British Medical Bulletin Advance Access published May 8, 2015 British Medical Bulletin, 2015, 1–11 doi: 10.1093/bmb/ldv017
Antipsychotic medication in schizophrenia: a review John Lally†,* and James H. MacCabe‡ Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience (IoPPN), King’s College London, London, United Kingdom, and ‡National Psychosis Service, South London and Maudsley NHS Foundation Trust, London, United Kingdom *Correspondence address. Department of Psychosis Studies, PO63, Institute of Psychiatry, Psychology & Neuroscience (IoPPN), King’s College London, De Crespigny Park, London SE5 8AF. Tel: +(0044) (0)20 7848 0216; Fax: +(0044) 020 7848 0287; E-mail [email protected] Accepted 1 April 2015
Abstract Introduction: Antipsychotic medications are mainstays in the treatment of schizophrenia and a range of other psychotic disorders. Sources of data: Recent meta-analyses of antipsychotic efficacy and tolerability have been included in this review, along with key papers on antipsychotic use in schizophrenia and other psychotic illnesses. Areas of agreement: The heterogeneity in terms of individuals’ response to antipsychotic treatment and the current inability to predict response leads to a trial-and-error strategy with treatment choice. Clozapine is the only effective medication for treatment-resistant schizophrenia. Areas of controversy: There are a significant number of side effects associated with antipsychotic use. With a reduction in the frequency of extrapyramidal side effects with the use of second-generation antipsychotics, there has been a significant shift in the side effect burden, with an increase in the risk of cardiometabolic dysfunction. Growing points: There exist small and robust efficacy differences between medications (other than clozapine), and response and tolerability to each antipsychotic drug vary, with there being no first-line antipsychotic drug that is suitable for all patients. Areas timely for developing research: A focus on the different symptom domains of schizophrenia may lead to endophenotypic markers being identified, e.g. for negative symptoms and cognitive deficits (as well as for positive symptoms) that can promote the development of novel therapeutics, which
© The Author 2015. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: [email protected]
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†
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will rationally target cellular and molecular targets, rather than just the dopamine 2 receptor. Future developments will target additional processes, including glutamatergic, cholinergic and cannabinoid receptor targets and will utilize personalized medicine techniques, such as pharmacogenetic variants and biomarkers allowing for a tailored and safer use of antipsychotics. Key words: schizophrenia, antipsychotic medication, psychotic disorders
Introduction
Mechanism of antipsychotic action D2 receptor antagonism in the brain is a general pharmacodynamic property of all antipsychotics; this has given rise to the hypothesis that schizophrenia involves a dysregulation of dopaminergic circuits
Clozapine: a special case Clozapine is unique among antipsychotic medications and can be viewed as a standalone ‘third class’ of antipsychotic. It is the only antipsychotic medication that has proven effectiveness in treatment-resistant schizophrenia (TRS). The precise mechanism of clozapine’s superior effectiveness in TRS has not been established, but some 50–60% of patients with schizophrenia refractory to other antipsychotics will respond to clozapine.5 Clozapine produces robust antipsychotic effect at 100% of the BNF-licenced maximum dose. High-dose antipsychotic therapy is defined by the Royal College of Psychiatrists (RCPsych) as a total daily dose of a single antipsychotic that exceeds the upper limit stated in the BNF, or a total daily dose of two or more antipsychotics that exceeds the BNF maximum as calculated by percentages using the antipsychotic dose ready reckoner [example calculation: fluphenazine depot 100 mg monthly (50%) and olanzapine 15 mg daily (75%) = 50% + 75% =
Downloaded from http://bmb.oxfordjournals.org/ at Freie Universitaet Berlin on May 12, 2015
Long-acting injection (depot) medications and combination/ high-dose therapy
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125% (>100% therefore ‘high dose’)].30 For all those treated with high-dose antipsychotics, it is important to regularly monitor for metabolic abnormalities and for evidence of ECG changes, especially QTc prolongation.
