Treatment principles Schizophrenia.

Treatment principles Schizophrenia

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 In most patients, the formal onset of schizophrenia is preceded by a period of symptoms, known as the prodromal period.[Lieberman et al., 2001] Symptoms in this stage can include mood disturbances and cognitive symptoms, as well as positive symptoms.[Lieberman et al., 2001; McGlashan, 1996] Treatment with antipsychotic therapy can ameliorate psychotic symptoms, and maintenance therapy is effective in preventing relapse.[Lieberman et al., 2001] Because the clinical deterioration of schizophrenia may begin in the prodromal phase, early identification is important to allow timely intervention.[Lieberman et al., 2001; McGlashan, 1996] References: Lieberman JA, Perkins D, Belger A, et al. The early stages of schizophrenia: speculations on pathogenesis, pathophysiology, and therapeutic approaches. Biol Psychiatry 2001; 50 (11): 884–897. McGlashan TH. Early detection and intervention in schizophrenia: research. Schizophr Bull 1996; 22 (2): 327–345. Birth 10 20 30 40 50 60 Age (years) Lieberman et al. Biol Psychiatry 2001;50(11):884–897

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 Costs and unintended adverse consequences Adverse events Discrimination Direct and indirect costs Related health risks Key message: Treatment outcomes can be optimised for an individual by skilful utilisation and coordination of pharmacological, psychosocial, and educational resources. Background A clinically effective treatment is characterised by:1 long-term reduction in symptoms of disease, treatment burden (adverse events), and impact of the disease on the patient and members of his or her social circle sustained adherence by the patient to the prescribed treatment regimen long-term increase in healthy behaviours and restoration of wellness Skilful utilisation and coordination of available pharmacological, psychosocial, and educational resources targeted to each patient’s personal situation, goals, and current phase of illness can ultimately maximise clinical effectiveness across all four of the outcome domains (symptoms of disease, treatment burden, disease burden, and overall health and wellness).1 A recovery orientation, along with a culture of setting specific treatment goals, selecting treatments with a larger evidence base, and monitoring the individual patient’s response to treatment in a reliable and explicit manner serve to minimise disease burden (while adding minimal treatment burden) in order to maximise the health and wellness of the individual patient.1 Reference: 1. Tandon R, Targum SD, Nasrallah HA, et al. Strategies for maximizing clinical effectiveness in the treatment of schizophrenia. J Psychiatr Pract 2006; 12 (6): 348–363. Adds to treatment burden Adapted from: Tandon et al. J Psychiatr Pract 2006;12(6):348–363

Psychosocial interventions should be tailored to the goals, needs, abilities and circumstances of patients Vocational training and support Cognitive behavioural therapy (CBT) Patient has Patient needs help with 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 Medication treatment adherence and relapse prevention Consumer involvement (empowerment) in setting rehabilitation goals Key message: Psychosocial interventions should be tailored to the carefully assessed goals, needs, abilities, and circumstances of individuals rather than assuming a ‘one size fits all’ approach. Background Psychosocial interventions work synergistically with medication to optimise treatment adherence and successful community living.1 Optimal management requires the integration of medical and psychosocial interventions.1 Such interventions should not be seen as competing approaches but, in most cases, as necessary complementary interventions to improve clinical symptoms, functional outcome and quality of life.1 Effective psychosocial interventions may improve medication adherence, reduce risk of relapse and the need for readmission to hospital, reduce distress resulting from symptoms, improve functioning and quality of life, and provide support for patients, their families and caregivers.1 Common comorbid conditions such as substance abuse, anxiety disorders, and depression need to be recognised and addressed with psychosocial interventions.1 Reference: 1. Canadian Psychiatric Association. Clinical practice guidelines. Treatment of schizophrenia. Can J Psychiatry 2005; 50 (13 Suppl. 1): 7S–57S. Family psychoeducation Psychoeducation Peer support, self- help and recovery Canadian Psychiatric Association. Can J Psychiatry 2005;50(13 Suppl. 1):7S–57S

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 The slide summarises the main phases of schizophrenia, and the frequency of patients transitioning between phases based on a wide-ranging literature review.[Carbon & Correll, 2014] After reviewing the literature, the authors conclude that a key problem in understanding the course of schizophrenia is the differences in definitions and concepts used to identify the various stages.[Carbon & Correll, 2014] However, the review did identify the duration of untreated psychosis as a modifiable risk factor that clinicians can act upon now, as well as nonadherence to antipsychotic medications, and certain comorbidities.[Carbon & Correll, 2014] Reference: Carbon M, Correll CU. Clinical predictors of therapeutic response to antipsychotics in schizophrenia. Dialogues Clin Neurosci 2014; 16 (4): 505–524. Recovery Acute Stabilisation Maintenance Treatment phase aIn antipsychotic discontinuation studies; bmedian (interquartile range) FES=first-episode schizophrenia Carbon & Correll. Dialogues Clin Neurosci 2014;16(4):505–524

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 Stable phase 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 Stabilisation phase 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 According to the American Psychiatric Association guidelines on the treatment of schizophrenia, the goals of treatment are adapted to the stage of the illness.[Lehman et al., 2010] Acute phase The goals of treatment during the acute phase of a psychotic exacerbation are to prevent harm, control disturbed behaviour, reduce the severity of psychosis and associated symptoms (e.g., agitation, aggression, negative symptoms, affective symptoms), determine and address the factors that led to the occurrence of the acute episode, effect a rapid return to the best level of functioning, develop an alliance with the patient and family, formulate short- and long-term treatment plans, and connect the patient with appropriate aftercare in the community.[Lehman et al., 2010] Stabilisation phase During the stabilisation phase, the aims of treatment are to sustain symptom remission or control, minimise stress on the patient, provide support to minimise the likelihood of relapse, enhance the patient’s adaptation to life in the community, facilitate the continued reduction in symptoms and consolidate remission, and promote the process of recovery.[Lehman et al., 2010] Stable phase Treatment during the stable phase is designed to sustain symptom remission or control, minimise the risk and consequences of relapse, and optimise functioning and the process of recovery.[Lehman et al., 2010] Reference: Lehman AF, Lieberman JA, Dixon LB, et al.; American Psychiatric Association: steering committee on practice guidelines. Practice guideline for the treatment of patients with schizophrenia, second edition. Am J Psychiatry 2004; 161 (2 Suppl.): 1–56. Acute phase Adapted from: Lehman et al. Am J Psychiatry 2004;161(2 Suppl.):1–56

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 Because schizophrenia is a chronic illness that influences virtually all aspects of life of the affected persons, treatment planning has three goals:[Lehman et al., 2010] 1) reduce or eliminate symptoms 2) maximise quality of life and adaptive functioning 3) promote and maintain recovery from the debilitating effects of illness to the maximum extent possible. Accurate diagnosis has enormous implications for short- and long-term treatment planning, and it is essential to note that diagnosis is a process rather than a one-time event.[Lehman et al., 2010] As new information becomes available about the patient and his or her symptoms, the patient’s diagnosis should be re-evaluated, and, if necessary, the treatment plan should be changed.[Lehman et al., 2010] Reference: Lehman AF, Lieberman JA, Dixon LB, et al.; American Psychiatric Association: steering committee on practice guidelines. Practice guideline for the treatment of patients with schizophrenia, second edition. Am J Psychiatry 2004; 161 (2 Suppl.): 1–56. Other reference used on slide: Oh J, Ko YH, Paik JW, et al. Variables influencing subjective well-being in patients with schizophrenia. Korean J Schizophr Res 2014; 17 (2): 93–99. 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

