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Treatment principles

Treatment principles

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  1. Treatment principles Schizophrenia

  2. The progression of schizophrenia and functional decline Premorbid Prodromal Progression/clinical deterioration Chronic residual Healthy Illness-driven decline in functioning plateaus Clinical deterioration begins here and occurs throughout the 5–10 years before the first episode Patients may not recover from subsequent psychotic episodes as quickly or as fully as they did from previous episodes, and may experience greater degrees of residual symptomology and disability The longer the period of untreated psychosis, the worse the prognosis Number of relapses may be related to greater deterioration Onset Worsening of severity of signs and symptoms Birth 10 20 30 40 50 60 Age (years) Lieberman et al. Biol Psychiatry 2001;50(11):884–897

  3. Treatment should be optimised for each individual in order to improve the outcome • Treatment (reduce symptoms and prevent relapse) • Medications • Psychosocial interventions (e.g. cognitive behavioural therapy) Treatment and other services • Recovery • Health and wellness • Vocational and/or educational functioning • Independent living • Better physical health • Instrumental competence • Social integration • Improved quality of life • Rehabilitation (enhance adaptive skills) • Social skills training Reduces disease burden • Supports (environmental changes) • Supported housing • Supported employment Adds to treatment burden • Costs and unintended adverse consequences • Adverse events • Discrimination • Direct and indirect costs • Related health risks Adapted from: Tandon et al. J PsychiatrPract 2006;12(6):348–363

  4. Psychosocial interventions should be tailored to the goals, needs, abilities and circumstances of patients Cognitive behavioural therapy (CBT) Vocational training and support Patient needs help with Patient has Dysphoria and/or depression; stress and relapse prevention Ability and interest in working Patient Social interaction skills Integrated substance use programme Social skills training Substance use issues Family members available; ongoing treatment, monitoring of recovery, and support Consumer involvement (empowerment) in setting rehabilitation goals Medication treatment adherence and relapse prevention Family psychoeducation Psychoeducation Peer support, self-help and recovery Canadian Psychiatric Association. Can J Psychiatry 2005;50(13 Suppl. 1):7S–57S

  5. Disease phases in schizophrenia 10–45% (FES: ~10%) Resistance Any duration:a 57.3% Relapse Exacerbation 18–65% (FES: 40–87%) Response Illness severity Any duration: 44%; 7–52% (FES: 17–81%) Remission 13.5% [8–20%]b (FES: 16.6%)b Recovery Maintenance Treatment phase Acute Stabilisation aIn antipsychotic discontinuation studies; bmedian (interquartile range)FES=first-episode schizophrenia Carbon & Correll. Dialogues Clin Neurosci 2014;16(4):505–524

  6. Different phases of schizophrenia have different treatment goals • Sustain symptom remission or control (effectively treat increases in symptoms or relapses) • Maintain or improve functioning and quality of life • Continue to monitor adverse treatment effects Stablephase • Reduce stress/support and develop adaptation to life in the community • Facilitate continued reduction in symptoms and consolidation of remission • Reduce relapse risk and promote the process of recovery Stabilisationphase • Prevent harm/control disturbed behaviour • Reduce the severity of psychosis and symptoms/promote rapid return to the best level of functioning • Determine and address causes • Formulate short- and long-term treatment plans • Engage, collaborate with family/connect to community services Acutephase Adapted from: Lehman et al. Am J Psychiatry 2004;161(2 Suppl.):1–56

  7. Factors to consider when setting treatment goals Key considerations Relapse prevention1 by reducing or eliminating symptoms 3. Maximising treatment adherence1 so promoting and maintaining recovery from the debilitating effects of illness to the maximum extent possible 2. Quality of life and subjective well-being2 by maximizing quality of life and adaptive functioning Assessing positive and negative symptoms2 Managing depressive symptoms2 Minimising medication adverse events2 Adapted from: 1. Lehman et al. Am J Psychiatry 2004;161(2 Suppl.):1–56; 2. Oh et al. Korean J Schizophr Res 2014;17(2):93–99