Clinical indications for antipsychotics
evidence to support the use of quetiapine, aripiprazole, olanzapine and risperidone as antidepressant augmentation strategies in TRD, with the best evidence existing for the use of quetiapine and aripiprazole.34 Quetiapine (150–300 mg daily) is licensed in the UK as an antidepressant augmentation strategy.35 Antipsychotics for augmentation in TRD are prescribed at lower doses than what would be used in schizophrenia or BPAD (e.g. olanzapine 5–12.5 mg/day, quetiapine 150–300 mg/day). In psychotic depression, the combination of an antipsychotic and antidepressant is more effective than the use of an antidepressant alone, with olanzapine combined with fluoxetine probably the best evidenced combination.36
Bipolar affective disorder (BPAD) Multiple international guidelines recommend the use of antipsychotic medication in the treatment of all stages of BPAD.18,31,32 For acute mania, antipsychotics (particularly olanzapine, risperidone and quetiapine) along with mood stabilisers are consistently identified as primary treatment options. A recent meta-analysis identified that antipsychotics are more effective than mood stabilisers in the treatment of acute mania.33 Olanzapine and quetiapine are recommended first-line treatments for bipolar depression. Both quetiapine and olanzapine are associated with a rapid onset of action in bipolar depression, with efficacy demonstrated from the first week of treatment onwards. In clinical practice, quetiapine is now considered more for its mood-stabilising properties than for its antipsychotic effects. Similarly, the antipsychotics that are indicated for acute mania are generally recommended for maintenance therapy in BPAD. Clozapine has evidence of effectiveness in refractory mania and should be considered for this.
Anxiety disorders Antipsychotic medications have long been used as augmentation strategies for anxiety disorders, with the best evidence for their use as selective serotonin reuptake inhibitor augmentation strategies in obsessive compulsive disorder (OCD) and for the use of quetiapine in generalized anxiety disorder (GAD).37
Update on new antipsychotics In the UK, several SGAs are now off patent, including risperidone, olanzapine, amisulpride and quetiapine (instant-release formulation). However, given the heterogeneous patient response to and tolerability of antipsychotics, there remains a need to improve the therapeutic efficacy of available agents and to aid choice in improving treatment tolerability for patients. The newer branded SGAs, asenapine and lurasidone, have less impact on weight and metabolic parameters than older agents such as olanzapine.
Unipolar depression
Paliperidone
The use of antipsychotics as augmentation treatment options in unipolar depression and anxiety disorders is an off-label use, meaning that this use is not formally licensed (but with a growing evidence base to indicate the efficacy of certain antipsychotics). For treatmentresistant unipolar depression (TRD), antipsychotics are used as off-label augmentation strategies. There is
Paliperidone is the active metabolite of risperidone and is available in oral and LAI formulations, both demonstrating efficacy and tolerability and a delay in time to relapse in schizophrenia. It is not hepatically metabolised, making it safe to use in hepatic impairment and with limited risk of pharmacokinetic drug interactions.18 Paliperidone is further licensed for the
Downloaded from http://bmb.oxfordjournals.org/ at Freie Universitaet Berlin on May 12, 2015
Antipsychotic medications are effective in a range of disorders other than schizophrenia. In addition to their antipsychotic effects, antipsychotics may also have mood-stabilising, antimanic, antidepressant and anxiolytic effects.
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Asenapine Asenapine has demonstrated efficacy in the acute and maintenance phases of schizophrenia treatment and in the treatment of acute mania in BPAD, but it is only currently licensed for the treatment of mania in the UK.35 Asenapine has high affinity for multiple serotonin receptors, with antagonism at 5-HT2A, 5-HT2C and 5-HT7 and 5-HT1A agonism, along with potent D2 and D3 antagonism and some histamine (H) 1 antagonism.18 Asenapine is subject to first-pass metabolism and thus inactive if swallowed. It is, therefore, available only as an orally disintegrating tablet, meaning that it is absorbed via oral mucosa. This is in contrast to the other antipsychotic orodispersible tablets of olanzapine, risperidone and aripiprazole, all of which must be swallowed to be effective. This means that patients must be informed that asenapine cannot be swallowed and that food or drink must be avoided for at least 10 min after administration. Asenapine does not require dose titration and can be dosed at 5 mg bd for acute schizophrenia with doses of up to 10 mg twice daily shown efficacy in preventing relapses in schizophrenia. Asenapine has a half-life of 24 h and as such could theoretically be prescribed as a once-daily medication, but the efficacy of a once-daily prescription remains to be studied in trials. It appears to be a metabolically neutral antipsychotic with low propensity to cause weight gain (though some evidence for a higher propensity for weight gain in acute mania
exists) and has little effect on prolactin levels.39 It can cause akathisia (increased occurrence at 10 mg twicedaily dosing compared with 5 mg twice daily), sedation and taste disturbance.40
