Treatment Resistance in Early Psychosis: Comparison
View Latest Version
Please note this is a comparison between Version 3 by Lily Guo and Version 2 by Lily Guo.

Treatment resistance is prevalent in early intervention in psychosis services, and causes a significant burden for the individual. A wide range of variables are shown to contribute to treatment resistance in first episode psychosis (FEP). Heterogeneity in illness course and the complex, multidimensional nature of the concept of recovery calls for an evidence base to better inform practice at an individual level. Current gold standard treatments, adopting a ‘one-size fits all’ approach, may not be addressing the needs of many individuals.

  • Treatment Resistance in Early Psychosis

1. Introduction

The lack of consensus over a clear definition of treatment resistance and validated instruments to assess the concept remains problematic for research in this area [9,10][1][2]. Treatment resistance is often conceptualized by the persistence of unremitted positive symptoms, despite the sequential use of at least two antipsychotic medications at a therapeutic dose, for a minimum duration of six weeks[3][4]. [4,11].

However, this definition disregards other symptoms which are shown to influence outcomes in psychosis, such as cognitive impairment and negative symptoms, which tend to be unresponsive to standard treatments [12,13,14][5][6][7]. The lack of broadness in the definition of treatment resistance has also meant that other key outcome domains, such as one’s social and role functioning and quality of life, are overlooked [15][8]. Finally, the term itself may be conceived as stigmatizing, as it places onus on the individual for ‘not responding adequately’ or ‘failing’ their treatment, which may add to the increased shame and stigma that an individual may already experience as a result of receiving their diagnosis [16][9].

An alternative definition that has been proposed is the concept of ‘incomplete recovery’, which considers persisting impairment in psychosocial and functional domains, despite intervention with evidence-based psychosocial and pharmacological treatments; the term also reflects the potential for improved therapeutic outcomes [10,17][2][10]. Within this concept, the lack of recovery following adequate treatment is distinguished from non-adherence to treatment; each may contribute to incomplete recovery and should be identified and addressed early to promote recovery in FEP [9,10][1][2].

2. Prevalence and Predictors of Treatment Resistance and Incomplete Recovery

The rates of treatment resistance and incomplete recovery vary widely in FEP. This disparity is likely a result of studies adopting different criteria to define treatment resistance. The inclusion of participants with affective and non-affective psychosis is also likely to add to this heterogeneity, given that outcomes tend to be more favorable in those with prominent affective trajectories [18,19][11][12]. Recent publications in longitudinal FEP cohorts report rates between 22–34% for individuals who are resistant to antipsychotic medication [5,20,21][13][14][15]. Findings from systematic reviews on relapse and incomplete symptomatic recovery in FEP again show variation in the rates reported (19–89%), but notably, the risk of relapse is significantly reduced by sustained antipsychotic therapy [3,22,23,24][16][17][18][19]. Finally, incomplete recovery within social and vocational domains are shown to vary between 46% and 86% in FEP [3,25][16][20]. These findings highlight that current evidenced-based treatments and services are not adequately addressing the needs of all its service users.

There is also complexity in predicting outcomes in FEP; incomplete recovery appears to be multidimensionally determined and impacts separable domains of recovery [1,17][21][10]. Variables shown to contribute to incomplete recovery include: long delay in untreated psychosis (DUP), younger age at onset of psychosis, poorer premorbid adjustment, cognitive impairment, negative symptoms, affective comorbidity, non-adherence and disengagement with treatment, male gender, and initial response to treatment [4,5,14,26,27,28,29,30,31][3][13][7][22][23][24][25][26][27]. It is likely that each individual will have their own unique combination that will determine their outcome, which makes predictions at the individual level challenging, particularly in the early stages of psychosis where illness trajectories are forming and the clinical picture is still emerging [1][21].

It is also likely that illness trajectories are long-standing, and impairment pre-dates formal illness onset [32][28]. Supporting this view is the dimensional approach to illness whereby the heterogeneity in early psychosis is characterized by differing illness subtypes, rooted early in development [33,34][29][30]. Indeed, early cognitive and neurodevelopmental impairment has been associated with psychosis liability and core schizophrenia [15[8][31],35], and it is hypothesised that aberrations in the neurodevelopmental process, linked to cognitive deficits, lie at the heart of early and enduring impairment in psychosis [15][8]. Such an approach may have utility for subtyping individuals on their early course or premorbid features, potentially aiding in the parsing of clinical heterogeneity [33].