  8. The importance of relapse prevention Long-term symptoms and disability1,2 Increased risk of suicide attempts3,4 Decrease in treatment response4 Progressive decline in brain function5 Negative impact on HRQoL6 Multiple relapses and subsequent exacerbations Increased use of healthcare resources4 Increased burden on family and caregivers4 HRQoL=Health-related quality of life 1. Birchwood et al. Adv Psychiatr Treat 2000;6(2):93–101;2. Shepherd et al. Psychol Med Monogr Suppl 1989;15:1–46;3. Ascher-Svanum et al. BMC Psychiatry 2010;10:2; 4. Kane. J Clin Psychiatry 2007;68(Suppl. 14):27–30; 5. Lieberman et al. PsychiatrServ 2008;59(5):487–496; 6. Briggs et al. Health Qual Life Outcomes 2008;6:105

  9. Antipsychotic therapy significantly reduces relapse rates Favours drug Favours placebo aWeighted by sample size of individual trials. In a meta-regression, antipsychotic drug–placebo advantages decreased with study length CI=confidence interval; NNT=number needed to treat Adapted from: Leucht et al. Lancet 2012;379(9831):2063–2071

  10. Continuous maintenance treatment may decrease deterioration in symptoms during the second year following diagnosis Survival analysis for clinical deteriorationa for patients receiving maintenance antipsychotic treatment versus intermittent treatment1 1.0 0.8 0.6 Cumulative survival 0.4 Maintenance treatment is more effective than targeted intermittent treatment in preventing relapse1 Intermittent treatment (n=21) 0.2 Maintenance treatment (n=23) 0.0 30 weeks 50 weeks 10 weeks Time in second year of study aIncrease from baseline in the sum of PANSS positive and negative scores ≥25%, or ≥10 points (if baseline value ≤40), or a CGI-C score ≥6;CGI-C=Clinical Global Impression – Change; PANSS=Positive and Negative Syndrome Scale 1. Gaebel et al. J Clin Psychiatry 2011;72(2):205–218

  11. Only a small proportion of patients with schizophrenia achieve recovery A 3-year observational study of adults with schizophrenia (n=6,642)1 Long-lasting symptomatic remission Defined as CGI-SCH positive, negative, cognitive, and overall severity score <4, plus no inpatient admission for ≥24 months Long-lasting adequate quality of life Defined as ≥70 on the EQ-5D VAS for ≥24 months Long-lasting functional remission Defined as employed/student/housewife, plus independent living, plus active social interactions for ≥24 months Recovery, defined as all 3 of the above Employment, independent living, social activity, and medicationadherencewere important predictors of recovery1 CGI-SCH=Clinical Global Impression – Schizophrenia;EQ-5D VAS=EuroQoL5 dimensions visual analogue scale 1. Novick et al. Schizophr Res 2009;108(1–3):223–230

  12. Selecting the most suitable treatment – minimal adverse events and maximum adherence

  13. Selecting suitable treatments for schizophrenia can pose a dilemma for psychiatrists In selecting treatments for schizophrenia, physicians consider variables related to the:1,2 An ‘ideal’ medication is one that can:2 • Treat psychosis • Lead to symptom resolution • Lead to remission • Overcome treatment resistance • Effectively protect against relapse • Have a benign adverse-event profile (with minimal sedation and akathisia) • Have efficacy for symptoms of anxiety and depression Illness • Patient Medication Environment The long-term nature of adverse events, including metabolic, endocrine and cardiac complications, can pose a dilemma for physicians in providing effectivetreatment while avoiding adverse events3 Physicians have to consider how adverse events interact with the patient’s health and lifestyle (e.g., age, weight, cardiovascular health, co-prescribed medications, previously experienced adverse events)4-6 1. Kane et al. Dialogues Clin Neurosci 2010;12(3):345–357; 2. Correll. J Clin Psychiatry 2011;72(Suppl. 1):9–13; 3. Abidi et al. Can J Psychiatry 2003;48(11):749‒755; 4. Leucht et al. Lancet 2013;382(9896):951‒962; 5. Uçok et al. World Psychiatry 2008;7(1):58‒62; 6. Barnes et al. J Psychopharmacol 2011;25(2):567‒620