Lurasidone Lurasidone is licensed for the treatment of schizophrenia35 and has shown efficacy as an adjunctive treatment for bipolar depression, and it is a licensed therapy for bipolar depression in the USA. Lurasidone has full D2 antagonism and is an antagonist at 5HT2A and 5HT7 receptors, with partial agonism at 5-HT1A receptors, and with low affinity for 5HT2C, H1 and muscarinic receptors.40 Lurasidone is a once-daily prescription, simplifying its administration. It is dosed in adults at 37 mg once daily initially and increased if necessary to a maximum of 148 mg once daily. For schizophrenia, a dose range of 37–148 mg daily is recommended, with a lower dose range of 18.5–120 mg daily, recommended for bipolar depression (lurasidone at lower doses of 20–60 mg daily has been shown to be as clinically efficacious in bipolar depression, as at the higher dose range of 80– 100 mg/day). Lurasidone is metabolized by CYP3A4 enzymes, meaning that its dose should be reduced when used with concomitant CYP3A4 inhibitors (e.g. diltiazem, erythromycin). Lurasidone is generally well tolerated, with low incidences of weight gain and metabolic dysfunction. It is associated with akathisia (increased incidence at doses of 120 mg or greater), sedation and nausea, but similarly to asenapine, despite been a full D2 antagonist, it is not associated with higher incidences of EPSEs (excluding akathisia) and hyperprolactinaemia.40
Conclusions Maintaining the status Quo in antipsychotic treatment It remains the case that there has been no fundamental innovation in psychopharmacology for schizophrenia since the discovery of clozapine in the late 1950s. This is further exacerbated by the recent retreat of the pharmaceutical industry away from
Downloaded from http://bmb.oxfordjournals.org/ at Freie Universitaet Berlin on May 12, 2015
treatment of psychotic and manic symptoms of schizoaffective disorder. Its adverse effect profile is similar to that of the parent compound risperidone, with increased weight gain, hyperprolactinaemia and EPSEs at higher doses, along with case reports of tardive dyskinesia.38 At doses of 9–12 mg of oral paliperidone (equivalent to risperidone 4–6 mg daily), the risk of EPSEs is increased. The therapeutic dose range is 6–9 mg once daily (equivalent to risperidone 3–4 mg daily).18 Paliperidone palmitate is the LAI formulation, which achieves active serum levels within days of initiation and allows deltoid, rather than gluteal muscle administration.
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research and development in psychiatric disorders. For all the benefits bought by antipsychotics and the initially perceived advantages of SGAs, we are still working with medications that are not fully effective and often carry significant adverse effect burdens.
SGAs or FGAs?
Change in approach to medication development There is a growing consensus in academic psychiatry, acknowledging that schizophrenia is not a single disease entity and that the positive symptoms of psychosis (delusions, hallucinations) which antipsychotics work best to treat, are only one aspect of the disorder’s pathology. We need to focus future pharmaceutical development on symptoms domains of schizophrenia, with a particular need for treatments to target negative symptoms and cognitive impairments in schizophrenia. A more concentrated focus on the different symptom domains may lead to endophenotypic markers being identified for negative symptoms and cognitive deficits (as well as for positive symptoms) that can promote novel medication discovery. If medications are discovered for separate symptom domains of schizophrenia, then we could expect to be able to develop concurrent medication strategies, with antipsychotics used in combination with medications for negative symptoms or along with those that have cognitive enhancing effects.
Novel therapeutic strategies Our current level of knowledge regarding the pathogenesis of schizophrenia continues to improve, leading to the hope that in future novel therapeutics that will rationally target cellular and molecular targets, rather than just the D2 receptor, can be developed. All antipsychotic medications that have been developed over the past six decades have been based on the targeting of D2 receptors, and later the characteristic 5-HT2A antagonism of SGAs. Future developments will target additional processes, including glutamatergic, cholinergic and cannabinoid receptor targets, and the emerging field of pharmacogenetics will aim for treatments to be tailored to individual patients in terms of efficacy and tolerability.
Conclusion The heterogeneity in terms of individuals’ response to antipsychotic treatment and the current inability to predict response leads to a trial-and-error strategy with treatment. It remains the case that we are no closer to mirroring the effects of clozapine in TRS, with its mechanism of action proving elusive to identify and replicate in other antipsychotic therapies for schizophrenia.
Funding Dr Lally and Dr MacCabe are both supported by CRESTAR (CRESTAR project, http://www.crestarproject.eu/) EU-FP7 grant number 279227; Dr MacCabe is supported by STRATA (MRC grant no. MR/L011794/) and by the National Institute for Health Research (NIHR), Biomedical Research Centre for Mental Health at the South London and Maudsley NHS Foundation Trust and Institute of Psychiatry, Psychology and Neuroscience, Kings College London. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health.
