Evaluation and management of treatment-resistant schizophrenia
- John Kane, MD
John Kane, MD
- Professor of Psychiatry and Molecular Medicine
- Hofstra Northwell School of Medicine
- Taishiro Kishimoto, MD
Taishiro Kishimoto, MD
- Assistant Professor of Neuropsychiatry
- Keio University School of Medicine
- Christoph U Correll, MD
Christoph U Correll, MD
- Professor of Psychiatry and Molecular Medicine
- Hofstra Northwell School of Medicine
Antipsychotic medication is first-line treatment for schizophrenia. Most patients show substantial improvement in psychotic symptoms in response to antipsychotics; however, for many, improvement is insufficient to meet stringent criteria for remission, and a substantial proportion experience residual treatment-resistant symptoms.
Patients who do not respond adequately to antipsychotics should be reevaluated to rule out or address causes other than nonresponsiveness to medication. Current medication and psychosocial interventions should be optimized. Treatment strategies for patients who remain incompletely responsive include changes to antipsychotic doses and drugs, use of clozapine, and drug augmentation.
This topic addresses the evaluation and management of treatment-resistant schizophrenia. Topics discussed separately include: the epidemiology, pathogenesis, clinical manifestations, course, assessment, and diagnosis of schizophrenia; comorbid anxiety; comorbid depression; acute, maintenance, and long-acting pharmacotherapy; guidelines for prescribing clozapine; and psychosocial interventions for schizophrenia. (See "Schizophrenia in adults: Epidemiology and pathogenesis" and "Schizophrenia in adults: Clinical manifestations, course, assessment, and diagnosis" and "Pharmacotherapy for schizophrenia: Acute and maintenance phase treatment" and "Pharmacotherapy for schizophrenia: Side effect management" and "Pharmacotherapy for schizophrenia: Long-acting injectable antipsychotic drugs" and "Co-occurring schizophrenia and substance use disorder: Epidemiology, pathogenesis, clinical manifestations, course, assessment and diagnosis" and "Anxiety in schizophrenia" and "Depression in schizophrenia" and "Guidelines for prescribing clozapine in schizophrenia".)
Clinical trials and practice guidelines have employed various definitions of treatment resistance in schizophrenia. No clear consensus exists for a single definition for use across populations and settings . Existing definitions do not clearly distinguish treatment resistance from terms indicating other levels of response, such as partial response, lack of remission, or failure to prevent relapse [2,3].
For the purpose of determining a patient’s eligibility for a trial of clozapine, we define treatment resistance as an inadequate response to at least two antipsychotic drugs at the maximally tolerated dose within the recommended therapeutic range (table 1) in trials lasting six weeks or more. Termination of a medication due to adverse events before reaching the appropriate dose and duration should not be regarded as a failed trial due to nonresponse to the medication.
- Correll CU, Kishimoto T, Nielsen J, Kane JM. Quantifying clinical relevance in the treatment of schizophrenia. Clin Ther 2011; 33:B16.
- Andreasen NC, Carpenter WT Jr, Kane JM, et al. Remission in schizophrenia: proposed criteria and rationale for consensus. Am J Psychiatry 2005; 162:441.
- Liberman RP, Kopelowicz A, Ventura J, Gutkind D. Operational criteria and factors related to recovery from schizophrenia. Int Rev Psychiatry 2002; 14:256.
- Correll CU, Kishimoto T, Kane JM. Randomized controlled trials in schizophrenia: opportunities, limitations, and trial design alternatives. Dialogues Clin Neurosci 2011; 13:155.
- Hegarty JD, Baldessarini RJ, Tohen M, et al. One hundred years of schizophrenia: a meta-analysis of the outcome literature. Am J Psychiatry 1994; 151:1409.
- Lehman AF, Lieberman JA, Dixon LB, et al. Practice guideline for the treatment of patients with schizophrenia, second edition. Am J Psychiatry 2004; 161:1.
- Helldin L, Kane JM, Karilampi U, et al. Remission in prognosis of functional outcome: a new dimension in the treatment of patients with psychotic disorders. Schizophr Res 2007; 93:160.
- De Hert M, van Winkel R, Wampers M, et al. Remission criteria for schizophrenia: evaluation in a large naturalistic cohort. Schizophr Res 2007; 92:68.
- Jääskeläinen E, Juola P, Hirvonen N, et al. A systematic review and meta-analysis of recovery in schizophrenia. Schizophr Bull 2013; 39:1296.
- Flockhart D. Drug Interactions: Cytochrome P450 Drug Interaction Table. 2007. http://medicine.iupui.edu/clinpharm/ddis/table.aspx (Accessed on August 15, 2012).
- Velligan DI, Weiden PJ, Sajatovic M, et al. The expert consensus guideline series: adherence problems in patients with serious and persistent mental illness. J Clin Psychiatry 2009; 70 Suppl 4:1.