  14. Guidelines for good practice are measurement-based and individualised Ongoing, careful monitoring is critical1-3 • Reliable and repeated assessment of the efficacy of treatment using defined treatment targets is important1,2 • Using standard rating scales such as BPRS and PANSS will facilitate this goal3 • Careful assessment of possible adverse effects of treatment1,3 • Ongoing collaboration with patient in decision-making2 Standard protocols should be customised in response to individual vulnerabilities/needs and specific drug1 BPRS=Brief Psychiatric Rating Scale; PANSS=Positive and Negative Syndrome Scale 1. Canadian Psychiatric Association. Can J Psychiatry 2005;50(13 Suppl. 1):7S–57S [CPA Guidelines];2. Lehman et al. Am J Psychiatry 2004;161(Suppl. 2):1–56 [APA Practice Guidelines];3. Hasan et al. World J Biol Psychiatry 2013;14(1):2–44 [WFSBP guidelines]

  15. Treatment of schizophrenia needs a rational approach with minimal tolerability issues to optimise patient functioning APA guidelines NICE guidelines APA guidelines recommend choosing a medication that offers good clinical response without intolerable adverse events1 NICE guidelines recommend regular monitoring of adverse events systematically throughout treatment, and especially during the titration phase2 Patients who experience serious adverse events may decide that the adverse events outweigh the benefits of medication1 Antipsychotics that minimise EPS, cardiovascular risk, and activating and sedating adverse events may optimise the physical health and social functioning of patients with schizophrenia APA=American Psychiatric Association; EPS=extrapyramidal symptoms; NICE=National Institute for Health and Care Excellence 1. Lehman et al. Am J Psychiatry 2004;161(Suppl. 2):1–56; 2. Kuipers et al. Psychosis and schizophrenia in adults. NICE clinical guideline 178. 2014

  16. 1.3.4.1 For people with first episode psychosis offer: - Oral antipsychotic medication in conjunction with - Psychological interventions (family intervention and individual CBT)1.4.2.1 For people with an acute exacerbation or recurrence of psychosis or schizophrenia offer: - Oral antipsychotic medication - Psychological interventions (family intervention and individual CBT) CBT=cognitive behavioural therapy NICE. Psychosis and schizophrenia in adults: prevention and management. NICE clinical guideline 178. 2014

  17. Choice of antipsychotic medication1.3.5.1 The choice of antipsychotic medication should be made by the service user and healthcare professional together, taking into account the views of the carer if the service user agrees. Provide information and discuss the likely benefits and possible side effects of each drug, including: - Metabolic (including weight gain and diabetes) - Extrapyramidal (including akathisia, dyskinesia, and dystonia) - Cardiovascular (including prolonging the QT interval) - Hormonal (including increasing plasma prolactin) - Other (including unpleasant subjective experiences) NICE. Psychosis and schizophrenia in adults: prevention and management. NICE clinical guideline 178. 2014

  18. Antipsychotics should be chosen individually, respecting the patient’s mental and somatic condition with special attention to side effectsThe selection of an antipsychotic medication should be guided by the patient’s previous experience of symptom response and side effects, intended route of administration, the patient’s preferences for a particular medication, the presence of comorbid medical conditions, and potential interactions with other prescribed medications. Special attention needs to be given to antipsychotic-related side effects Hasan et al. World J Biol Psychiatry 2012; 13 (5): 318–378

  19. Shared decision-making and patient centered care lead to better health outcomes • Shared decision-making is a process in which clinicians and patients work together to make decisions about care and treatment based on clinical evidence and the patient’s informed preferences1 • A central part of shared decision-making is the recognition that patients and clinicians bring different, but equally important, knowledge and expertise to the process:1,2 Diagnosis Social circumstances Clinician’sexpertise Patient’sexpertise Disease aetiology Attitude to risk Prognosis Values Treatment options Preferences Outcome probabilities Experience of illness When patients are involved in decisions about their health and care, the decisions are better, health and health outcomes improve, and resources are allocated more efficiently1 1. Foot et al. People in control of their own health and care. The King’s Fund. 2014; 2. Coulter & Collins. Making shared decision-making a reality. The King’s Fund. 2011

