D: Medication adherence of individuals with a first episode of psychosis. Acta Psychiatr Scand 2002, 106:286-290.
• [7]Tiihonen J, Haukka J, Taylor M, Haddad PM, Patel MX, Korhonen P: A nationwide cohort study of oral and depot antipsychotics after first hospitalization for schizophrenia. Am J Psychiatry 2011, 168:603-609.
• [8]Miller BJ: A review of second-generation antipsychotic discontinuation in first-episode psychosis. J Psychiatr Pract 2008, 14:289-300.
• [9]Miller BJ, Bodenheimer C, Crittenden K: Second-Generation Antipsychotic Discontinuation in First Episode Psychosis: An Updated Review. Clin Psychopharmacol Neurosci 2011, 9:45-53.
• [10]Emsley R, Oosthuizen PP, Koen L, Niehaus DJ, Martinez L: Symptom Recurrence Following Intermittent Treatment in First Episode Schizophrenia Successfully Treated for Two Years. In J Clin Psychiatry 2012. In press
• [11]Emsley R, Nuamah I, Hough D, Gopal S: Treatment response after relapse in a placebo controlled maintenance trial in schizophrenia. Schizophr Res 2012, 138(1):29-34. Epub 2012 Mar 23
• [12]Emsley R, Oosthuizen PP, Koen L, Niehaus DJ, Martinez L: Comparison of Treatment Response in Second Episode Versus First Episode Schizophrenia. J Clin Psychopharmaco 2013, 33(1):80-83.
• [13]Moller HJ, von Ziersen D, et al.: Course and outcome of schizophrenia. In Schizophrenia. Oxford: Blackwell; 1995:127.
• [14]Kane JM, Jeste DV, Barnes TR: Tardive dyskinesia: A task force report of the American Psychiatric Association. Washington, D.C: American Psychiatric Association; 1992. Ref Type: Report
• [15]Meltzer HY: Neuroleptic withdrawal in schizophrenic patients. An idea whose time has come. Arch Gen Psychiatry 1995, 52:200-202.
• [16]Newcomer JW: Metabolic considerations in the use of antipsychotic medications: a review of recent evidence. J Clin Psychiatry 2007, 68(Suppl 1):20-27.
• [17]Bostwick JR, Guthrie SK, Ellingrod VL: Antipsychotic-induced hyperprolactinemia. Pharmacotherapy 2009, 29:64-73.
• [18]Correll CU, Schenk EM: Tardive dyskinesia and new antipsychotics. Curr Opin Psychiatry 2008, 21:151-156.
• [19]Perkins DO, Gu H, Weiden PJ, McEvoy JP, Hamer RM, Lieberman JA: 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, 69:106-113.
• [20]Gilbert PL, Harris MJ, McAdams LA, Jeste DV: Neuroleptic withdrawal in schizophrenic patients. A review of the literature. Arch Gen Psychiatry 1995, 52:173-188.
• [21]Gitlin M, Nuechterlein K, Subotnik KL, Ventura J, Mintz J, Fogelson DL, et al.: Clinical outcome following neuroleptic discontinuation in patients with remitted recent-onset schizophrenia. Am J Psychiatry 2001, 158:1835-1842.
• [22]Chen EY, Hui CL, Lam MM, Chiu CP, Law CW, Chung DW, et al.: Maintenance treatment with quetiapine versus discontinuation after one year of treatment in patients with remitted first episode psychosis: randomised controlled trial. BMJ 2010, 341:c4024.
• [23]Boonstra G, Burger H, Grobbee DE, Kahn RS: Antipsychotic prophylaxis is needed after remission from a first psychotic episode in schizophrenia patients: results from an aborted randomised trial. Int J Psychiatry Clin Pract 2011, 15:128-134.
• [24]Kane JM, Rifkin A, Quitkin F, Nayak D, Ramos-Lorenzi J: Fluphenazine vs placebo in patients with remitted, acute first-episode schizophrenia. Arch Gen Psychiatry 1982, 39:70-73.
• [25]Wunderink L, Nienhuis FJ, Sytema S, Slooff CJ, Knegtering R, Wiersma D: Guided discontinuation versus maintenance treatment in remitted first-episode psychosis: relapse rates and functional outcome. J Clin Psychiatry 2007, 68:654-661.