There are also a number of established social antecedents in the development of psychosis; an accumulation of these risk and protective factors over time may not only increase someone’s risk of psychosis, but may continue to operate within the process of recovery [1][21]. It is established that social gradients are heavily implicated in the development of psychosis, such as: urbanicity, social marginalization and fragmentation, ethnic minority status, and childhood adversity [36,37][32][33]. These factors are likely to lead to a vicious cycle of disadvantage, which, if not addressed, will continue to drive enduring impairment [38][34]. For example, hostile and critical family environments are associated with relapse and depression in psychosis, and changing these environments via family interventions are indeed shown to be effective at reducing relapse rates [39][35]. More recently, the concept of urban remediation in psychosis has been proposed as a new recovery-oriented strategy to manage urban stress, but at present, this remains a goal for future research[36]. [40].

From the evidence presented above, there appears to a gap in the knowledge base for understanding the evolutionary continuity between alterations in neurodevelopmental process and exposure to stressful life events, with later onset of psychosis [34][30]. Longitudinal prospective studies in children and young people are essential to improve our understanding of neurodevelopmental markers in children and young people with varying levels of psychosis risk, and how these might be linked to long term prognoses.

3. Current Approaches for Managing Emerging Treatment Resistance in Early Psychosis

The first 3–5 years following illness onset, including the period of untreated psychosis, represents a ‘critical period’ of illness progression[37][38]. [7,41] It is during this time in which interventions are likely to have their greatest impact [41][38].

EIS provides specialist assertive outreach-style care during the ‘critical period’, and are effective at improving a number of clinical and functional outcomes for young people with FEP [42][39]. However, there appears to be a group of individuals whose psychosis remains ‘unresponsive’ to standard high quality EIS care, embodying National Institute for Clinical Excellence (NICE) approved psychosocial and pharmacological interventions; strongly suggesting that earlier, targeted interventions are urgently needed to allow such individuals to maximise their life chances [3,21][16][17].

A recent publication by Drake and colleagues[23] [27] demonstrated the importance of having such timely interventions. In their longitudinal modelling study, they demonstrated a curvilinear relationship between DUP with symptom severity and treatment response, meaning that symptoms become more refractory with a longer DUP, but this response was more rapid at first and then plateaued [27][23]. These recent findings place even greater emphasis on providing individuals with prompt access to a range of interventions ideally within the first few weeks of illness onset [27][23].

However, despite the implementation of EIS leading to a significant reduction DUP, a proportion of individuals continue to have DUPs exceeding 6 months [43,44][40][41]. Furthermore, whilst earlier studies provide evidence that intervention programmes can be successful at reducing DUP, for example, the Treatment and Intervention in Psychosis Study (TIPS), where DUP was reduced from 16 to five weeks, a recent systematic and meta-analytic review of 16 studies did not find any conclusive summary evidence for controlled interventions in reducing DUP [45,46][42][43].

Reducing DUP, particularly in areas where DUPs are consideringly long, should remain a priority to improve outcomes. Large scale collaborative studies with rigorous study designs and robust assessments of DUP are needed to inform more effective interventions [46][43].

Another important finding by Drake and colleagues was that DUP was not linked to any symptoms at presentation, except depression [27][23]. It is established that depression in psychosis is associated with a range of poor outcomes, but yet there is a lack of large-scale controlled trials investigating the effectiveness of adjunctive antidepressants, or cognitive behavioural therapy (CBT), to target depression within psychosis [26,47,48][22][44][45]. This calls for more effective recognition and management of depression to maximise recovery within EIS.

NICE guidelines in the UK advocate for antipsychotic medication and CBT as first line treatments for all individuals with psychosis[4] [11]. Clozapine is the only evidence-based treatment for refractory psychosis, and current guidelines recommend commencement after two unsuccessful trials of standard antipsychotics [11,49][4][46]. A recently published study investigating the pathways to prescribing clozapine for treatment resistance within UK EIS centres, showed a marked delay in clozapine prescription for those who were eligible [21][15]. A clear stasis in treatment was evident for these individuals, where the majority either remained on the same medication despite persisting symptoms, or they continued to be placed on other antipsychotics which were also unsuccessful [21][15].