  20. Efficacy for positive and negative symptoms are higher priorities than tolerability for physicians when choosing a treatment Common reasons for selecting an antipsychotic reported by 872 European and US physicians1 31–40% of patients 0–10% of patients Familiarity with drug Reduced agitation Reduced risk of tardive dyskinesia Reduced risk of QTc irregularity 11–30% of patients Improved compliance Reduced aggression Patient responded previously Tried and tested Effect on mood/ affective symptoms Reduced risk of cognitive impairment Efficacy in refractory patients 41–60% of patients 61–100% of patients Effect on positive symptoms (91%) Reduced risk of EPS/parkinsonism Well tolerated Complete symptom control Reduced risk of weight gain Avoidance of sedation Induction of sedation Effect on negative symptoms (62%) Improvement in cognitive function Patient acceptability n=6,523 EPS=extrapyramidal symptoms Lecrubier et al. Eur Psychiatry 2007;22(6):371–379

  21. Negative symptoms and the treatment of schizophrenia • Negative symptoms impact greatly on a person’s quality of life, and affect their ability to experience many life-fulfilling activities1 • However, negative symptoms are unlikely to result in the person’s hospitalisation, or to the person coming into contact with the criminal justice system1 • Negative symptoms have an economic cost to society:1 • They prevent a large number of people with schizophrenia from working • They result in a substantial economic cost added to the emotional and psychological burden on patients, carers, and healthcare professionals • Diagnosing schizophrenia can be challenging for the healthcare professional, and complex for the patient to understand1 • The identification and quantification of negative symptoms, in practice, can be a overwhelming task because:1,2 • There is an inherent subjectivity to negative symptoms, and they can be mistaken for other mental illnesses • There is an obvious discomfort for the healthcare professional when identifying the ‘lack’ of something 1. Living with schizophrenia website. https://www.livingwithschizophreniauk.org/information-sheets/negative-symptoms-understanding/;2. Mitra et al. Ind Psychiatry J 2016;25(2):135–144

  22. Depressive symptoms and the treatment of schizophrenia • Individuals living with schizophrenia are commonly affected by depression:1 • Some experience episodic major depression • Some experience mild depression symptoms on a chronic basis • In schizophrenia, depression may impact the motivation to perform potentially reinforcing acts, possibly through the induction of anhedonia1 • Depression has a major adverse impact on everyday functioning1 Improving the recognition and management of depressive symptoms may reduce the adverse impact of severe mental illness on everyday functioning1 1. Harvey. Innov Clin Neurosci 2011;8(10):14–18

  23. Negative feelings towards medication are associated with lower scores in both affect and self-esteem quality of life subscales Effects of sociodemographic variables, psychopathology, antipsychotic-induced adverse events, and attitude toward medication on QoL (multiple linear regression analysis)1 • General life satisfaction • Work, p<0.01 • Cognitive symptoms (PANSS), p<0.001 • Affect • Work, p<0.001 • General life satisfaction • Depression/anxiety (PANSS), p<0.05 • Parkinsonism, p<0.05 • Affect • Negative feelings and effects (DAI), p<0.01 • Self-esteem • Depression/anxiety (PANSS), p<0.01 • Parkinsonism, p<0.001 • Negative feelings and effects (DAI), p<0.05 Positive correlation of variable with QoL subscale Negative correlation of variable with QoL subscale Lancashire QoL profile subscales: General life satisfaction, Affect, Self-esteem DAI=Drug Attitude Inventory; PANSS=Positive and Negative Syndrome Scale; QoL=quality of life 1. Hofer et al. J Clin Psychiatry 2004;65(7):932–939