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 As shown on the slide, there are many functional consequences of relapse, including long-term disability, an increased risk of suicide, decline in cognitive function, and decreased quality of life.[Ascher- Svanum et al., 2010; Birchwood et al., 2000; Briggs et al., 2008; Lieberman et al., 2008; Kane, 2007] It is increasingly clear that patients with schizophrenia are a heterogenous group in each domain of recovery.[Lieberman et al., 2008] A limitation of the current approach to therapy is the lack of a consistent and specific terminology to allow communication between advocates, researchers, and policy makers.[Lieberman et al., 2008] Coupled with the current incomplete understanding of the pathophysiology of schizophrenia, this has led some to pessimistically predict that in the immediate future, therapies are likely to be restorative for some patients, ameliorative for most, but ineffective for some.[Lieberman et al., 2008] References: Ascher-Svanum H, Zhu B, Faries DE, et al. The cost of relapse and the predictors of relapse in the treatment of schizophrenia. BMC Psychiatry 2010; 10: 2. Birchwood M, Spencer E, McGovern D. Schizophrenia: early warning signs. Adv Psychiatr Treat 2000; 6 (2): 93–101. Briggs A, Wild D, Lees M, et al. Impact of schizophrenia and schizophrenia treatment-related adverse events on quality of life: direct utility elicitation. Health Qual Life Outcomes 2008; 6: 105. Kane JM. Treatment strategies to prevent relapse and encourage remission. J Clin Psychiatry 2007; 68 (Suppl. 14): 27–30. Lieberman JA, Drake RE, Sederer LI, et al. Science and recovery in schizophrenia. Psychiatr Serv 2008; 59 (5): 487–496. Shepherd M, Watt D, Falloon I, Smeeton N. The natural history of schizophrenia: a five-year follow-up study of outcome and prediction in a representative sample of schizophrenics. Psychol Med Monogr Suppl 1989; 15: 1–46. 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. Psychiatr Serv 2008;59(5):487–496; 6. Briggs et al. Health Qual Life Outcomes 2008;6:105

Antipsychotic therapy significantly reduces relapse rates
Parameter No. of studies included Drug group Control group Mean study duration, monthsa Risk ratio (95% CI) NNT (95% CI) Relapse 7–12 months 24 392/1,465 (27%) 773/1,204 (64%) 11 0.40 (0.33–0.49) 3 (2–3) Relapse independent of duration 62 744/3,395 (22%) 1,718/2,997 (57%) 9 0.35 (0.29–0.41) Participant readmitted to hospital 16 112/1,132 (10%) 245/958 (26%) 13 0.38 (0.27–0.55) 5 (4–9) Dropout for any reason 57 802/2,642 (30%) 1,130/2,076 (54%) 0.53 (0.46–0.61) 4 (3–6) Dropout because of inefficacy 46 412/2,539 (16%) 830/2,007 (41%) 8 0.37 (0.31–0.44) 4 (3–5) A systematic review and meta-analysis, published in 2012, identified 116 reports from 65 trials of antipsychotic therapy in patients with schizophrenia.[Leucht et al., 2012] This information amounted to data for 6,493 patients.[Leucht et al., 2012] The results demonstrated that maintenance antipsychotic therapy has benefits for patients, including reduced risk of relapse, improved quality of life, and reduced aggressive acts.[Leucht et al., 2012] However, the authors caution that the benefits of antipsychotics must be weighed against the risk of adverse events.[Leucht et al., 2012] Reference: 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 (9831): 2063–2071. 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

Time in second year of study
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 0.4 0.2 0.0 Cumulative survival 10 weeks 30 weeks 50 weeks Time in second year of study Intermittent treatment (n=21) Maintenance treatment (n=23) Maintenance treatment is more effective than targeted intermittent treatment in preventing relapse1 Key message: Continuous maintenance treatment is more effective than targeted intermittent treatment in preventing relapse. Background This randomised controlled trial investigated the impact of continuous maintenance treatment versus targeted intermittent treatment after stepwise discontinuation in the second year following the diagnosis of schizophrenia.1 A total of 96 first-episode patients were enrolled from the German Research Network on Schizophrenia, and 44 were assigned to treatment.1 Participants assigned to the maintenance treatment arm in the second year of the trial demonstrated lower risk of relapse and a higher survival rate from deterioration than those assigned to intermittent treatment.1 Clinical deterioration: Increase from baseline in the sum of Positive and Negative Syndrome Scale (PANSS) positive and negative scores ≥25%, or ≥10 points (if baseline value ≤40), or a Clinical Global Impression – Change (CGI-C) score ≥6.1 Mean survival time (Kaplan–Meier estimates): intermittent treatment 41.0 weeks; maintenance treatment 50.0 weeks; log rank=13.4; p< Reference: 1. Gaebel W, Riesbeck M, Wölwer W, et al. Relapse prevention in first-episode schizophrenia – maintenance vs intermittent drug treatment with prodrome-based early intervention: results of a randomized controlled trial within the German Research Network on Schizophrenia. J Clin Psychiatry 2011; 72 (2): 205–218. 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

A 3-year observational study of adults with schizophrenia (n=6,642)1
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 Key message: Some patients with schizophrenia may achieve recovery with effective treatment. Social functioning, medication adherence, and type of antipsychotic, are important predictors of recovery. Background: In a 3-year observational study of adults with schizophrenia (n=6,642), the frequency and predictors of patient outcomes were assessed.1 The average age at entry was 40.2 years (standard deviation: 12.9 years), and mean duration of illness was 11.8 years.1 Long-lasting symptomatic remission was defined as achieving a level of severity that was mild or less (i.e., a score of <4 on a scale from 1 to 7) in the Clinical Global Impression – Schizophrenia (CGI-SCH) positive, negative, cognitive, and overall severity scores, plus no inpatient admission for a minimum period of 24 months maintained until the 36-month visit:1 Approximately 33% achieved long-lasting symptomatic remission. Long-lasting adequate quality of life was defined as achieving an EuroQoL5 dimensions visual analogue scale (EQ-5D VAS) score ≥70 for a minimum period of 24 months and maintaining it until the 36-month visit:1 Approximately 27% achieved long-lasting adequate quality of life. Long-lasting functional remission was defined as fulfilling the following three criteria for a minimum period of 24 months and maintaining them until the 36-month visit: (1) a positive occupational/vocational status (i.e., paid or unpaid full- or part-time employment, being an active student, or being a housewife); (2) living independently; and (3) having active social interactions (i.e., having more than one social contact during the past 4 weeks or having a spouse or partner):1 Approximately 13% achieved long-lasting functional remission. Although the results should be interpreted conservatively because of the observational, non- randomised study design, they indicate that only a small proportion of patients with schizophrenia achieve recovery.1 Reference: 1. Novick D, Haro JM, Suarez D, et al. Recovery in the outpatient setting: 36-month results from the Schizophrenia Outpatients Health Outcomes (SOHO) study. Schizophr Res 2009; 108 (1–3): 223–230. Employment, independent living, social activity, and medication adherence were 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