Given the evidence of the superior efficacy of clozapine in reducing suicide risk, improving symptomatic and functional recovery, and reducing mortality rates, this may reflect a missed opportunity to influence recovery during the significant ‘critical period’ [21,50,51][15][47][48].Ongoing education of the benefits of clozapine and emphasis on the national standards for commencement of clozapine in the community is perhaps needed to improve uptake on clozapine for those who are eligible [22][16]. But despite its superiority in treating refractory symptoms, it must be acknowledged that 30–40% of individuals will still show an insufficient response to clozapine, and others are unable to tolerate the medication; the move toward community commencement of clozapine would also require national standards on clozapine discontinuation for those who are unable to tolerate [52,53][49][50].

Conventional CBT for psychosis is also less likely to be effective for subgroups of individuals with particularly complex illness presentations [52[49][51][52],54,55], and there is considerable heterogeneity in response to psychosocial interventions in psychosis [56][53]. Baseline factors are shown to contribute a large amount of this variance. For example, cognitive impairments are shown to have a rate-limiting impact on treatment progress [57,58][54][55].

Encouragingly, a recent randomised controlled trial provides an example of a tailored approach to those who are treatment resistant within early psychosis. A specialised social CBT, namely social recovery therapy (SRT), is shown to be effective at increasing structured activity in a sizeable group of young people whose severe social disability had proved unresponsive to standard EIS [54][51]. Potentially, individuals who are likely on a pathway to treatment resistance may receive SRT earlier in their illness trajectory to prevent their disability from becoming entrenched.

The benefits of such an intervention may also potentially extend to individuals who are disengaged with their treatment; the basis of SRT is to motivate individuals who are perhaps ambivalent about change, whilst also addressing any underlying blocks to change, or in this instance, interventions such as SRT may be helpful to address any underlying reasons for non-adherence to treatment [54][51].

Finally, there is further scope for the refinement of the SRT to ensure that the therapy is being delivered appropriately, such as greater precision in the identification of individuals who are less likely to benefit from such interventions, and a greater understanding of the mechanistic markers of change to inform the process of early treatment stratification [59][56].