  24. Adverse events are associated with lower adherence • In a survey of patients with schizophrenia (n=876), the adjusted odds ratios for the impact of each adverse event on complete adherence were significant for the following variables: Odds ratio 0.00–0.50 Odds ratio 0.51–1.00 • Agitation • Decreased interest in sex • Difficult or painful menstrual periods • Insomnia • Nausea/vomiting • Restlessness/feeling jittery • Constipation • Dizziness • Increase in blood glucose levels • Male breast enlargement or secretions • Sedation • Sexual dysfunction • Sleepiness • Tremors • Weight gain Experiencing adverse events of medication increases the risk of non-adherence Adherence defined as a score of zero on the Morisky Medication Adherence Scale DiBonaventura et al. BMC Psychiatry 2012;12:20

  25. Adherence to antipsychotic therapy • Individual studies have reported that a majority of patients become non-adherent within 1–2 years of discharge from hospital1 • Mean rates of adherence ranging from 47–95%have been reported in a systematic review of studies of antipsychotic medication1 Ensuring continuous delivery of antipsychotic medication in schizophrenia constitutes a significant challenge1-3 1. Sendt et al. Psychiatry Res 2015;225(1–2):14–30; 2. Tiihonen et al. Am J Psychiatry 2011;168(6):603–609; 3. Ascher-Svanum et al. J Clin Psychiatry 2006;67(7):1114–1123

  26. The risks and consequences of non-adherence • In one study of antipsychotic discontinuation in a cohort of 2,588 patients in Finland, only 58% of patients collected a prescription for an antipsychotic therapy within 30 days of being discharged from hospital1 Adherence rates in a large nationwide cohort study in Finland1 Systematic review of the rate of recurrence following a remission from a first episode of non-affective psychosis2 Continued their initial treatment for 30 days or longer following discharge from hospital Collected an antipsychotic prescription during the first 30 days after hospital discharge The risk of symptom recurrence in remitted patients following discontinuation of antipsychotic therapy is high2 1. Tiihonen et al. Am J Psychiatry 2011;168(6):603–609; 2. Zipursky et al. Schizophr Res 2014;152(2–3):408–414

  27. Improving adherence with LAIs can lead to improved outcomes Meta-analysis of 116 publications of LAI versus oral formulations of antipsychotic therapy1 Favours drug Favours placebo Mirror image studies Cohort studies • A meta-analysis of mirror-image studies showed that LAIs were superior to oral antipsychotics in:2 • Preventing hospitalisation (16 studies, n=4,066):risk ratio: 0.43 (95% CI: 0.35, 0.53); p<0.001 • Reducing the number of hospitalisations(15 studies, 6,342 person-years):rate ratio: 0.38 (95% CI: 0.28, 0.51); p<0.001 • A meta-analysis of prospective and retrospective cohort studies showed that LAIs were superior to oral antipsychotics in:3 • Decreasing hospitalisation rates (15 studies, 68,009 person-years): rate ratio: 0.85 (95% CI: 0.78–0.93); p<0.001 • Improving discontinuation rates (10 studies, n=37,293):risk ratio: 0.78 (95% CI: 0.67–0.91); p=0.001 CI=confidence interval; LAI=long-acting injectable; RCT=randomised controlled trial 1. Adapted from: Leucht et al. Lancet 2012;379(9831):2063–2071;2. Kishimoto et al. J Clin Psychiatry 2013;74(10):957–965; 3. Kishimoto et al. Schizophr Bull 2018;44(3):603–619

  28. Take home points • A key challenge for physicians is to choose an antipsychotic that effectively controls symptoms, while minimising adverse events – however, physicians typically prioritise efficacy for positive and negative symptoms • Adverse events are associated with lower adherence to treatment • Non-adherence to antipsychotic therapy is common, and increases the risk of psychotic relapse • LAI formulations increase adherence rates, and reduce the risk of relapse LAI=Long-acting injectable

  29. How do adverse events impact a patient’s functioning? …are these adverse events a necessary compromise for continued symptom control?