• [26]Crow TJ, MacMillan JF, Johnson AL, Johnstone EC: A randomised controlled trial of prophylactic neuroleptic treatment. In Br J Psychiatry 1986, 148:120-127.
• [27]Gaebel W, Riesbeck M, Wolwer W, Klimke A, Eickhoff M, Von WM, et al.: Relapse prevention in first-episode schizophrenia–maintenance vs intermittent drug treatment with prodrome-based early intervention: results of a randomized controlled trial within the German Research Network on Schizophrenia. J Clin Psychiatry 2011, 72:205-218.
• [28]Takeuchi H, Suzuki T, Uchida H, Watanabe K, Mimura M: Antipsychotic treatment for schizophrenia in the maintenance phase: a systematic review of the guidelines and algorithms. Schizophr Res 2012, 134:219-225.
• [29]Gefvert O, Eriksson B, Persson P, Helldin L, Bjorner A, Mannaert E, et al.: Pharmacokinetics and D2 receptor occupancy of long-acting injectable risperidone (Risperdal Consta) in patients with schizophrenia. Int J Neuropsychopharmacol 2005, 8:27-36.
• [30]Moncrieff J: Does antipsychotic withdrawal provoke psychosis? Review of the literature on rapid onset psychosis (supersensitivity psychosis) and withdrawal-related relapse. Acta Psychiatr Scand 2006, 114:3-13.
• [31]Chouinard G, Jones BD: Neuroleptic-induced supersensitivity psychosis: clinical and pharmacologic characteristics. Am J Psychiatry 1980, 137:16-21.
• [32]Birchwood M, Smith J, MacMillan F, Hogg B, Prasad R, Harvey C, et al.: Predicting relapse in schizophrenia: the development and implementation of an early signs monitoring system using patients and families as observers, a preliminary investigation. Psychol Med 1989, 19:649-656.
• [33]Yung AR, McGorry PD: The prodromal phase of first-episode psychosis: past and current conceptualizations. Schizophr Bull 1996, 22:353-370.
• [34]Bustillo J: Buchanan RW. Carpenter WT Jr: Prodromal symptoms vs. early warning signs and clinical action in schizophrenia. Schizophr Bull 1995, 21:553-559.
• [35]Norman RM, Malla AK: Prodromal symptoms of relapse in schizophrenia: a review. Schizophr Bull 1995, 21:527-539.
• [36]Gaebel W, Riesbeck M: Revisiting the relapse predictive validity of prodromal symptoms in schizophrenia. Schizophr Res 2007, 95:19-29.
• [37]Gaebel W, Frick U, Kopcke W, Linden M, Muller P, Muller-Spahn F, et al.: Early neuroleptic intervention in schizophrenia: are prodromal symptoms valid predictors of relapse? Br J Psychiatry Suppl 1993, 21:8-12.
• [38]Herz MI, Melville C: Relapse in schizophrenia. Am J Psychiatry 1980, 137:801-805.
• [39]Henmi Y: Prodromal symptoms of relapse in schizophrenic outpatients: retrospective and prospective study. Jpn J Psychiatry Neurol 1993, 47:753-775.
• [40]Tarrier N, Barrowclough C, Bamrah JS: Prodromal signs of relapse in schizophrenia. Soc Psychiatry Psychiatr Epidemiol 1991, 26:157-161.
• [41]Gleeson JF, Rawlings D, Jackson HJ, McGorry PD: Early warning signs of relapse following a first episode of psychosis. Schizophr Res 2005, 80:107-111.
• [42]Birchwood M, Spencer E: Early intervention in psychotic relapse. Clin Psychol Rev 2001, 21:1211-1226.
• [43]Emsley R, Medori R, Koen L, Oosthuizen PP, Niehaus DJ, Rabinowitz J: Long-acting injectable risperidone in the treatment of subjects with recent-onset psychosis: a preliminary study. J Clin Psychopharmacol 2008, 28:210-213.
• [44]Wyatt RJ: Neuroleptics and the natural course of schizophrenia. Schizophr Bull 1991, 17:325-351.