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

Selecting suitable treatments for schizophrenia can pose a dilemma for psychiatrists
In selecting treatments for schizophrenia, physicians consider variables related to the:1,2 Patient Illness Medication Environment 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 The long-term nature of adverse events, including metabolic, endocrine and cardiac complications, can pose a dilemma for physicians in providing effective treatment 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 Please note, this slide builds Key message: When selecting treatments for schizophrenia, physicians have to consider many variables, including the patient’s health and lifestyle, co-prescribed medications, and previously experienced adverse events. Background In selecting treatments for schizophrenia, clinicians have to consider variables related to the patient (e.g., age, history of response), the illness (e.g., duration, symptom type, comorbidity), the medication (e.g., pharmacodynamics, pharmacokinetics, efficacy, tolerability, cost) and the patient’s environment.1,2 The ideal antipsychotic would:2 Reduce excess dopamine levels in the mesolimbic pathway and/or associative striatum to treat psychosis, while maintaining adequate dopamine levels where dopamine is needed. Cause minimal histaminergic blockade (associated with sedation, weight gain, and metabolic complications), cholinergic blockade (associated with dry mouth, constipation and impaired cognition), and α1-adrenergic blockade (associated with orthostasis). Have a sufficiently broad gap between efficacy and toxicity, so that dosing could be increased as needed without triggering excessive adverse events. Have efficacy for depression and anxiety. Cause no or minimal extrapyramidal symptoms (EPS) and akathisia, and have little risk of tardive dyskinesia (TD). Be weight-neutral, cause no metabolic abnormalities, and reverse weight gain and/or lipid abnormalities. References: 1. Kane JM, Correll CU. Pharmacologic treatment of schizophrenia. Dialogues Clin Neurosci 2010; 12 (3): 345–357. 2. Correll CU. What are we looking for in new antipsychotics? J Clin Psychiatry 2011; 72 (Suppl. 1): 9– 13. Other references used on slide: Abidi S, Bhaskara SM. From chlorpromazine to clozapine – antipsychotic adverse effects and the clinician’s dilemma. Can J Psychiatry 2003; 48 (11): 749–755. 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 (9896): 951–962. Uçok A, Gaebel W. Side effects of atypical antipsychotics: a brief overview. World Psychiatry 2008; 7 (1): 58–62. Barnes TR; Schizophrenia Consensus Group of British Association for Psychopharmacology. Evidence- based guidelines for the pharmacological treatment of schizophrenia: recommendations from the British Association for Psychopharmacology. J Psychopharmacol 2011; 25 (5): 567–620. 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

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 Key message: Guidelines for the treatment of schizophrenia recommend regular monitoring for adverse events and efficacy of treatment. Background Symptoms (mental and physical), signs, activities of daily living (ADL), level of functioning, and adverse events are key areas to assess at all phases of the illness.1 Collateral information (e.g., from family members, caregivers and healthcare professionals) is usually essential for a more complete understanding of symptoms, signs and functioning.1 Longitudinal follow-up by the same clinician(s) to monitor improvements or worsening is optimal.1 The patient’s competency to accept or refuse treatment must be periodically assessed and recorded.1 Regular and ongoing evaluations are equally necessary when patients respond to medications, when they fail to respond, and when they develop adverse events.1 Standardised scales are useful tools for baseline and later assessments.1 Patients will often not spontaneously bring complaints and information to clinicians, and therefore, active, specific questioning, and informed examination and investigation are usually necessary.1 Medications must be individualised because the individual response is highly variable.1 Patients must be involved in decisions and choices for pharmacotherapy.1 Reference: 1. Canadian Psychiatric Association. Clinical practice guidelines. Treatment of schizophrenia. Can J Psychiatry 2005; 50 (13 Suppl. 1): 7S–57S. Other references used on slide: Lehman AF, Lieberman JA, Dixon LB, et al. Practice guideline for the treatment of patients with schizophrenia, second edition. Am J Psychiatry 2004; 161 (Suppl. 2): 1–56. Hasan A, Falkai P, Wobrock T, et al.; WFSBP Task force on Treatment Guidelines for Schizophrenia. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of schizophrenia, part 2: update 2012 on the long-term treatment of schizophrenia and management of antipsychotic-induced side effects. World J Biol Psychiatry 2013; 14 (1): 2–44. 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]

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 Please note, this slide builds Key message: There is a need for a rational approach to the management of schizophrenia. Treatment guidelines recommend choosing a medication that offers good clinical response without intolerable adverse events, as well as regular monitoring of adverse events. References used on slide: Lehman AF, Lieberman JA, Dixon LB, et al. Practice guideline for the treatment of patients with schizophrenia, second edition. Am J Psychiatry 2004; 161 (Suppl. 2): 1–56. Kuipers E, Kendall T, Udechuku AY, et al. Psychosis and schizophrenia in adults. Treatment and management. National Clinical Guideline Number 178. NICE, 2014. 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

1. 3. 4. 1 For people with first episode psychosis offer:
For people with first episode psychosis offer: - Oral antipsychotic medication in conjunction with - Psychological interventions (family intervention and individual CBT) For people with an acute exacerbation or recurrence of psychosis or schizophrenia offer: - Oral antipsychotic medication - Psychological interventions (family intervention and individual CBT) Reference used on slide: National Institute for Health and Care Excellence. Psychosis and schizophrenia in adults: prevention and management. National Clinical Guideline Number 178. NICE, 2014. CBT=cognitive behavioural therapy NICE. Psychosis and schizophrenia in adults: prevention and management. NICE clinical guideline

Choice of antipsychotic medication 1. 3. 5. 1
Choice of antipsychotic medication 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) Reference used on slide: National Institute for Health and Care Excellence. Psychosis and schizophrenia in adults: prevention and management. National Clinical Guideline Number 178. NICE, 2014. NICE. Psychosis and schizophrenia in adults: prevention and management. NICE clinical guideline

Antipsychotics should be chosen individually, respecting the patient’s mental and somatic condition with special attention to side effects The 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 Reference used on slide: Hasan A, Falkai P, Wobrock T, et al.; World Federation of Societies of Biological Psychiatry (WFSBP) Task Force on Treatment Guidelines for Schizophrenia. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of schizophrenia, part 1: update 2012 on the acute treatment of schizophrenia and the management of treatment resistance. World J Biol Psychiatry 2012; 13 (5): 318–378. Hasan et al. World J Biol Psychiatry 2012; 13 (5): 318–378