- Kane JM, Kishimoto T, Correll CU. Non-adherence to medication in patients with psychotic disorders: epidemiology, contributing factors and management strategies. World Psychiatry 2013; 12:216.
- Kane JM, Correll CU. Past and present progress in the pharmacologic treatment of schizophrenia. J Clin Psychiatry 2010; 71:1115.
- Wykes T, Steel C, Everitt B, Tarrier N. Cognitive behavior therapy for schizophrenia: effect sizes, clinical models, and methodological rigor. Schizophr Bull 2008; 34:523.
- Pharoah F, Mari J, Rathbone J, Wong W. Family intervention for schizophrenia. Cochrane Database Syst Rev 2010; :CD000088.
- Kurtz MM, Mueser KT. A meta-analysis of controlled research on social skills training for schizophrenia. J Consult Clin Psychol 2008; 76:491.
- Coldwell CM, Bender WS. The effectiveness of assertive community treatment for homeless populations with severe mental illness: a meta-analysis. Am J Psychiatry 2007; 164:393.
- Joy CB, Adams CE, Rice K. Crisis intervention for people with severe mental illnesses. Cochrane Database Syst Rev 2006; :CD001087.
- Schizophrenia: Core interventions in the treatment and management of schizophrenia in adults in primary and secondary care. National Institute for Health and Clinical Excellence, 2009. http://www.nice.org.uk/nicemedia/live/11786/43608/43608.pdf (Accessed on June 10, 2016).
- Buchanan RW, Kreyenbuhl J, Kelly DL, et al. The 2009 schizophrenia PORT psychopharmacological treatment recommendations and summary statements. Schizophr Bull 2010; 36:71.
- Argo TR, Crismon ML, Miller AL, et al.. Texas Medication Algorithm Project Procedural Manual. Schizophrenia Treatment Algorithm., Texas Department of State Health Services, 2008.
- Canadian Psychiatric Association. Clinical practice guidelines. Treatment of schizophrenia. Can J Psychiatry 2005; 50:7S.
- Souza JS, Kayo M, Tassell I, et al. Efficacy of olanzapine in comparison with clozapine for treatment-resistant schizophrenia: evidence from a systematic review and meta-analyses. CNS Spectr 2013; 18:82.
- Essali A, Al-Haj Haasan N, Li C, Rathbone J. Clozapine versus typical neuroleptic medication for schizophrenia. Cochrane Database Syst Rev 2009; :CD000059.
- Kane J, Honigfeld G, Singer J, Meltzer H. Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine. Arch Gen Psychiatry 1988; 45:789.
- Leucht S, Komossa K, Rummel-Kluge C, et al. A meta-analysis of head-to-head comparisons of second-generation antipsychotics in the treatment of schizophrenia. Am J Psychiatry 2009; 166:152.
- Samara MT, Dold M, Gianatsi M, et al. Efficacy, Acceptability, and Tolerability of Antipsychotics in Treatment-Resistant Schizophrenia: A Network Meta-analysis. JAMA Psychiatry 2016; 73:199.
- Kane JM, Correll CU. The Role of Clozapine in Treatment-Resistant Schizophrenia. JAMA Psychiatry 2016; 73:187.
- Schooler NR, Marder SR, Chengappa KN, et al. Clozapine and risperidone in moderately refractory schizophrenia: a 6-month randomized double-blind comparison. J Clin Psychiatry 2016; 77:628.
- Petrides G, Malur C, Braga RJ, et al. Electroconvulsive therapy augmentation in clozapine-resistant schizophrenia: a prospective, randomized study. Am J Psychiatry 2015; 172:52.
- Wang W, Pu C, Jiang J, et al. Efficacy and safety of treating patients with refractory schizophrenia with antipsychotic medication and adjunctive electroconvulsive therapy: a systematic review and meta-analysis. Shanghai Arch Psychiatry 2015; 27:206.
- Otani VH, Shiozawa P, Cordeiro Q, Uchida RR. A systematic review and meta-analysis of the use of repetitive transcranial magnetic stimulation for auditory hallucinations treatment in refractory schizophrenic patients. Int J Psychiatry Clin Pract 2015; 19:228.
- Shi C, Yu X, Cheung EF, et al. Revisiting the therapeutic effect of rTMS on negative symptoms in schizophrenia: a meta-analysis. Psychiatry Res 2014; 215:505.
- Singh SP, Singh V, Kar N, Chan K. Efficacy of antidepressants in treating the negative symptoms of chronic schizophrenia: meta-analysis. Br J Psychiatry 2010; 197:174.
- Hecht EM, Landy DC. Alpha-2 receptor antagonist add-on therapy in the treatment of schizophrenia; a meta-analysis. Schizophr Res 2012; 134:202.
- Berk M, Copolov D, Dean O, et al. N-acetyl cysteine as a glutathione precursor for schizophrenia--a double-blind, randomized, placebo-controlled trial. Biol Psychiatry 2008; 64:361.