References

  1. Conley, R.R.; Kelly, D.L. Management of treatment resistance in schizophrenia. Biological Psychiatry 2001, 50, 898-911, doi:https://doi.org/10.1016/S0006-3223(01)01271-9.
  2. Pantelis, C.; Lambert, T.J.R. Managing patients with “treatment-resistant” schizophrenia. Medical Journal of Australia 2003, 178, S62-S66, doi:10.5694/j.1326-5377.2003.tb05310.x.
  3. Lally, J.; Ajnakina, O.; Forti, M.; Trotta, A.; Demjaha, A.; Kolliakou, A.; Mondelli, V.; Marques, T.; Pariante, C.; Dazzan, P., et al. Two distinct patterns of treatment resistance: clinical predictors of treatment resistance in first-episode schizophrenia spectrum psychoses. Psychological Medicine 2016, 46, 1-10, doi:10.1017/S0033291716002014.
  4. National Institute for Clinical Excellence (NICE), N.I.f.H.a.C.E. Psychosis and Schizophrenia in Adults: Treatment and Management. Royal College of Psychiatrists: London, 2014.
  5. Goldberg, T.E.; Goldman, R.S.; Burdick, K.E.; Malhotra, A.K.; Lencz, T.; Patel, R.C.; Woerner, M.G.; Schooler, N.R.; Kane, J.M.; Robinson, D.G. Cognitive Improvement After Treatment With Second-Generation Antipsychotic Medications in First-Episode Schizophrenia: Is It a Practice Effect? Archives of General Psychiatry 2007, 64, 1115-1122, doi:10.1001/archpsyc.64.10.1115.
  6. Allott, K.; Liu, P.; Proffitt, T.M.; Killackey, E. Cognition at illness onset as a predictor of later functional outcome in early psychosis: systematic review and methodological critique. Schizophr Res 2011, 125, 221-235, doi:10.1016/j.schres.2010.11.001.
  7. Santesteban-Echarri, O.; Paino, M.; Rice, S.; González-Blanch, C.; McGorry, P.; Gleeson, J.; Alvarez-Jimenez, M. Predictors of functional recovery in first-episode psychosis: A systematic review and meta-analysis of longitudinal studies. Clinical Psychology Review 2017, 58, 59-75, doi:https://doi.org/10.1016/j.cpr.2017.09.007.
  8. Bartholomeusz, C.F.; Allott, K. Neurocognitive and Social Cognitive Approaches for Improving Functional Outcome in Early Psychosis: Theoretical Considerations and Current State of Evidence. Schizophrenia Research and Treatment 2012, 2012, 815315, doi:10.1155/2012/815315.
  9. Heriot-Maitland, C.; Allan, S.; Bradstreet, S.; Gumley, A. Antipsychotic treatments: who is really failing here? The Lancet Psychiatry 2018, 5, 785, doi:10.1016/S2215-0366(18)30336-5.
  10. Lambert, T.J. Disease Management: Multidimensional Approaches to Incomplete Recovery in Psychosis. Advances in Biological Psychiatry 2011, 26, 87-113, doi:10.1159/000319811.
  11. Jäger, M.; Haack, S.; Becker, T.; Frasch, K. Schizoaffective disorder--an ongoing challenge for psychiatric nosology. Eur Psychiatry 2011, 26, 159-165, doi:10.1016/j.eurpsy.2010.03.010.
  12. Leighton, S.P.; Krishnadas, R.; Chung, K.; Blair, A.; Brown, S.; Clark, S.; Sowerbutts, K.; Schwannauer, M.; Cavanagh, J.; Gumley, A.I. Predicting one-year outcome in first episode psychosis using machine learning. PloS one 2019, 14, e0212846-e0212846, doi:10.1371/journal.pone.0212846.
  13. Demjaha, A.; Lappin, J.M.; Stahl, D.; Patel, M.X.; MacCabe, J.H.; Howes, O.D.; Heslin, M.; Reininghaus, U.A.; Donoghue, K.; Lomas, B., et al. Antipsychotic treatment resistance in first-episode psychosis: prevalence, subtypes and predictors. Psychol Med 2017, 47, 1981-1989, doi:10.1017/s0033291717000435.
  14. Lally, J.; Gaughran, F.; Timms, P.; Curran, S. Treatment-resistant schizophrenia: Current insights on the pharmacogenomics of antipsychotics. Pharmacogenomics and Personalized Medicine 2016, Volume 9, 117-129, doi:10.2147/PGPM.S115741.
  15. Stokes, I.; Griffiths, S.L.; Jones, R.; Everard, L.; Jones, P.B.; Fowler, D.; Hodgekins, J.; Amos, T.; Freemantle, N.; Sharma, V., et al. Prevalence of treatment resistance and clozapine use in early intervention services. BJPsych Open 2020, 6, e107, doi:10.1192/bjo.2020.89.