Clinician’s expertise
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 Clinician’s expertise Patient’s expertise Diagnosis Disease aetiology Prognosis Treatment options Outcome probabilities Experience of illness Social circumstances Values Preferences Attitude to risk Key message: Shared decision-making is a an important process, in which clinicians and patients work together to make decisions about care and treatment, and it can lead to better adherence to treatment and medication. Background A report, entitled “People in control of their own health and care: the state of involvement”, produced by the King’s Fund concentrates on individual’s involvement in their own health and care, and the involvement of an individual’s family or other carers.1 Shared decision-making involves the following stages:1 Information exchange, in which the clinician provides reliable, evidence-based information, outlines the options, their likely outcomes, and uncertainties and risks, and the patient shares their own knowledge of the condition, and the beliefs, values and preferences that may impact on their decision. Deliberation, during which the options are discussed and preferences are clarified. Implementation, when the clinician and patient work together to achieve consensus, and the patient’s decisions are then recorded and implemented. 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 References: 1. Foot C, Gilburt H, Dunn P, et al. People in control of their own health and care: the state of involvement. The King’s Fund, 2014. 2. Coulter A, Collins A. Making shared decision-making a reality: no decision about me, without me. The King’s Fund, 2011. 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

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 0–10% of patients 31–40% of patients Familiarity with drug Reduced agitation Reduced risk of tardive dyskinesia Reduced risk of QTc irregularity 11–30% of patients Improved compliance Patient responded previously Tried and tested Reduced aggression Effect on mood/ affective symptoms Reduced risk of cognitive impairment 61–100% of patients Effect on positive symptoms (91%) Effect on negative symptoms (62%) Efficacy in refractory patients 41–60% of patients Reduced risk of EPS/parkinsonism Well tolerated Complete symptom control Reduced risk of weight gain Avoidance of sedation Please note, this slide builds Key message: When choosing a treatment, physicians prioritise efficacy for positive and negative symptoms over tolerability. Background: In a large, multinational, cross-sectional survey, psychiatrists in the US and five European countries (France, Germany, Italy, Spain and the United Kingdom) who had prescribed antipsychotics for ≥15 patients with schizophrenia within the preceding 3 months, provided data on their patients’ demographic and clinical characteristics, on their antipsychotic prescribing practices, and on drug attributes influencing treatment choice.1 Data were collected from 872 physicians on 6,523 patients (85% European, 15% US).1 Most patients were aged 25–44 years, 63% were men and 66% were outpatients.1 As shown on the slide, efficacy for positive symptoms, efficacy for negative symptoms, and tolerability were the top three leading reasons for physicians when choosing a particular antipsychotic medication.1 Control of positive and negative symptoms was considered to be the leading unmet need of current antipsychotic treatment.1 Note: the data in this slide are from a paper published in Around this time, expectations for drugs treating negative symptoms were high.2 References: 1. Lecrubier Y, Perry R, Milligan G. Physician observations and perceptions of positive and negative symptoms of schizophrenia: a multinational, cross-sectional survey. Eur Psychiatry 2007; 22 (6): 371– 379. 2. Stahl SM. Positive findings for negative symptoms of schizophrenia: no longer untreatable? Acta Psychiatr Scand 2006; 114 (5): 301–302. Induction of sedation Improvement in cognitive function Patient acceptability n=6,523 EPS=extrapyramidal symptoms Lecrubier et al. Eur Psychiatry 2007;22(6):371–379

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 Negative symptoms are so called because they describe thoughts or behaviour that a person used to have, before they developed schizophrenia, but now no longer have (or have to a lesser extent).[Living with schizophrenia, 2019; Mitra et al., 2016] Essentially, negative symptoms are normal aspects of a person’s behaviour that patients with schizophrenia no longer experience.[Living with schizophrenia, 2019; Mitra et al., 2016] There are eight symptoms that are collectively called ‘negative symptoms’:[Living with schizophrenia, 2019] 1. Apathy 2. Absent, blunted or incongruous emotional responses 3. Reductions in speech 4. Social withdrawal 5. Impaired attention 6. Anhedonia 7. Sexual problems 8. Lethargy Reference: Living with schizophrenia – negative symptoms of schizophrenia: understanding them. Available at: Accessed May 2019. Mitra S, Mahintamani T, Kavoor AR, Nizamie SH. Negative symptoms in schizophrenia. Ind Psychiatry J 2016; 25 (2): 135–144. 1. Living with schizophrenia website Mitra et al. Ind Psychiatry J 2016;25(2):135–144

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 In patients with schizophrenia, the connection between depression and cognitive performance has not been well studied, and the link between the presence of depressive symptoms and functional impairment in patients with schizophrenia is a contested one.[Harvey, 2011] Somewhat paradoxically, some have associated depressive symptoms with better social and cognitive performance.[Rieckmann et al., 2005] Taken together, though, the weight of evidence suggests that mood symptoms in patients with schizophrenia are associated with greater real-world disability.[Harvey, 2011] References: Harvey PD. Mood symptoms, cognition, and everyday functioning in major depression, bipolar disorder, and schizophrenia. Innov Clin Neurosci 2011; 8 (10): 14–18. Rieckmann N, Reichenberg A, Bowie CR, et al. Depressed mood and its functional correlates in institutionalized schizophrenia patients. Schizophr Res 2005; 77 (2–3): 179–187. 1. Harvey. Innov Clin Neurosci 2011;8(10):14–18

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 Positive correlation of variable with QoL subscale Negative correlation of variable with QoL subscale 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 Key message: Negative feelings towards medication are associated with lower scores in both affect and self-esteem. Background Cross-sectional study investigating patients aged 19–60 (n=80) with schizophrenic disorder according to International Classification of Diseases 10th revision (ICD-10) criteria who had a duration of illness >1 year and whose discharge from an inpatient unit had been ≥6 weeks earlier.1 The aim of the study was to investigate the relationship between antipsychotic-induced adverse events and subjective quality of life (QoL).1 Various rating scales were used: Positive and Negative Syndrome Scale (PANSS), St. Hans Rating Scale for Extrapyramidal Syndromes, the UKU Side Effect Rating Scale, the Drug Attitude Inventory (DAI), and the Lancashire Quality of Life Profile.1 The combined effects of sociodemographic variables, psychopathology, type of antipsychotic medication, antipsychotic-induced adverse events, and attitude toward medication, on QoL were analysed with multiple linear regression analysis (summarised on the slide).1 Reference: 1. Hofer A, Kemmler G, Eder U, et al. Quality of life in schizophrenia: the impact of psychopathology, attitude toward medication, and side effects. J Clin Psychiatry 2004; 65 (7): 932–939. 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