- Singh SP, Singh V. Meta-analysis of the efficacy of adjunctive NMDA receptor modulators in chronic schizophrenia. CNS Drugs 2011; 25:859.
- Correll CU, Maayan L, Kane JM, et al. Efficacy for Psychopathology and Body Weight and Safety of Topiramate-Antipsychotic Cotreatment in Patients with Schizophrenia-Spectrum Disorders: Results from a Meta-analysis of Randomized Controlled Trials. J Clin Psychiatry 2016.
- Fusar-Poli P, Berger G. Eicosapentaenoic acid interventions in schizophrenia: meta-analysis of randomized, placebo-controlled studies. J Clin Psychopharmacol 2012; 32:179.
- Laan W, Grobbee DE, Selten JP, et al. Adjuvant aspirin therapy reduces symptoms of schizophrenia spectrum disorders: results from a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry 2010; 71:520.
- Akhondzadeh S, Tabatabaee M, Amini H, et al. Celecoxib as adjunctive therapy in schizophrenia: a double-blind, randomized and placebo-controlled trial. Schizophr Res 2007; 90:179.
- Oya K, Kishi T, Iwata N. Efficacy and tolerability of minocycline augmentation therapy in schizophrenia: a systematic review and meta-analysis of randomized controlled trials. Hum Psychopharmacol 2014; 29:483.
- Kelly DL, Sullivan KM, McEvoy JP, et al. Adjunctive Minocycline in Clozapine-Treated Schizophrenia Patients With Persistent Symptoms. J Clin Psychopharmacol 2015; 35:374.
- Ghanizadeh A, Dehbozorgi S, OmraniSigaroodi M, Rezaei Z. Minocycline as add-on treatment decreases the negative symptoms of schizophrenia; a randomized placebo-controlled clinical trial. Recent Pat Inflamm Allergy Drug Discov 2014; 8:211.
- Correll CU, Rummel-Kluge C, Corves C, et al. Antipsychotic combinations vs monotherapy in schizophrenia: a meta-analysis of randomized controlled trials. Schizophr Bull 2009; 35:443.
- Barbui C, Signoretti A, Mulè S, et al. Does the addition of a second antipsychotic drug improve clozapine treatment? Schizophr Bull 2009; 35:458.
- Taylor DM, Smith L. Augmentation of clozapine with a second antipsychotic--a meta-analysis of randomized, placebo-controlled studies. Acta Psychiatr Scand 2009; 119:419.
- Sommer IE, Begemann MJ, Temmerman A, Leucht S. Pharmacological augmentation strategies for schizophrenia patients with insufficient response to clozapine: a quantitative literature review. Schizophr Bull 2012; 38:1003.
- Sommer IE, de Witte L, Begemann M, Kahn RS. Nonsteroidal anti-inflammatory drugs in schizophrenia: ready for practice or a good start? A meta-analysis. J Clin Psychiatry 2012; 73:414.
- Nitta M, Kishimoto T, Müller N, et al. Adjunctive use of nonsteroidal anti-inflammatory drugs for schizophrenia: a meta-analytic investigation of randomized controlled trials. Schizophr Bull 2013; 39:1230.
- Muscatello MR, Bruno A, Pandolfo G, et al. Topiramate augmentation of clozapine in schizophrenia: a double-blind, placebo-controlled study. J Psychopharmacol 2011; 25:667.
- Afshar H, Roohafza H, Mousavi G, et al. Topiramate add-on treatment in schizophrenia: a randomised, double-blind, placebo-controlled clinical trial. J Psychopharmacol 2009; 23:157.
- Roy Chengappa K, Kupfer DJ, Parepally H, et al. A placebo-controlled, random-assignment, parallel-group pilot study of adjunctive topiramate for patients with schizoaffective disorder, bipolar type. Bipolar Disord 2007; 9:609.
- Tiihonen J, Wahlbeck K, Kiviniemi V. The efficacy of lamotrigine in clozapine-resistant schizophrenia: a systematic review and meta-analysis. Schizophr Res 2009; 109:10.
- Chua WL, de Izquierdo SA, Kulkarni J, Mortimer A. Estrogen for schizophrenia. Cochrane Database Syst Rev 2005; :CD004719.
- EVALUATION AND MANAGEMENT
- Assess for pseudoresistance
- - Reevaluation of the primary diagnosis
- - Co-occurring conditions
- - Antipsychotic drug side effects
- - Medication nonadherence
- Optimize nonpharmacologic treatment
- Optimize antipsychotic drugs
- Clozapine trial
- - Eligibility
- - Efficacy
- - Administration
- - Discontinuation
- Antipsychotic drug augmentation
- - Electroconvulsive therapy
- - Transcranial magnetic stimulation
- - Antidepressant drugs
- - N-acetyl cysteine (acetylcysteine)
- - D-serine
- - Topiramate
- - Other adjunctive medications
- SUMMARY AND RECOMMENDATIONS