  30. Adverse events can impose a significant burden on patients In a study of 1,825 participants with psychosis1 • Adverse events impair a patient’s functional ability, reducing quality of life1,2 • If not addressed, antipsychotic adverse events can cause long-term distress and contribute to chronic health complications3 • A small shift in functional status may have marked effects on an individual’s quality of life2 Reported impairment intheir daily life as a result of medication adverse events Reported medication adverse events Reported moderate or severe impairment 1. Morgan et al. Aust N Z J Psychiatry 2012;46(8):735–752;2. Awad et al. Acta Psychiatr Scand Suppl 1994;380:27–32;3. Barnes et al. J Psychopharmacol 2011;25(5):567–620

  31. Adverse events can be classified into different groups Anxiety Restlessness Sedation Somnolence Agitation Insomnia Hypersomnia Activating Sedating Akathisia Fatigue Antipsychotic-induced adverse events1-5 Cardiac arrhythmias Parkinsonism Extrapyramidal symptoms Cardiovascular QT interval prolongation Dyskinesia Dystonia Hyperglycaemia Hyperlipidaemia Sexual dysfunction Sexual/endocrine Metabolic Weight gain Metabolic syndrome Diabetes mellitus Hyperprolactinaemia 1. UpToDate website. https://www.uptodate.com/contents/second-generation-antipsychotic-medications-pharmacology-administration-and-side-effects. Accessed April 2019; 2. Lehman et al. Am J Psychiatry 2004;161(Suppl. 2):1–56; 3. Lieberman et al. N Engl J Med 2005;353(12):1209–1223; 4. Kane et al. Schizophr Res 2016;174(1–3):93–98;5. Cheng-Shannon et al. J Child AdolescPsychopharmacol 2004;14(3):372–394; 6. Citrome. J Clin Psychopharmacol 2017;37(2):138–147

  32. There are multiple clinical benefits of a low risk of extrapyramidal symptoms Reduced negative symptoms Enhanced compliance Reduced extrapyramidal symptoms Lower tardive dyskinesia risk Less impaired cognition Less dysphoria Fewer motor adverse events Note: All antipsychotic drugs carry a significant risk for extrapyramidal symptoms for which active management is recommended. While antipsychotics have been shown to contribute to the these adverse events, each drug has its own specific risk profile Tandon & Jibson. Ann Clin Psychiatry 2002;14(2):123–129

  33. Akathisia is associated with emotional symptoms and cognitive impairment Mental control3 Reduced self-esteem1 Anxiety2 Emotional symptoms Cognitive impairment Associate learning3 Obsessive–compulsive3 Selective attention2 Somatization3 Discrimination2 Depression3 Perception2 Paranoid ideation3 Coping responses2 Severe subjective distress3 1. Hofer et al. J Clin Psychiatry 2004;65(7):932–939; 2. Kim & Byun. J Clin Pharm Ther 2007;32:461–467; 3. Kim et al. Compr Psychiatry 2002;43(6):456–462

  34. Gastrointestinal adverse events can occur with antipsychotics Gastrointestinal adverse events that can occur with antipsychotics include:1 • Dyspepsia • Vomiting • Nausea • Oesophageal dysmotility • Hypersalivation • Dry mouth • Constipation • In a retrospective study of 273 patients with schizophrenia, over a period of 22 months:2 36.3% had at least 1 pharmacological intervention for constipation 1. MHRA Antipsychotics learning module 2015. Available at: http://www.mhra.gov.uk/antipsychotics-learning-module/con155606?useSecondary=&showpage=8, Accessed April 2019; 2. De Hert et al. BMC Gastroenterol 2011;11:17

  35. Weight gain can occur with antipsychotics • Weight gain has been ranked among the most bothersome of the antipsychotic adverse events – by patients with schizophrenia, and by physicians1 • Weight gain has been associated with drug affinity for the H1 receptor; affinity for the D2, 5-HT1A, 5-HT2C, and adrenergic α2 receptors have also been implicated2 • A meta-analysis identified 257 publications of clinical trials reporting weight change3 • The majority of the publications were trials where patients were switched between different antipsychotics3 • All but 3 specific antipsychotics showed a degree of weight gain after prolonged use, however, switching to one of these 3 antipsychotics did not result in weight loss3 Virtually all antipsychotics cause weight gain, which is a bothersome adverse event1,3 1. Llorca et al. BMC Psychiatry 2017;17(1):67; 2. Nasrallah. Mol Psychiatry 2008;13(1):27–35; 3. Bak et al. PLOS One 2014;9(4):e94112