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 Sedation Dizziness Sexual dysfunction Increase in blood glucose levels Sleepiness Tremors Male breast enlargement or secretions Weight gain Key message: Medication adverse events are highly prevalent and significantly associated with medication non-adherence. Background Data were analysed from a 2007–2008 nationwide survey of adults who self-reported a diagnosis of schizophrenia and were currently using an antipsychotic medication (n=876).1 Adherence to medications was assessed by using the four-item Morisky Medication Adherence Scale (MMAS). Adherence was defined as a score of zero on the MMAS.1 Medication adverse events were self-reported.1 Most of the adverse events assessed were significantly associated with a decreased likelihood of medication adherence.1 Sensitivity analyses using the more restrictive definition of adverse event presence did not change overall model results with respect to significance or magnitude.1 EPS/agitation-related adverse events were the most strongly associated with nonadherence, and were commonly reported.1 Adverse events of antipsychotic medications are highly prevalent and significantly associated with lower adherence, which is associated with increased healthcare resource use.1 Reference: 1. DiBonaventura M, Gabriel S, Dupclay L, et al. A patient perspective of the impact of medication side effects on adherence: results of a cross-sectional nationwide survey of patients with schizophrenia. BMC Psychiatry 2012; 12: 20. 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

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 There are several lines of evidence showing that only a minority of patients with schizophrenia strictly adhere to their antipsychotic medication.[Tiihonen et al., 2011; Sendt et al., 2015; Ljungdalh, 2017] Several risk factors are associated with medication non-adherence in patients with schizophrenia, including illicit drug and alcohol use, antidepressant treatment, and greater levels of patient-reported medication-related cognitive impairment.[Ascher-Svanum et al., 2006] One recently conducted systematic literature review of adherence rates in schizophrenia reported a wide range of adherence values ranging from 11–72%.[Ljungdalh, 2017] Part of the explanation for this range is the non-standard way in which adherence, and non-adherence, are defined and monitored in clinical trials.[Ljungdalh, 2017; Osterberg & Blaschke, 2005] This makes it challenging to develop and implement interventions to foster good adherence.[Ljungdalh, 2017; Osterberg & Blaschke, 2005] References: Ascher-Svanum H, Zhu B, Faries D, et al. A prospective study of risk factors for nonadherence with antipsychotic medication in the treatment of schizophrenia. J Clin Psychiatry 2006; 67 (7): 1114–1123. Ljungdalh PM. Non-adherence to pharmacological treatment in schizophrenia and schizophrenia spectrum disorders – an updated systematic literature review. Eur J Psychiatry 2017; 31 (4): 172–186. Osterberg L, Blaschke T. Adherence to medication. N Engl J Med 2005; 353 (5): 487–497. Sendt KV, Tracy DK, Bhattacharyya S. A systematic review of factors influencing adherence to antipsychotic medication in schizophrenia-spectrum disorders. Psychiatry Res 2015; 225 (1–2): 14–30. 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 (6): 603–609. 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

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 Collected an antipsychotic prescription during the first 30 days after hospital discharge Continued their initial treatment for 30 days or longer following discharge from hospital Only a minority of patients with schizophrenia are strictly adherent to antipsychotic medication.[Tiihonen et al., 2011; Ljungdalh, 2017] The consequences of non-adherence can be severe; because antipsychotic medications effectively reduce the risk of psychotic relapse, non-adherence increases the risk of relapse.[Zipursky et al., 2014] Indeed, in one systematic review of relapse rate in the year following a first episode of non-affective psychosis, the rate of relapse was 3% in patients taking antipsychotics, compared with 77% in patients who were not treated with antipsychotic medication.[Zipursky et al., 2014] References: Ljungdalh PM. Non-adherence to pharmacological treatment in schizophrenia and schizophrenia spectrum disorders – an updated systematic literature review. Eur J Psychiatry 2017; 31 (4): 172–186. 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 (6): 603–609. Zipursky RB, Menezes NM, Streiner DL. Risk of symptom recurrence with medication discontinuation in first-episode psychosis: a systematic review. Schizophr Res 2014; 152 (2–3): 408–414. 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

Improving adherence with LAIs can lead to improved outcomes
Meta-analysis of 116 publications of LAI versus oral formulations of antipsychotic therapy1 Number of RCTs Drug group Control group Risk ratio (95% CI) LAI antipsychotic 7 60/332 (18%) 202/331 (61%) 0.31 (0.23–0.41) Oral antipsychotic 14 307/1,017 (30%) 507/768 (66%) 0.46 (0.37–0.57) Favours drug Favours placebo Mirror image 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 Cohort studies 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 A systematic review and meta-analysis, published in 2012, identified 116 reports from 65 trials of antipsychotic therapy in patients with schizophrenia.[Leucht et al., 2012] This information amounted to data for 6,493 patients.[Leucht et al., 2012] The results demonstrated that maintenance antipsychotic therapy has benefits for patients, including reduced risk of relapse, improved quality of life, and reduced aggressive acts.[Leucht et al., 2012] However, the authors caution that the benefits of antipsychotic treatment must be weighed against the risk of adverse events.[Leucht et al., 2012] Reference: 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 (9831): 2063–2071. Other references used on slide: Kishimoto T, Hagi K, Nitta M, et al. Effectiveness of long-acting injectable vs oral antipsychotics in patients with schizophrenia: a meta-analysis of prospective and retrospective cohort studies. Schizophr Bull 2018; 44 (3): 603–619. Kishimoto T, Nitta M, Borenstein M, et al. Long-acting injectable versus oral antipsychotics in schizophrenia: a systematic review and meta-analysis of mirror-image studies. J Clin Psychiatry 2013; 74 (10): 957–965. 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

Adverse events are associated with lower adherence to treatment
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

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

Adverse events can impose a significant burden on patients
In a study of 1,825 participants with psychosis1 Reported medication adverse events Reported impairment in their daily life as a result of medication adverse events Reported moderate or severe impairment 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 Please note, this slide builds. Key message: Treatment adverse events, which are reported by the majority of patients with schizophrenia, can impose a significant burden on patients, reducing quality of life and causing long- term distress if not treated. Background In an Australian study that combined the findings of two studies of patients with psychosis (the first in 1997–1998 [n=687], the second in 2010 [n=1,211]), 77.4% reported medication adverse events in the previous 4 weeks, 61.0% reported impairment due to medication adverse events, and 29.9% reported moderate/severe impairment due to adverse events.1 The ‘Psychosis Screener’ was used for census month screening, and the ‘Diagnostic Interview for Psychosis’ was used for the interview.1 The proportions reporting medication adverse events and associated impairment were comparable for both survey periods.1 Questions from the 1997−1998 psychosis survey were included to enable an assessment of change over time.1 Reference: 1. Morgan VA, Waterreus A, Jablensky A, et al. People living with psychotic illness in 2010: the second Australian national survey of psychosis. Aust N Z J Psychiatry 2012; 46 (8): 735–752. Other references used on slide: Awad AG, Hogan TP. Subjective response to neuroleptics and the quality of life: implications for treatment outcome. Acta Psychiatr Scand Suppl 1994; 380: 27–32. Barnes TR; Schizophrenia Consensus Group of British Association for Psychopharmacology. Evidence- based guidelines for the pharmacological treatment of schizophrenia: recommendations from the British Association for Psychopharmacology. J Psychopharmacol 2011; 25 (5): 567–620. 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