• [45]Lieberman JA, Jody D, Geisler S, Alvir J, Loebel A, Szymanski S, et al.: Time course and biologic correlates of treatment response in first-episode schizophrenia. Arch Gen Psychiatry 1993, 50:369-376.
• [46]Marshall M, Lewis S, Lockwood A, Drake R, Jones P, Croudace T: Association between duration of untreated psychosis and outcome in cohorts of first-episode patients: a systematic review. Arch Gen Psychiatry 2005, 62:975-983.
• [47]McEvoy JP, Hogarty GE, Steingard S: Optimal dose of neuroleptic in acute schizophrenia. A controlled study of the neuroleptic threshold and higher haloperidol dose. Arch Gen Psychiatry 1991, 48:739-745.
• [48]Curson DA, Barnes TR, Bamber RW, Platt SD, Hirsch SR, Duffy JC: Long-term depot maintenance of chronic schizophrenic out-patients: the seven year follow-up of the Medical Research Council fluphenazine/placebo trial. III. Relapse postponement or relapse prevention? The implications for long-term outcome. Br J Psychiatry 1985, 146:474-480.
• [49]Glovinsky D, Kirch DG, Wyatt RJ: Early antipsychotic response to resumption of neuroleptics in drug-free chronic schizophrenic patients. Biol Psychiatry 1992, 31:968-970.
• [50]Wyatt RJ, Henter ID, Bartko JJ: The long-term effects of placebo in patients with chronic schizophrenia. Biol Psychiatry 1999, 46:1092-1105.
• [51]Levine SZ, Leucht S: Elaboration on the early-onset hypothesis of antipsychotic drug action: treatment response trajectories. Biol Psychiatry 2010, 68:86-92.
• [52]McGlashan TH: Is active psychosis neurotoxic? Schizophr Bull 2006, 32:609-613.
• [53]Zipursky RB, Reilly JL, Murray RM: The myth of schizophrenia as a progressive brain disease. Schizophr Bull 2012. Epub ahead of print
• [54]Wiersma D, Nienhuis FJ, Slooff CJ, Giel R: Natural course of schizophrenic disorders: a 15-year followup of a Dutch incidence cohort. Schizophr Bull 1998, 24:75-85.
• [55]Kapur S, Mamo D: Half a century of antipsychotics and still a central role for dopamine D2 receptors. Prog Neuropsychopharmacol Biol Psychiatry 2003, 27:1081-1090.
• [56]Howes OD, Kapur S: The dopamine hypothesis of schizophrenia: version III–the final common pathway. Schizophr Bull 2009, 35:549-562.
• [57]Howes OD, Kambeitz J, Kim E, Stahl D, Slifstein M, Abi-Dargham A, et al.: The Nature of Dopamine Dysfunction in Schizophrenia and What This Means for Treatment: Meta-analysis of Imaging Studies. Arch Gen Psychiatry 2012, 69(8):776-786.
• [58]Kapur S: Psychosis as a state of aberrant salience: a framework linking biology, phenomenology, and pharmacology in schizophrenia. Am J Psychiatry 2003, 160:13-23.
• [59]Agid O, Kapur S, Arenovich T, Zipursky RB: Delayed-onset hypothesis of antipsychotic action: a hypothesis tested and rejected. Arch Gen Psychiatry 2003, 60:1228-1235.
• [60]Leucht S, Busch R, Hamann J, Kissling W, Kane JM: Early-onset hypothesis of antipsychotic drug action: a hypothesis tested, confirmed and extended. Biol Psychiatry 2005, 57:1543-1549.
• [61]Emsley R, Rabinowitz J, Medori R: Time course for antipsychotic treatment response in first-episode schizophrenia. Am J Psychiatry 2006, 163:743-745.
• [62]Kapur S, Agid O, Mizrahi R, Li M: How antipsychotics work-from receptors to reality. NeuroRx 2006, 3:10-21.
• [63]Schwartz TL, Sachdeva S, Stahl SM: Glutamate neurocircuitry: theoretical underpinnings in schizophrenia. Front Pharmacol 2012, 3:195.