  16. Leighton, S.P.; Upthegrove, R.; Krishnadas, R.; Benros, M.E.; Broome, M.R.; Gkoutos, G.V.; Liddle, P.F.; Singh, S.P.; Everard, L.; Jones, P.B., et al. Development and validation of multivariable prediction models of remission, recovery, and quality of life outcomes in people with first episode psychosis: a machine learning approach. The Lancet Digital Health 2019, 1, e261-e270, doi:10.1016/S2589-7500(19)30121-9.
  17. Zipursky, R.B.; Menezes, N.M.; Streiner, D.L. Risk of symptom recurrence with medication discontinuation in first-episode psychosis: a systematic review. Schizophr Res 2014, 152, 408-414, doi:10.1016/j.schres.2013.08.001.
  18. Alvarez-Jimenez, M.; O'Donoghue, B.; Thompson, A.; Gleeson, J.F.; Bendall, S.; Gonzalez-Blanch, C.; Killackey, E.; Wunderink, L.; McGorry, P.D. Beyond Clinical Remission in First Episode Psychosis: Thoughts on Antipsychotic Maintenance vs. Guided Discontinuation in the Functional Recovery Era. CNS Drugs 2016, 30, 357-368, doi:10.1007/s40263-016-0331-x.
  19. Taylor, M.; Jauhar, S. Are we getting any better at staying better? The long view on relapse and recovery in first episode nonaffective psychosis and schizophrenia. Therapeutic Advances in Psychopharmacology 2019, 9, 2045125319870033, doi:10.1177/2045125319870033.
  20. Hodgekins, J.; French, P.; Birchwood, M.; Mugford, M.; Christopher, R.; Marshall, M.; Everard, L.; Lester, H.; Jones, P.; Amos, T., et al. Comparing time use in individuals at different stages of psychosis and a non-clinical comparison group. Schizophrenia Research 2015, 161, 188-193, doi:https://doi.org/10.1016/j.schres.2014.12.011.
  21. Power, P. Outcome and recovery in first-episode psychosis. British Journal of Psychiatry 2017, 211, 331-333, doi:10.1192/bjp.bp.117.205492.
  22. Upthegrove, R.; Marwaha, S.; Birchwood, M. Depression and Schizophrenia: Cause, Consequence, or Trans-diagnostic Issue? Schizophrenia Bulletin 2016, 43, 240-244, doi:10.1093/schbul/sbw097.
  23. Drake, R.J.; Husain, N.; Marshall, M.; Lewis, S.W.; Tomenson, B.; Chaudhry, I.B.; Everard, L.; Singh, S.; Freemantle, N.; Fowler, D., et al. Effect of delaying treatment of first-episode psychosis on symptoms and social outcomes: a longitudinal analysis and modelling study. The Lancet Psychiatry 2020, 7, 602-610, doi:https://doi.org/10.1016/S2215-0366(20)30147-4.
  24. Lally, J.; Ajnakina, O.; Stubbs, B.; Cullinane, M.; Murphy, K.C.; Gaughran, F.; Murray, R.M. Remission and recovery from first-episode psychosis in adults: systematic review and meta-analysis of long-term outcome studies. British Journal of Psychiatry 2017, 211, 350-358, doi:10.1192/bjp.bp.117.201475.
  25. McCutcheon, R.; Beck, K.; D'Ambrosio, E.; Donocik, J.; Gobjila, C.; Jauhar, S.; Kaar, S.; Pillinger, T.; Reis Marques, T.; Rogdaki, M., et al. Antipsychotic plasma levels in the assessment of poor treatment response in schizophrenia. Acta psychiatrica Scandinavica 2018, 137, 39-46, doi:10.1111/acps.12825.
  26. Legge, S.E.; Dennison, C.A.; Pardiñas, A.F.; Rees, E.; Lynham, A.J.; Hopkins, L.; Bates, L.; Kirov, G.; Owen, M.J.; O'Donovan, M.C., et al. Clinical indicators of treatment-resistant psychosis. The British Journal of Psychiatry 2020, 216, 259-266, doi:10.1192/bjp.2019.120.
  27. Griffiths, S.L.; Birchwood, M.; Khan, A.; Wood, S.J. Predictors of social and role outcomes in first episode psychosis: A prospective 12-month study of social cognition, neurocognition and symptoms. Early Intervention in Psychiatry n/a, doi:https://doi.org/10.1111/eip.13056.
  28. Griffiths, S.L.; Wood, S.J.; Birchwood, M. Vulnerability to psychosocial disability in psychosis. Epidemiology and psychiatric sciences 2018, 10.1017/s2045796018000495, 1-6, doi:10.1017/s2045796018000495.