Adverse events can be classified into different groups
Anxiety Restlessness Sedation Somnolence Agitation Activating Insomnia Sedating Hypersomnia Akathisia Fatigue Antipsychotic- induced adverse events1-5 Parkinsonism Cardiac arrhythmias Extrapyramidal symptoms Cardiovascular QT interval prolongation Dystonia Dyskinesia Hyperglycaemia Hyperlipidaemia Please note, this slide builds. Key message: There are many different adverse events that can be induced by antipsychotics, and these can be classified into different groups, such as sedating, activating, metabolic, etc. References used on slide: Cheng-Shannon J, McGough JJ, Pataki C, McCracken JT. Second-generation antipsychotic medications in children and adolescents. J Child Adolesc Psychopharmacol 2004; 14 (3): 372–394. Citrome L. Activating and sedating adverse effects of second-generation antipsychotics in the treatment of schizophrenia and major depressive disorder: absolute risk increase and number needed to harm. J Clin Psychopharmacol 2017; 37 (2): 138–147. Lehman AF, Lieberman JA, Dixon LB, et al. Practice guideline for the treatment of patients with schizophrenia, second edition. Am J Psychiatry 2004; 161 (Suppl. 2): 1–56. Lieberman JA, Stroup TS, McEvoy JP, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 2005; 353 (12): 1209–1223. Kane JM, Skuban A, Hobart M, et al. Overview of short- and long-term tolerability and safety of brexpiprazole in patients with schizophrenia. Schizophr Res 2016; 174 (1–3): 93–98. UpToDate website. Jibson MD. Second-generation antipsychotic medications: pharmacology, administration, and comparative side effects. generation-antipsychotic-medications-pharmacology-administration-and-side-effects. Accessed April Sexual dysfunction Sexual/ endocrine Metabolic Weight gain Metabolic syndrome Diabetes mellitus Hyperprolactinaemia 1. UpToDate website. 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 Adolesc Psychopharmacol 2004;14(3):372–394; 6. Citrome. J Clin Psychopharmacol 2017;37(2):138–147

Reduced extrapyramidal symptoms
There are multiple clinical benefits of a low risk of extrapyramidal symptoms Reduced negative symptoms Enhanced compliance Reduced extrapyramidal symptoms Less impaired cognition Lower tardive dyskinesia risk Less dysphoria Fewer motor adverse events Strength of evidence Very strong, almost certain Moderately strong, probable Mild-to-moderate, possible Some suggestion, little to no data Key message: EPS adversely impact several aspects of antipsychotic efficacy and tolerability, thereby worsening the outcome for the afflicted individuals. Therefore, there are multiple clinical benefits of drugs with low risk of EPS. Note: ‘Atypical’ (‘second generation’) antipsychotics are associated with a lower risk of EPS compared to older conventional antipsychotics, and are therefore better able to separate the therapeutic antipsychotic effect from EPS. Background The costs of EPS are not limited to parkinsonian motor manifestations, but extend to increased negative symptoms and cognitive impairment, more dysphoria, higher likelihood of non-compliance, and greater risk of developing tardive dyskinesia.1 Expression of EPS significantly increases the likelihood of subsequent tardive dyskinesia – tardive dyskinesia, in turn, is associated with increased morbidity and mortality.1 EPS contribute to secondary negative symptoms, increasing the severity of this symptom dimension and attendant dysfunction.1 EPS are associated with cognitive dysfunction.1 Significant EPS may be correlated with dysphoria.1 The primary advantage of newer agents is their superior adverse event profiles, particularly with regard to EPS.1 The implications of EPS reduction potentially touch virtually every domain of pathology in schizophrenia, including short- and long-term movement disorders, negative symptoms, non- compliance, relapse rate, cognitive dysfunction, and dysphoria.1 This EPS advantage of atypical antipsychotics is likely to lead to improved patient compliance and a superior long-term outcome in patients treated with these medications.1 Reference: 1. Tandon R, Jibson MD. Extrapyramidal side effects of antipsychotic treatment: scope of problem and impact on outcome. Ann Clin Psychiatry 2002; 14 (2): 123–129. 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

Akathisia is associated with emotional symptoms and cognitive impairment
Reduced self-esteem1 Mental control3 Anxiety2 Emotional symptoms Cognitive impairment Associate learning3 Obsessive–compulsive3 Selective attention2 Somatization3 Discrimination2 Depression3 Perception2 Paranoid ideation3 Please note, this slide builds. Key message: Akathisia is associated with emotional symptoms (e.g., reduced self-esteem, anxiety, depression and paranoid ideation) and cognitive impairment (e.g., problems with mental control, associate learning, perception and coping). Background In a cross-sectional study, 80 patients with a schizophrenic disorder (according to ICD-10 criteria) who had an illness duration of >1 year were investigated, by using various rating scales: Positive and Negative Syndrome Scale (PANSS), the St. Hans Rating Scale for EPS, the UKU Side Effect Rating Scale, the Drug Attitude Inventory, and the Lancashire Quality of Life Profile.1 Mild to moderate akathisia was reported in 23% of all patients, and there was a significant negative correlation between akathisia (St. Hans scale) and self-esteem (-0.32, p<0.01).1 In another study, 67 outpatients with schizophrenia receiving stable doses of specific antipsychotic therapies were evaluated for akathisia and other extrapyramidal adverse events.2 Subjective cognitive dysfunction was comprehensively assessed by using the Frankfurt Complaint Questionnaire (FCQ).2 The severity of subjective cognitive deficits was compared between the groups with and without akathisia.2 The akathisia group (n=25) scored significantly higher (worse) on the FCQ Total score than the non-akathisia group (n=42) (p<0.05).2 In phenomenological subscale scores, the akathisia group had significantly higher (worse) scores on various subscales, i.e., ‘anxiety’, ‘disorder of selective attention’, ‘deterioration of discrimination’, ‘perceptual disorder’ and ‘disorder of coping responses’ than the non-akathisia group (p<0.05).2 In a third study, 41 stable and chronic patients with schizophrenia, who were receiving maintenance antipsychotic treatment, were rated by using the Barnes Akathisia Rating Scale (BARS) for drug-induced akathisia.3 Subjective symptoms were evaluated by using the Symptom Checklist-90-Revised (SCL-90-R), and cognitive function was assessed by using the Wechsler Memory Scale (WMS).3 Analysis of covariance (ANCOVA) with relevant variables as covariates revealed that patients with akathisia (n=17) had significantly higher (worse) scores on the depression subscale of the SCL-90-R than those without akathisia (n=24) (p<0.01).3 Patients with akathisia also had significantly lower (worse) scores on the mental control subtest of the WMS (p<0.05).3 Further analysis using ordinal logistic regression revealed that the depression subscale of the SCL- 90-R and the mental control subtest of the WMS were significantly associated with the severity of akathisia.3 References: 1. Hofer A, Kemmler G, Eder U, et al. Quality of life in schizophrenia: the impact of psychopathology, attitude toward medication, and side effects. J Clin Psychiatry 2004; 65 (7): 932–939. 2. Kim JH, Byun HJ. Association of subjective cognitive dysfunction with akathisia in patients receiving stable doses of risperidone or haloperidol. J Clin Pharm Ther 2007; 32 (5): 461–467. 3. Kim JH, Lee BC, Park HJ, et al. Subjective emotional experience and cognitive impairment in drug- induced akathisia. Compr Psychiatry 2002; 43 (6): 456–462. Severe subjective distress3 Coping responses2 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