Conflict of Interest statement None declared.
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Despite the lack of clear-cut differences in clinical efficacy between SGAs and FGAs (with the exception of clozapine), the introduction of the SGAs from the early 1990s onwards represented meaningful steps in attempting to improve pharmacotherapy for patients with schizophrenia. While we are improving our knowledge of what different treatments can and cannot do,10 we still remain a long way from being able to recommend with precision, specific treatments for individual patients, in terms of the clinical response and lack of adverse events. There is also no longitudinal evidence to support attempts to identify those patients who will and who will not require long-term antipsychotic medication with FGAs or SGAs.
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References 1. Ginovart N, Kapur S. Role of dopamine D(2) receptors for antipsychotic activity. Handb Exp Pharmacol 2012; 212:27–52. 2. Kapur S, Remington G. Dopamine D(2) receptors and their role in atypical antipsychotic action: still necessary and may even be sufficient. Biol Psychiatry 2001;50:873–83. 3. Howes OD, Murray RM. Schizophrenia: an integrated sociodevelopmental-cognitive model. Lancet 2014;383: 1677–87.
5. Meltzer HY. Treatment of the neuroleptic-nonresponsive schizophrenic patient. Schizophr Bull 1992;18:515–42. 6. Lieberman JA, Stroup TS, McEvoy JP, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 2005;353:1209–23. 7. Jones PB, Barnes TR, Davies L, et al. Randomized controlled trial of the effect on Quality of Life of second- vs first-generation antipsychotic drugs in schizophrenia: Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS 1). Arch Gen Psychiatry 2006; 63:1079–87. 8. Leucht S, Tardy M, Komossa K, et al. Antipsychotic drugs versus placebo for relapse prevention in schizophrenia: a systematic review and meta-analysis. Lancet 2012;379:2063–71. 9. Leucht S, Hierl S, Kissling W, et al. Putting the efficacy of psychiatric and general medicine medication into perspective: review of meta-analyses. Br J Psychiatry 2012; 200:97–106. 10. Leucht S, Cipriani A, Spineli L, et al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet 2013;382:951–62. 11. Newcomer JW. Second-generation (atypical) antipsychotics and metabolic effects: a comprehensive literature review. CNS Drugs 2005;1:1–93. 12. Mitchell AJ, Vancampfort D, Sweers K, et al. Prevalence of metabolic syndrome and metabolic abnormalities in schizophrenia and related disorders--a systematic review and meta-analysis. Schizophr Bull 2013;39:306–18. 13. Allison DB, Mentore JL, Heo M, et al. Antipsychoticinduced weight gain: a comprehensive research synthesis. Am J Psychiatry 1999;156:1686–96. 14. Bak M, Fransen A, Janssen J, et al. Almost all antipsychotics result in weight gain: a meta-analysis. PLoS One 2014;9:e94112.
15. Crawford MJ, Jayakumar S, Lemmey SJ, et al. Assessment and treatment of physical health problems among people with schizophrenia: national cross-sectional study. Br J Psychiatry 2014;205:473–7. 16. NICE. Psychosis and schizophrenia in adults: treatment and management (Clinical guideline 178). London: Royal College of Psychiatrists, 2014. 17. Agid O, Kapur S, Arenovich T, et al. Delayed-onset hypothesis of antipsychotic action: a hypothesis tested and rejected. Arch Gen Psychiatry 2003;60:1228–35. 18. Taylor D, Paton C, Kapur S. The Maudsley Prescribing Guidelines in Psychiatry. Wiley, 2012. 19. Robinson D, Woerner MG, Alvir JM, et al. Predictors of relapse following response from a first episode of schizophrenia or schizoaffective disorder. Arch Gen Psychiatry 1999;56:241–7. 20. Girgis RR, Phillips MR, Li X, et al. Clozapine v. chlorpromazine in treatment-naive, first-episode schizophrenia: 9-year outcomes of a randomised clinical trial. Br J Psychiatry 2011;199:281–8. 21. Howes OD, Vergunst F, Gee S, et al. Adherence to treatment guidelines in clinical practice: study of antipsychotic treatment prior to clozapine initiation. Br J Psychiatry 2012;201:481–5. 22. Tiihonen J, Lonnqvist J, Wahlbeck K, et al. 11-year follow-up of mortality in patients with schizophrenia: a population-based cohort study (FIN11 study). Lancet 2009;374:620–7. 23. Cramer JA, Rosenheck R. Compliance with medication regimens for mental and physical disorders. Psychiatr Serv 1998;49:196–201. 24. Leucht S, Heres S. Epidemiology, clinical consequences, and psychosocial treatment of nonadherence in schizophrenia. J Clin Psychiatry 2006;5:3–8. 25. Masand PS, Roca M, Turner MS, et al. Partial adherence to antipsychotic medication impacts the course of illness in patients with schizophrenia: a review. Prim Care Companion J Clin Psychiatry 2009;11:147–54. 26. Valenstein M, Kavanagh J, Lee T, et al. Using a pharmacy-based intervention to improve antipsychotic adherence among patients with serious mental illness. Schizophr Bull 2011;37:727–36. 27. Tiihonen J, Haukka J, Taylor M, et al. A nationwide cohort study of oral and depot antipsychotics after first hospitalization for schizophrenia. Am J Psychiatry 2011;168:603–9. 28. Rosenheck RA, Krystal JH, Lew R, et al. Long-acting risperidone and oral antipsychotics in unstable schizophrenia. N Engl J Med 2011;364:842–51. 29. Correll CU, Rummel-Kluge C, Corves C, et al. Antipsychotic combinations vs monotherapy in schizophrenia:
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4. Kapur S, Zipursky R, Jones C, et al. Relationship between dopamine D(2) occupancy, clinical response, and side effects: a double-blind PET study of first-episode schizophrenia. Am J Psychiatry 2000;157:514–20.
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treatment of unipolar depressive disorders. World J Biol Psychiatry 2013;14:334–85. Joint Formulary Committee. British National Formulary (BNF) 67. Pharmaceutical Press, 2014. Rothschild AJ. Challenges in the Treatment of Major Depressive Disorder With Psychotic Features. Schizophr Bull 2013;39:787–96. Baldwin DS, Anderson IM, Nutt DJ, et al. Evidencebased pharmacological treatment of anxiety disorders, post-traumatic stress disorder and obsessive-compulsive disorder: a revision of the 2005 guidelines from the British Association for Psychopharmacology. J Psychopharmacol 2014;28:403–39. Lally J, Byrne F, Walsh E. A case of paliperidonepalmitate-induced tardive dyskinesia. Gen Hosp Psychiatry 2013;35:14. Citrome L. Asenapine review, part II: clinical efficacy, safety and tolerability. Expert Opin Drug Saf 2014; 13:803–30. Citrome L. A review of the pharmacology, efficacy and tolerability of recently approved and upcoming oral antipsychotics: an evidence-based medicine approach. CNS Drugs 2013;27:879–911.
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a meta-analysis of randomized controlled trials. Schizophr Bull 2009;35:443–57. Royal College of Psychiatrists. Consensus statement on high-dose antipsychotic medication (CR190). London: Royal College of Psychiatrists, 2014. Yatham LN, Kennedy SH, Parikh SV, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) collaborative update of CANMAT guidelines for the management of patients with bipolar disorder: update 2013. Bipolar Disord 2013;15:1–44. NICE. National Institute for Health and Clinical Excellence. Bipolar disorder (update): the management of bipolar disorder in adults, children and adolescents in primary and secondary care. (Clinical Guideline 185). London: NICE, 2014. Cipriani A, Barbui C, Salanti G, et al. Comparative efficacy and acceptability of antimanic drugs in acute mania: a multiple-treatments meta-analysis. Lancet 2011;378:1306–15. Bauer M, Pfennig A, Severus E, et al. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of unipolar depressive disorders, part 1: update 2013 on the acute and continuation
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Antipsychotic medication in schizophrenia: a review John Lally†,* and James H. MacCabe‡ Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience (IoPPN), King’s College London, London, United Kingdom, and ‡National Psychosis Service, South London and Maudsley NHS Foundation Trust, London, United Kingdom *Correspondence address. Department of Psychosis Studies, PO63, Institute of Psychiatry, Psychology & Neuroscience (IoPPN), King’s College London, De Crespigny Park, London SE5 8AF. Tel: +(0044) (0)20 7848 0216; Fax: +(0044) 020 7848 0287; E-mail [email protected] Accepted 1 April 2015
Abstract Introduction: Antipsychotic medications are mainstays in the treatment of schizophrenia and a range of other psychotic disorders. Sources of data: Recent meta-analyses of antipsychotic efficacy and tolerability have been included in this review, along with key papers on antipsychotic use in schizophrenia and other psychotic illnesses. Areas of agreement: The heterogeneity in terms of individuals’ response to antipsychotic treatment and the current inability to predict response leads to a trial-and-error strategy with treatment choice. Clozapine is the only effective medication for treatment-resistant schizophrenia. Areas of controversy: There are a significant number of side effects associated with antipsychotic use. With a reduction in the frequency of extrapyramidal side effects with the use of second-generation antipsychotics, there has been a significant shift in the side effect burden, with an increase in the risk of cardiometabolic dysfunction. Growing points: There exist small and robust efficacy differences between medications (other than clozapine), and response and tolerability to each antipsychotic drug vary, with there being no first-line antipsychotic drug that is suitable for all patients. Areas timely for developing research: A focus on the different symptom domains of schizophrenia may lead to endophenotypic markers being identified, e.g. for negative symptoms and cognitive deficits (as well as for positive symptoms) that can promote the development of novel therapeutics, which