  36. Some antipsychotics are associated with high rates of sedating adverse events, which can worsen outcomes Antipsychotic-induced sedating adverse events have been associated with: Medication non-adherence2 Reduced cognitive performance and functional capacity1 Risk of unintentional injury3 Concerns over the safety of dependants,4 particularly as women are more sensitive to sedative effects5 For agitated patients, sedating adverse events and true antipsychotic effects are sometimes incorrectly thought to be the same6 Sedation may be considered necessary for controlling positive symptoms; however, selecting a less sedating antipsychotic for patients who experience excessive sleeping can improve outcomes7 1. Loebel et al. CNS Spectr 2014;19(2):197–205; 2. DiBonaventura et al. BMC Psychiatry 2012;12:20; 3. Said et al. Pharmacoepidemiol Drug Saf 2008;17(4):354–364; 4. Seeman. Psychiatr Q 2012;83(1):83–89; 5. Lindberg et al. Int Clin Psychopharmacol 2002;17(4):177–184; 6. Miller. CurrPsychiatr 2007;6(8):38–51; 7. Miller et al. Prim Care Companion J Clin Psychiatry 2004;6(Suppl. 2):3–7

  37. Sedation impacts patient functioning and caregiver burden Patient Caregiver “No energy” “They do not want to get out of bed or participate in activities” “Constantly feel tired” “Cannot think clearly” Effects of patient sedation can increase caregiver burden Patients may also have impaired cognitive and motor performance and increased risk of injury Persistent sedation or somnolence1 Impacts on patient’s quality of life1,2 Patient discontinues treatment, or becomes non-adherent1 Dissatisfaction with medication1 Functional impairments in vocational, academic, social and recreational activities1 1. Kane & Sharif. J Clin Psychiatry 2008;69(Suppl. 1):18–31; 2. Hofstetter et al. BMC Psychiatry 2005;5:13

  38. Activating and sedating effects are among the most ‘bothersome’ antipsychotic adverse events EPS/activating*** Sedating/cognition* Prolactin/endocrine* Metabolic** GI In this cross-sectional study (n=876), 86.2% of patients with schizophrenia reported the presence of any medication adverse event *p<0.05, **p<0.01, ***p<0.001 for the association with a lower likelihood of adherenceEPS=extrapyramidal symptoms; GI=gastrointestinal DiBonaventura et al. BMC Psychiatry 2012;12:20

  39. Medication adverse events can impair workplace performance and act as a barrier to entering or returning to work In a focus group of patients with schizophrenia, stigma of adverse events was most felt in employment and occupation; adverse events led to some individuals reducing their dose or skipping regular medication1 Consequence of schizophrenia Perception by others Flight of ideas Lack of concentration ‘Lazy’ ‘Pretending’ Tiredness Muscle rigidity and clumsiness ‘Addiction problems’ ‘Ridiculous’ Treatment adverse events, symptoms and risk of relapse may make entering or returning to work difficult2 • The onset of schizophrenia during the teens and early twenties can interrupt:2 • Education • Early career • Transition to independent living Employers and colleagues may be cautious of working with someone with schizophrenia due to negativemisconceptions of their ability and/or nature2 1. Novak & Švab. PsychiatrDanub 2009;21(1):99–102;2. Steadman. Working with schizophrenia: employment, recovery and inclusion in Germany. The Work Foundation. 2015

  40. Emotional and practical burdens of schizophrenia on families are intertwined Difficulties in meeting practical demands e.g., frustration Negative emotional response e.g., anxiety e.g., financial burden Patient symptoms aggravated e.g., further attempts to find employment are more difficult The subjective burden of social stigma for relatives of patients includes feelings of frustration, anxiety, low self-esteem and helplessness Tsang et al. Int J Rehabil Res 2003;26(2):123–130