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 Key message: Gastrointestinal adverse events, such as constipation, can occur with antipsychotics. Background This was a retrospective study in patients with schizophrenia consecutively admitted, between 2007–2009, and treated with antipsychotic medication.1 Various electronic patient data were linked to evaluate the prevalence and severity of constipation in patients with schizophrenia under routine treatment conditions.1 Constipation was defined as having at least one new prescription of a laxative.1 Over the 22-month observation period, there were 371 admissions of 273 individual patients with schizophrenia.1 The mean age of the sample was 40.1 years (range 17–82) and 65.6% were male.1 Over a period of 22 months, 36.3% of patients (n=99) received a pharmacological treatment for constipation at least once.1 On average, medication for constipation was prescribed for 273 days.1 Severe cases that were unresponsive to initial treatment, underwent plain X-ray of the abdomen.1 In 68.4% of patients, faecal impaction was found.1 A high prevalence of constipation, often severe and needing medical intervention, was confirmed during the study period.1 Reference: 1. De Hert M, Dockx L, Bernagie C, et al. Prevalence and severity of antipsychotic related constipation in patients with schizophrenia: a retrospective descriptive study. BMC Gastroenterol 2011; 11: 17. Other reference used on slide: MHRA Antipsychotics learning module Available at learning-module/con155606?useSecondary=&showpage=8. Accessed April 2019. 1. MHRA Antipsychotics learning module Available at: module/con155606?useSecondary=&showpage=8, Accessed April 2019; 2. De Hert et al. BMC Gastroenterol 2011;11:17

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 This meta-analysis identified 257 clinical trials from a pool of 2,374 records.[Bak et al., 2014] The analysis included raw changes in weight, change in BMI (body mass index), ≥7% weight gain, ≥7% weight loss, and a separate analysis of patients who were antipsychotic naïve on entering a study.[Bak et al., 2014] Virtually all antipsychotics appeared to cause weight gain.[Bak et al., 2014] In antipsychotic-naïve patients, this weight gain was more pronounced.[Bak et al., 2014] Reference: Bak M, Fransen A, Janssen J, et al. Almost all antipsychotics result in weight gain: a meta-analysis. PLOS One 2014; 9 (4): e94112. Other references used on slide: Llorca PM, Lançon C, Hartry A, et al. Assessing the burden of treatment-emergent adverse events associated with atypical antipsychotic medications. BMC Psychiatry 2017; 17 (1): 67. Nasrallah HA. Atypical antipsychotic-induced metabolic side effects: insights from receptor-binding profiles. Mol Psychiatry 2008; 13 (1): 27–35. 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

Some antipsychotics are associated with high rates of sedating adverse events, which can worsen outcomes Antipsychotic-induced sedating adverse events have been associated with: Reduced cognitive performance and functional capacity1 Medication non-adherence2 Risk of unintentional injury3 Concerns over the safety of dependants,4 particularly as women are more sensitive to sedative effects5 Please note, this slide builds. Key message: The sedative adverse events of antipsychotics may have significant consequences for patients, leading to medication non-adherence, increased risk of unintentional injury, and reduced cognitive performance and functional capacity. Sedation can have a severe impact on many aspects of patient life, such as preventing patients from gaining improvement from treatment, interfering with functioning and quality of life, and reducing adherence to medication. Background Data were analysed from a 2007‒2008 US survey of adults who self-reported a diagnosis of schizophrenia and were currently using an antipsychotic medication (n=876).1 Adherence was defined as a score of zero on the MMAS.1 The MMAS items include the presence or absence of the following non-adherent behaviours: forgetting to take medication, careless at times about taking medication, stopping medication when feeling better, and stopping medication when feeling worse.1 A single logistic regression model assessed the relationship between adverse-event clusters and adherence.1 The adverse-event cluster of sedation/cognition (which included sedation, difficulty thinking or concentrating, sleepiness, and dizziness) was associated with a lower likelihood of adherence – sedation/cognition (odds ratio [OR]: 0.70, p=0.033).1 Reference: 1. DiBonaventura M, Gabriel S, Dupclay L, et al. A patient perspective of the impact of medication side effects on adherence: results of a cross-sectional nationwide survey of patients with schizophrenia. BMC Psychiatry 2012; 12: 20. References used on slide: Lindberg N, Virkkunen M, Tani P, et al. Effect of a single-dose of olanzapine on sleep in healthy females and males. Int Clin Psychopharmacol 2002; 17 (4): 177–184. Loebel AD, Siu CO, Cucchiaro JB, et al. Daytime sleepiness associated with lurasidone and quetiapine XR: results from a randomized double-blind, placebo-controlled trial in patients with schizophrenia. CNS Spectr 2014; 19 (2): 197–205. Miller DD. Atypical antipsychotics: sleep, sedation, and efficacy. Prim Care Companion J Clin Psychiatry 2004; 6 (Suppl. 2): 3–7. Miller DD. Sedation with antipsychotics. Curr Psychiatr 2007; 6 (8): 38–51. Said Q, Gutterman EM, Kim MS, et al. Somnolence effects of antipsychotic medications and the risk of unintentional injury. Pharmacoepidemiol Drug Saf 2008; 17 (4): 354–364. Seeman MV. Antipsychotic-induced somnolence in mothers with schizophrenia. Psychiatr Q 2012; 83 (1): 83–89. 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. Curr Psychiatr 2007;6(8):38–51; 7. Miller et al. Prim Care Companion J Clin Psychiatry 2004;6(Suppl. 2):3–7

Sedation impacts patient functioning and caregiver burden
“They do not want to get out of bed or participate in activities” Caregiver Effects of patient sedation can increase caregiver burden “Constantly feel tired” “No energy” “Cannot think clearly” Patient 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 Please note, this slide builds. Key message: Sedation impacts on patient functioning and caregiver burden, and can lead to dissatisfaction with medication and discontinuation of treatment. Background Many patients with schizophrenia experience disturbances in their sleep–wake cycle, which may be a result of the disease itself, of pharmacotherapy, or of a comorbid sleep disorder.1 These sleep disturbances can seriously impair patient functioning, as well as quality of life.1 Most patients develop a tolerance to the sedating effects of medications after the acute phase of treatment; however, a substantial minority will continue to experience persistent sedation or somnolence, impacting on their quality of life.1 Although patients may not be able to accurately describe their symptom as persistent sedation, they may complain that they have no energy, they constantly feel tired, or that they cannot think clearly.1 Patients’ families may also indicate that patients do not want to get out of bed or participate in any activities, which may increase the burden on the caregiver.1 Reference: 1. Kane JM, Sharif ZA. Atypical antipsychotics: sedation versus efficacy. J Clin Psychiatry 2008; 69 (Suppl. 1): 18–31. Other reference used on slide: Hofstetter JR, Lysaker PH, Mayeda AR. Quality of sleep in patients with schizophrenia is associated with quality of life and coping. BMC Psychiatry 2005; 5: 13. 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