  29. Compton, M.T.; Kelley, M.E.; Ionescu, D.F. Subtyping first-episode non-affective psychosis using four early-course features: potentially useful prognostic information at initial presentation. Early Intervention in Psychiatry 2014, 8, 50-58, doi:https://doi.org/10.1111/eip.12026.
  30. Petruzzelli, M.G.; Margari, L.; Bosco, A.; Craig, F.; Palumbi, R.; Margari, F. Early onset first episode psychosis: dimensional structure of symptoms, clinical subtypes and related neurodevelopmental markers. Eur Child Adolesc Psychiatry 2018, 27, 171-179, doi:10.1007/s00787-017-1026-7.
  31. Lecardeur, L.; Meunier-Cussac, S.; Dollfus, S. [Cognitive deficits in first episode psychosis patients and people at risk for psychosis: from diagnosis to treatment]. Encephale 2013, 39 Suppl 1, S64-71, doi:10.1016/j.encep.2012.10.011.
  32. van Os, J.; Kenis, G.; Rutten, B.P. The environment and schizophrenia. Nature 2010, 468, 203-212, doi:10.1038/nature09563.
  33. Kirkbride, J.B.; Errazuriz, A.; Croudace, T.J.; Morgan, C.; Jackson, D.; Boydell, J.; Murray, R.M.; Jones, P.B. Incidence of Schizophrenia and Other Psychoses in England, 1950–2009: A Systematic Review and Meta-Analyses. PLOS ONE 2012, 7, e31660, doi:10.1371/journal.pone.0031660.
  34. Heinz, A.; Deserno, L.; Reininghaus, U. Urbanicity, social adversity and psychosis. World Psychiatry 2013, 12, 187-197, doi:10.1002/wps.20056.
  35. Kuipers, E. Family interventions in schizophrenia: evidence for efficacy and proposed mechanisms of change. Journal of Family Therapy 2006, 28, 73-80, doi:10.1111/j.1467-6427.2006.00338.x.
  36. Baumann, P.S.; Söderström, O.; Abrahamyan Empson, L.; Söderström, D.; Codeluppi, Z.; Golay, P.; Birchwood, M.; Conus, P. Urban remediation: a new recovery-oriented strategy to manage urban stress after first-episode psychosis. Soc Psychiatry Psychiatr Epidemiol 2020, 55, 273-283, doi:10.1007/s00127-019-01795-7.
  37. Birchwood, M.; Todd, P.; Jackson, C. Early intervention in psychosis: the critical period hypothesis. The British journal of psychiatry 1998, 172, 53-59.
  38. Birchwood, M.; MacMillan, F. Early Intervention in Schizophrenia. Australian & New Zealand Journal of Psychiatry 1993, 27, 374-378, doi:10.3109/00048679309075792.
  39. Correll, C.U.; Galling, B.; Pawar, A.; Krivko, A.; Bonetto, C.; Ruggeri, M.; Craig, T.J.; Nordentoft, M.; Srihari, V.H.; Guloksuz, S., et al. Comparison of Early Intervention Services vs Treatment as Usual for Early-Phase Psychosis: A Systematic Review, Meta-analysis, and Meta-regression. JAMA Psychiatry 2018, 75, 555-565, doi:10.1001/jamapsychiatry.2018.0623.
  40. Marshall, M.; Husain, N.; Bork, N.; Chaudhry, I.B.; Lester, H.; Everard, L.; Singh, S.P.; Freemantle, N.; Sharma, V.; Jones, P.B., et al. Impact of early intervention services on duration of untreated psychosis: Data from the National EDEN prospective cohort study. Schizophrenia Research 2014, 159, 1-6, doi:https://doi.org/10.1016/j.schres.2014.07.005.
  41. Birchwood, M.; Connor, C.; Lester, H.; Patterson, P.; Freemantle, N.; Marshall, M.; Fowler, D.; Lewis, S.; Jones, P.; Amos, T., et al. Reducing duration of untreated psychosis: care pathways to early intervention in psychosis services. British Journal of Psychiatry 2013, 203, 58-64, doi:10.1192/bjp.bp.112.125500.
  42. Oliver, D.; Davies, C.; Crossland, G.; Lim, S.; Gifford, G.; McGuire, P.; Fusar-Poli, P. Can We Reduce the Duration of Untreated Psychosis? A Systematic Review and Meta-Analysis of Controlled Interventional Studies. Schizophr Bull 2018, 44, 1362-1372, doi:10.1093/schbul/sbx166.
  43. Melle, I.; Larsen, T.K.; Haahr, U.; Friis, S.; Johannessen, J.O.; Opjordsmoen, S.; Simonsen, E.; Rund, B.R.; Vaglum, P.; McGlashan, T. Reducing the Duration of Untreated First-Episode Psychosis: Effects on Clinical Presentation. Archives of General Psychiatry 2004, 61, 143-150, doi:10.1001/archpsyc.61.2.143.