• [64]Leonard BE, Schwarz M, Myint AM: The metabolic syndrome in schizophrenia: is inflammation a contributing cause? J Psychopharmacol 2012, 26:33-41.
• [65]Drzyzga L, Obuchowicz E, Marcinowska A, Herman ZS: Cytokines in schizophrenia and the effects of antipsychotic drugs. Brain Behav Immun 2006, 20:532-545.
• [66]Moller M, Du Preez JL, Viljoen FP, Berk M, Emsley R, Harvey BH: Social isolation rearing induces mitochondrial, immunological, neurochemical and behavioural deficits in rats, and is reversed by clozapine or N-acetyl cysteine. Brain Behavior and ImmunityEpub ahead of print
• [67]McAllister CG, van Kammen DP, Rehn TJ, Miller AL, Gurklis J, Kelley ME, et al.: Increases in CSF levels of interleukin-2 in schizophrenia: effects of recurrence of psychosis and medication status. Am J Psychiatry 1995, 152:1291-1297.
• [68]Miller BJ, Buckley P, Seabolt W, Mellor A, Kirkpatrick B: Meta-analysis of cytokine alterations in schizophrenia: clinical status and antipsychotic effects. Biol Psychiatry 2011, 70:663-671.
• [69]Miller BJ, Gassama B, Sebastian D, Buckley P, Mellor A: Meta-Analysis of Lymphocytes in Schizophrenia: Clinical Status and Antipsychotic Effects. Biol Psychiatry 2012. doi:pii: S0006-3223(12):00779-2.
• [70]Harvey BH, McEwen BS, Stein DJ: Neurobiology of antidepressant withdrawal: implications for the longitudinal outcome of depression. Biol Psychiatry 2003, 54:1105-1117.
• [71]Andreassen OA, Jorgensen HA: Neurotoxicity associated with neuroleptic-induced oral dyskinesias in rats, implications for tardive dyskinesia. Prog Neurobiol 2000, 61:525-531.
• [72]Naidu PS, Kulkarni SK: Excitatory mechanisms in neuroleptic-induced vacuous chewing movements (VCMs): possible involvement of calcium and nitric oxide. Behav Pharmacol 2001, 12:209-216.
• [73]Nel A, Harvey BH: Haloperidol-induced dyskinesia is associated with striatal NO synthase suppression: reversal with olanzapine. Behav Pharmacol 2003, 14:251-255.
• [74]Harvey BH, Joubert C, du Preez JL, Berk M: Effect of chronic N-acetyl cysteine administration on oxidative status in the presence and absence of induced oxidative stress in rat striatum. Neurochem Res 2008, 33:508-517.
• [75]Harvey BH, Bester A: Withdrawal-associated changes in peripheral nitrogen oxides and striatal cyclic GMP after chronic haloperidol treatment. Behav Brain Res 2000, 111:203-211.
• [76]Berk M, Copolov D, Dean O, Lu K, Jeavons S, Schapkaitz I, et al.: N-acetyl cysteine as a glutathione precursor for schizophrenia–a double-blind, randomized, placebo-controlled trial. Biol Psychiatry 2008, 64:361-368.
• [77]van Harten PN, Hoek HW, Matroos GE, Koeter M, Kahn RS: Intermittent neuroleptic treatment and risk for tardive dyskinesia: Curacao Extrapyramidal Syndromes Study III. Am J Psychiatry 1998, 155:565-567.
• [78]Samaha AN, Seeman P, Stewart J, Rajabi H, Kapur S: "Breakthrough" dopamine supersensitivity during ongoing antipsychotic treatment leads to treatment failure over time. J Neurosci 2007, 27:2979-2986.
• [79]Leucht S, Tardy M, Komossa K, Heres S, Kissling W, Salanti G, et al.: Antipsychotic drugs versus placebo for relapse prevention in schizophrenia: a systematic review and meta-analysis. Lancet 2012, 379:2063-2071.
• [80]Konopaske GT, Dorph-Petersen KA, Sweet RA, Pierri JN, Zhang W, Sampson AR, et al.: Effect of chronic antipsychotic exposure on astrocyte and oligodendrocyte numbers in macaque monkeys. Biol Psychiatry 2008, 63:759-765.