© The Author 2015. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: [email protected]
Downloaded from http://bmb.oxfordjournals.org/ at Freie Universitaet Berlin on May 12, 2015
†
J. Lally et al., 2015, Vol. 0, No. 0
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will rationally target cellular and molecular targets, rather than just the dopamine 2 receptor. Future developments will target additional processes, including glutamatergic, cholinergic and cannabinoid receptor targets and will utilize personalized medicine techniques, such as pharmacogenetic variants and biomarkers allowing for a tailored and safer use of antipsychotics. Key words: schizophrenia, antipsychotic medication, psychotic disorders
Introduction
Mechanism of antipsychotic action D2 receptor antagonism in the brain is a general pharmacodynamic property of all antipsychotics; this has given rise to the hypothesis that schizophrenia involves a dysregulation of dopaminergic circuits
Clozapine: a special case Clozapine is unique among antipsychotic medications and can be viewed as a standalone ‘third class’ of antipsychotic. It is the only antipsychotic medication that has proven effectiveness in treatment-resistant schizophrenia (TRS). The precise mechanism of clozapine’s superior effectiveness in TRS has not been established, but some 50–60% of patients with schizophrenia refractory to other antipsychotics will respond to clozapine.5 Clozapine produces robust antipsychotic effect at 100% of the BNF-licenced maximum dose. High-dose antipsychotic therapy is defined by the Royal College of Psychiatrists (RCPsych) as a total daily dose of a single antipsychotic that exceeds the upper limit stated in the BNF, or a total daily dose of two or more antipsychotics that exceeds the BNF maximum as calculated by percentages using the antipsychotic dose ready reckoner [example calculation: fluphenazine depot 100 mg monthly (50%) and olanzapine 15 mg daily (75%) = 50% + 75% =
Downloaded from http://bmb.oxfordjournals.org/ at Freie Universitaet Berlin on May 12, 2015
Long-acting injection (depot) medications and combination/ high-dose therapy
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125% (>100% therefore ‘high dose’)].30 For all those treated with high-dose antipsychotics, it is important to regularly monitor for metabolic abnormalities and for evidence of ECG changes, especially QTc prolongation.
Clinical indications for antipsychotics
evidence to support the use of quetiapine, aripiprazole, olanzapine and risperidone as antidepressant augmentation strategies in TRD, with the best evidence existing for the use of quetiapine and aripiprazole.34 Quetiapine (150–300 mg daily) is licensed in the UK as an antidepressant augmentation strategy.35 Antipsychotics for augmentation in TRD are prescribed at lower doses than what would be used in schizophrenia or BPAD (e.g. olanzapine 5–12.5 mg/day, quetiapine 150–300 mg/day). In psychotic depression, the combination of an antipsychotic and antidepressant is more effective than the use of an antidepressant alone, with olanzapine combined with fluoxetine probably the best evidenced combination.36
Bipolar affective disorder (BPAD) Multiple international guidelines recommend the use of antipsychotic medication in the treatment of all stages of BPAD.18,31,32 For acute mania, antipsychotics (particularly olanzapine, risperidone and quetiapine) along with mood stabilisers are consistently identified as primary treatment options. A recent meta-analysis identified that antipsychotics are more effective than mood stabilisers in the treatment of acute mania.33 Olanzapine and quetiapine are recommended first-line treatments for bipolar depression. Both quetiapine and olanzapine are associated with a rapid onset of action in bipolar depression, with efficacy demonstrated from the first week of treatment onwards. In clinical practice, quetiapine is now considered more for its mood-stabilising properties than for its antipsychotic effects. Similarly, the antipsychotics that are indicated for acute mania are generally recommended for maintenance therapy in BPAD. Clozapine has evidence of effectiveness in refractory mania and should be considered for this.