  44. Gregory, A.; Mallikarjun, P.; Upthegrove, R. Treatment of depression in schizophrenia: Systematic review and meta-analysis. British Journal of Psychiatry 2017, 211, 198-204, doi:10.1192/bjp.bp.116.190520.
  45. Dondé, C.; Vignaud, P.; Poulet, E.; Brunelin, J.; Haesebaert, F. Management of depression in patients with schizophrenia spectrum disorders: a critical review of international guidelines. 2018, 138, 289-299, doi:doi:10.1111/acps.12939.
  46. Lieberman, J.A.; Phillips, M.; Gu, H.; Stroup, S.; Zhang, P.; Kong, L.; Ji, Z.; Koch, G.; Hamer, R.M. Atypical and Conventional Antipsychotic Drugs in Treatment-Naive First-Episode Schizophrenia: A 52-Week Randomized Trial of Clozapine Vs Chlorpromazine. Neuropsychopharmacology 2003, 28, 995-1003, doi:10.1038/sj.npp.1300157.
  47. Thien, K.; O'Donoghue, B. Delays and barriers to the commencement of clozapine in eligible people with a psychotic disorder: A literature review. Early Interv Psychiatry 2019, 13, 18-23, doi:10.1111/eip.12683.
  48. Taipale, H.; Tanskanen, A.; Mehtala, J.; Vattulainen, P.; Correll, C.U.; Tiihonen, J. 20-year follow-up study of physical morbidity and mortality in relationship to antipsychotic treatment in a nationwide cohort of 62,250 patients with schizophrenia (FIN20). World Psychiatry 2020, 19, 61-68, doi:10.1002/wps.20699.
  49. Morrison, A.P.; Pyle, M.; Gumley, A.; Schwannauer, M.; Turkington, D.; MacLennan, G.; Norrie, J.; Hudson, J.; Bowe, S.E.; French, P., et al. Cognitive behavioural therapy in clozapine-resistant schizophrenia (FOCUS): an assessor-blinded, randomised controlled trial. The lancet. Psychiatry 2018, 5, 633-643, doi:10.1016/S2215-0366(18)30184-6.
  50. Chakos, M.; Lieberman, J.; Hoffman, E.; Bradford, D.; Sheitman, B. Effectiveness of second-generation antipsychotics in patients with treatment-resistant schizophrenia: a review and meta-analysis of randomized trials. American Journal of Psychiatry 2001, 158, 518-526.
  51. Fowler, D.; Hodgekins, J.; French, P.; Marshall, M.; Freemantle, N.; McCrone, P.; Everard, L.; Lavis, A.; Jones, P.B.; Amos, T., et al. Social recovery therapy in combination with early intervention services for enhancement of social recovery in patients with first-episode psychosis (SUPEREDEN3): a single-blind, randomised controlled trial. The Lancet Psychiatry 2017, 10.1016/S2215-0366(17)30476-5, doi:10.1016/S2215-0366(17)30476-5.
  52. Birchwood, M.; Michail, M.; Meaden, A.; Tarrier, N.; Lewis, S.; Wykes, T.; Davies, L.; Dunn, G.; Peters, E. Cognitive behaviour therapy to prevent harmful compliance with command hallucinations (COMMAND): a randomised controlled trial. Lancet Psychiatry 2014, 1, 23-33, doi:10.1016/s2215-0366(14)70247-0.
  53. Fiszdon, J.M.; Kurtz, M.M.; Parente, L.; Choi, J. What variables predict cognitive remediation associated improvement in individuals with psychosis? Schizophr Res Cogn 2020, 19, 100148, doi:10.1016/j.scog.2019.100148.
  54. Kurtz, M.M. Neurocognition as a predictor of response to evidence-based psychosocial interventions in schizophrenia: what is the state of the evidence? Clinical psychology review 2011, 31, 663-672, doi:10.1016/j.cpr.2011.02.008.
  55. Kurtz, M.M.; Gagen, E.; Rocha, N.B.F.; Machado, S.; Penn, D.L. Comprehensive treatments for social cognitive deficits in schizophrenia: A critical review and effect-size analysis of controlled studies. Clinical Psychology Review 2016, 43, 80-89, doi:10.1016/j.cpr.2015.09.003.
  56. Allott, K.; Alvarez-Jimenez, M.; Killackey, E.J.; Bendall, S.; McGorry, P.D.; Jackson, H.J. Patient predictors of symptom and functional outcome following cognitive behaviour therapy or befriending in first-episode psychosis. Schizophrenia Research 2011, 132, 125-130, doi:https://doi.org/10.1016/j.schres.2011.08.011.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/)
Feedback