  41. Take home points • Treatment adverse events – including activating, sedating, cardiovascular, metabolic, sexual, and endocrine effects, and extrapyramidal symptoms – are burdensome for patients, reducing functioning and quality of life • Some antipsychotics are associated with sedation, which worsens outcomes and increases caregiver burden • The adverse-event burden of antipsychotics reduces patient functioning, and can act as a barrier to entering or returning to work EPS=extrapyramidal symptoms

  42. The importance of early intervention for patients with schizophrenia

  43. Association between DUP and symptom severity at first treatment contact 1 study 1 study 1 study 2 studies 3 studies 2 studies 5 studies 6 studies Studies with positive effect size (Hedge’s gu >0.0) Studies with negative effect size (Hedge’s gu ≤0.0) In this meta-analysis of 43 studies, DUP was associated only with the severity of negative symptoms – not severity of global psychopathology, positive symptoms, or neurocognitive functioning DUP=duration of untreated psychosis Adapted from: Perkins et al. Am J Psychiatry 2005;162(10):1785–1804

  44. Association between DUP and treatment response 4 studies 4 studies 5 studies 7 studies Studies with positive effect size (Hedge’s gu >0.0) Studies with negative effect size (Hedge’s gu ≤0.0) In this meta-analysis of 43 studies, a shorter DUP was associated with greater response to antipsychotic treatment, as measured by severity of global psychopathology, positive symptoms, negative symptoms, and functional outcomes DUP=duration of untreated psychosis Adapted from: Perkins et al. Am J Psychiatry 2005;162(10):1785–1804

  45. Patients with long DUP were less likely to achieve remission Odds of no remission in the long versus short DUP groups Favours short DUP In this systematic review of patient outcomes, short DUP was associated with greater chance of remission CI=confidence interval; DUP=duration of untreated psychosis; GAF=Global Assessment of Functioning; PANSS=Positive and Negative Syndrome Scale; SAPS=Scale for the Assessment of Positive Symptoms; WHO=World Health Organization Marshall et al. Arch Gen Psychiatry 2005;62(9):975–983

  46. Shorter DUP leads to improved outcomes in patients with first-episode schizophrenia Patients relapsed within 1 year1 Patients with a favourablea illness course2 Shorter duration of untreated illness was associated with lower relapse rates Shorter DUP was associated with favourable course of illness aUnfavourable course defined as ‘continuous’ plus ‘episodic with intercritical residual symptoms’ according to DSM-IV-TR; favourable course defined as ‘episodic without intercritical residual symptoms’, plus ‘single episodes in partial remission’, and ‘single episode in full remission’DSM-IV-TR=Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision; DUP=duration of untreated psychosis 1. Owens et al. Br J Psychiatry 2010;196(4):296–301; 2. Primavera et al. Ann Gen Psychiatry 2012;11(1):21

  47. Early intervention services versus treatment as usual • In 10 studies among 2,105 patients, the risk of ≥1 psychiatric hospitalisation was significantly lower with early intervention studies than treatment as usual: • This equates to a number needed to treat (NNT) of 10.1 (95% CI: 6.4, 23.9), p=0.001 Risk of ≥1 psychiatric hospitalisation 42.4% 32.3% Risk ratio: 0.74 (95% CI: 0.61, 0.90), p=0.003 versus Early intervention Treatment as usual Adapted from: Correll et al. JAMA Psychiatry 2018;75(6):555–565

  48. Summary

  49. Summary Improved patient functioning and improved quality of life are important treatment goals at all stages of schizophrenia management Functional impairment may be the result of an insufficient treatment effect Agents with different pharmacological profiles may avoid the current treatment compromises, and help patients with schizophrenia to function at their optimal level The limitations of current treatments, e.g., the adverse-event burden, can be frustrating for all involved and can decrease quality of life Sedating or activating adverse events can prevent patients from functioning at their optimal level and can negatively impact their quality of life The adverse events associated with current treatments are often seen as a necessary compromise for continued symptom control For references, please see slide notes