Anxiety disorders Antipsychotic medications have long been used as augmentation strategies for anxiety disorders, with the best evidence for their use as selective serotonin reuptake inhibitor augmentation strategies in obsessive compulsive disorder (OCD) and for the use of quetiapine in generalized anxiety disorder (GAD).37
Update on new antipsychotics In the UK, several SGAs are now off patent, including risperidone, olanzapine, amisulpride and quetiapine (instant-release formulation). However, given the heterogeneous patient response to and tolerability of antipsychotics, there remains a need to improve the therapeutic efficacy of available agents and to aid choice in improving treatment tolerability for patients. The newer branded SGAs, asenapine and lurasidone, have less impact on weight and metabolic parameters than older agents such as olanzapine.
Unipolar depression
Paliperidone
The use of antipsychotics as augmentation treatment options in unipolar depression and anxiety disorders is an off-label use, meaning that this use is not formally licensed (but with a growing evidence base to indicate the efficacy of certain antipsychotics). For treatmentresistant unipolar depression (TRD), antipsychotics are used as off-label augmentation strategies. There is
Paliperidone is the active metabolite of risperidone and is available in oral and LAI formulations, both demonstrating efficacy and tolerability and a delay in time to relapse in schizophrenia. It is not hepatically metabolised, making it safe to use in hepatic impairment and with limited risk of pharmacokinetic drug interactions.18 Paliperidone is further licensed for the
Downloaded from http://bmb.oxfordjournals.org/ at Freie Universitaet Berlin on May 12, 2015
Antipsychotic medications are effective in a range of disorders other than schizophrenia. In addition to their antipsychotic effects, antipsychotics may also have mood-stabilising, antimanic, antidepressant and anxiolytic effects.
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Asenapine Asenapine has demonstrated efficacy in the acute and maintenance phases of schizophrenia treatment and in the treatment of acute mania in BPAD, but it is only currently licensed for the treatment of mania in the UK.35 Asenapine has high affinity for multiple serotonin receptors, with antagonism at 5-HT2A, 5-HT2C and 5-HT7 and 5-HT1A agonism, along with potent D2 and D3 antagonism and some histamine (H) 1 antagonism.18 Asenapine is subject to first-pass metabolism and thus inactive if swallowed. It is, therefore, available only as an orally disintegrating tablet, meaning that it is absorbed via oral mucosa. This is in contrast to the other antipsychotic orodispersible tablets of olanzapine, risperidone and aripiprazole, all of which must be swallowed to be effective. This means that patients must be informed that asenapine cannot be swallowed and that food or drink must be avoided for at least 10 min after administration. Asenapine does not require dose titration and can be dosed at 5 mg bd for acute schizophrenia with doses of up to 10 mg twice daily shown efficacy in preventing relapses in schizophrenia. Asenapine has a half-life of 24 h and as such could theoretically be prescribed as a once-daily medication, but the efficacy of a once-daily prescription remains to be studied in trials. It appears to be a metabolically neutral antipsychotic with low propensity to cause weight gain (though some evidence for a higher propensity for weight gain in acute mania
exists) and has little effect on prolactin levels.39 It can cause akathisia (increased occurrence at 10 mg twicedaily dosing compared with 5 mg twice daily), sedation and taste disturbance.40
Lurasidone Lurasidone is licensed for the treatment of schizophrenia35 and has shown efficacy as an adjunctive treatment for bipolar depression, and it is a licensed therapy for bipolar depression in the USA. Lurasidone has full D2 antagonism and is an antagonist at 5HT2A and 5HT7 receptors, with partial agonism at 5-HT1A receptors, and with low affinity for 5HT2C, H1 and muscarinic receptors.40 Lurasidone is a once-daily prescription, simplifying its administration. It is dosed in adults at 37 mg once daily initially and increased if necessary to a maximum of 148 mg once daily. For schizophrenia, a dose range of 37–148 mg daily is recommended, with a lower dose range of 18.5–120 mg daily, recommended for bipolar depression (lurasidone at lower doses of 20–60 mg daily has been shown to be as clinically efficacious in bipolar depression, as at the higher dose range of 80– 100 mg/day). Lurasidone is metabolized by CYP3A4 enzymes, meaning that its dose should be reduced when used with concomitant CYP3A4 inhibitors (e.g. diltiazem, erythromycin). Lurasidone is generally well tolerated, with low incidences of weight gain and metabolic dysfunction. It is associated with akathisia (increased incidence at doses of 120 mg or greater), sedation and nausea, but similarly to asenapine, despite been a full D2 antagonist, it is not associated with higher incidences of EPSEs (excluding akathisia) and hyperprolactinaemia.40
Conclusions Maintaining the status Quo in antipsychotic treatment It remains the case that there has been no fundamental innovation in psychopharmacology for schizophrenia since the discovery of clozapine in the late 1950s. This is further exacerbated by the recent retreat of the pharmaceutical industry away from
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treatment of psychotic and manic symptoms of schizoaffective disorder. Its adverse effect profile is similar to that of the parent compound risperidone, with increased weight gain, hyperprolactinaemia and EPSEs at higher doses, along with case reports of tardive dyskinesia.38 At doses of 9–12 mg of oral paliperidone (equivalent to risperidone 4–6 mg daily), the risk of EPSEs is increased. The therapeutic dose range is 6–9 mg once daily (equivalent to risperidone 3–4 mg daily).18 Paliperidone palmitate is the LAI formulation, which achieves active serum levels within days of initiation and allows deltoid, rather than gluteal muscle administration.
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research and development in psychiatric disorders. For all the benefits bought by antipsychotics and the initially perceived advantages of SGAs, we are still working with medications that are not fully effective and often carry significant adverse effect burdens.
SGAs or FGAs?
Change in approach to medication development There is a growing consensus in academic psychiatry, acknowledging that schizophrenia is not a single disease entity and that the positive symptoms of psychosis (delusions, hallucinations) which antipsychotics work best to treat, are only one aspect of the disorder’s pathology. We need to focus future pharmaceutical development on symptoms domains of schizophrenia, with a particular need for treatments to target negative symptoms and cognitive impairments in schizophrenia. A more concentrated focus on the different symptom domains may lead to endophenotypic markers being identified for negative symptoms and cognitive deficits (as well as for positive symptoms) that can promote novel medication discovery. If medications are discovered for separate symptom domains of schizophrenia, then we could expect to be able to develop concurrent medication strategies, with antipsychotics used in combination with medications for negative symptoms or along with those that have cognitive enhancing effects.
Novel therapeutic strategies Our current level of knowledge regarding the pathogenesis of schizophrenia continues to improve, leading to the hope that in future novel therapeutics that will rationally target cellular and molecular targets, rather than just the D2 receptor, can be developed. All antipsychotic medications that have been developed over the past six decades have been based on the targeting of D2 receptors, and later the characteristic 5-HT2A antagonism of SGAs. Future developments will target additional processes, including glutamatergic, cholinergic and cannabinoid receptor targets, and the emerging field of pharmacogenetics will aim for treatments to be tailored to individual patients in terms of efficacy and tolerability.
Conclusion The heterogeneity in terms of individuals’ response to antipsychotic treatment and the current inability to predict response leads to a trial-and-error strategy with treatment. It remains the case that we are no closer to mirroring the effects of clozapine in TRS, with its mechanism of action proving elusive to identify and replicate in other antipsychotic therapies for schizophrenia.
Funding Dr Lally and Dr MacCabe are both supported by CRESTAR (CRESTAR project, http://www.crestarproject.eu/) EU-FP7 grant number 279227; Dr MacCabe is supported by STRATA (MRC grant no. MR/L011794/) and by the National Institute for Health Research (NIHR), Biomedical Research Centre for Mental Health at the South London and Maudsley NHS Foundation Trust and Institute of Psychiatry, Psychology and Neuroscience, Kings College London. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health.
Conflict of Interest statement None declared.
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Despite the lack of clear-cut differences in clinical efficacy between SGAs and FGAs (with the exception of clozapine), the introduction of the SGAs from the early 1990s onwards represented meaningful steps in attempting to improve pharmacotherapy for patients with schizophrenia. While we are improving our knowledge of what different treatments can and cannot do,10 we still remain a long way from being able to recommend with precision, specific treatments for individual patients, in terms of the clinical response and lack of adverse events. There is also no longitudinal evidence to support attempts to identify those patients who will and who will not require long-term antipsychotic medication with FGAs or SGAs.
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