Prolactin/endocrine*
Activating and sedating effects are among the most ‘bothersome’ antipsychotic adverse events EPS/activating*** Sedating/cognition* Prolactin/endocrine* Metabolic** GI Key message: Activating (EPS, agitation) and sedating effects are among the most ‘bothersome’ antipsychotic adverse events, as rated by patients: 86.2% of patients with schizophrenia reported the presence of any adverse event. Background Data were analysed from a 2007–2008 US survey of adults who self-reported a diagnosis of schizophrenia and were currently using an antipsychotic medication (n=876).1 Adverse events were defined as ‘present’ if the patient reported that the adverse event was at least ‘somewhat bothered’.1 Adherence was defined as a score of zero on the MMAS, and the relationships between adherence and health resource use were also examined.1 A majority (86.2%) of patients reported experiencing at least one adverse event due to their medication, and only 42.5% reported complete adherence.1 Most adverse events were associated with a significantly reduced likelihood of adherence.1 When grouped as adverse event clusters in a single model, EPS/agitation (OR: 0.57, p=0.0007), sedation/cognition (OR: 0.70, p=0.033), prolactin/endocrine (OR: 0.69, p=0.0342), and metabolic adverse events (OR: 0.64, p=0.0079) were all significantly related to lower rates of adherence.1 Patients who reported complete adherence to their medication were significantly less likely to report a hospitalisation for a mental health reason (OR: 0.51, p=0.0006), a hospitalisation for a non-mental health reason (OR: 0.43, p=0.0002), or an emergency room (ER) visit for a mental health reason (OR: 0.60, p=0.008).1 Reference: 1. DiBonaventura M, Gabriel S, Dupclay L, et al. A patient perspective of the impact of medication side effects on adherence: results of a cross-sectional nationwide survey of patients with schizophrenia. BMC Psychiatry 2012; 12: 20. 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 adherence EPS=extrapyramidal symptoms; GI=gastrointestinal DiBonaventura et al. BMC Psychiatry 2012;12:20

Consequence of schizophrenia
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 negative misconceptions of their ability and/or nature2 Please note, this slide builds. Key message: Medication adverse events can impair workplace performance, and can act as a barrier to entering or returning to work. The stigma resulting from medication adverse events leads to perceptions of laziness and addiction problems in patients with schizophrenia, and this stigma causes some patients to reduce or skip their medication. Background This study was a semi-structured focus group, conducted in Slovenia.1 It included 10 inpatients (four women and six men aged 30–61 years) with schizophrenia or schizoaffective disorder with severe and remitting mental illness treated with antipsychotic medication.1 The aim was to obtain the patient’s personal views on how the adverse events of antipsychotic drugs contribute to the stigmatisation related to mental illness.1 Open-ended questions were posed about the influence of adverse events on illness disclosure, work performance, family relationships and treatment adherence.1 The patients felt most stigmatised in areas of employment and occupation.1 They repeatedly skipped or discontinued regular medication because of adverse events.1 A report from the ‘Work Foundation’ highlights the barriers experienced by people with schizophrenia in Germany to entering and remaining in the open labour market.2 In order to gain an in-depth understanding of the impact of how the structural, economic, clinical and attitudinal barriers to employment affect people with schizophrenia, previous studies were reviewed, and in-depth interviews with people with experience of living with schizophrenia were conducted.2 The opinions of professionals with expertise in the provision of health, social care and vocational rehabilitation, policy experts, and employers were also sought.2 Schizophrenia often has considerable influence on an individual’s employment opportunities.2 The symptoms of the illness, adverse events of the treatment and the possibility of relapse may make entering or returning to work difficult.2 This is exacerbated by the onset of schizophrenia commonly occurring during the teens and early twenties – interrupting education, early career and the transition to independent living.2 Illness onset can have significant implications for an individual’s employment prospects, with employers searching out employees with the best job history and qualifications.2 Similarly, the gaps in employment history caused by periods of ill health may reduce an individual’s attractiveness to employers, compared with other candidates.2 References: 1. Novak L, Švab V. Antipsychotics side effects’ influence on stigma of mental illness: focus group study results. Psychiatr Danub 2009; 21 (1): 99–102. 2. Steadman K. Working with schizophrenia: employment, recovery and inclusion in Germany. The Work Foundation 1. Novak & Švab. Psychiatr Danub 2009;21(1):99–102; 2. Steadman. Working with schizophrenia: employment, recovery and inclusion in Germany. The Work Foundation. 2015

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 Key message: Emotional and practical burdens of schizophrenia on families are intertwined with feelings of frustration, anxiety, low self-esteem and helplessness occurring in the relatives of patients. Background This study set out to explore the relationship between stigma, accessibility of mental health facilities and family burden through individual interviews of patients’ relatives.1 Ten interviewees from two outpatient psychiatric clinics were recruited and interviewed.1 Each interviewee had at least one family member receiving out-patient psychiatric services.1 A combination of unstructured and semi-structured interviewing was used to obtain interviewees’ perceptions of burden, the importance they attached to different issues and the feelings they had about the illness.1 Data analyses of the transcripts and interview notes (using the interpretive interview analysis method) showed that much of the burden on the patient’s family was related to stigma and to lack of mental health and rehabilitation services.1 Consequences of this burden included social isolation of the families, difficulties experienced by patients when trying to obtain competitive employment, and financial difficulties.1 Subjective burden resulting from social stigma included frustration, anxiety, low self-esteem and helplessness.1 The objective and subjective burdens on families were intertwined.1 For example, when relatives had difficulty meeting practical demands, they would most likely also have had a negative emotional response; such an emotional response would in turn affect their ability to cope with practical demands (i.e., objective and subjective burden can augment each other).1 Reference: 1. Tsang HW, Tam PK, Chan F, Cheung WM. Sources of burdens on families of individuals with mental illness. Int J Rehabil Res 2003; 26 (2): 123–130. 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

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

The importance of early intervention for patients with schizophrenia

Global psychopathology
Association between DUP and symptom severity at first treatment contact Global psychopathology Positive symptoms Negative symptoms Functioning Effect size: Positive, not significant Effect size: Negative, not significant Effect size: Positive, significant Effect size: Positive, not significant 1 study 1 study 2 studies 1 study 3 studies 5 studies 6 studies 2 studies Studies with positive effect size (Hedge’s gu >0.0) Studies with negative effect size (Hedge’s gu ≤0.0) This critical review searched for literature concerning duration of untreated psychosis published up to 2004, finding 43 publications that were carried over into the meta-analysis.[Perkins et al., 2005] Whilst a shorter duration of untreated psychosis was associated with greater response to antipsychotic treatment (as measured by severity of global psychopathology, positive symptoms, negative symptoms, and functional outcomes), duration of untreated psychosis was associated only with the severity of negative symptoms – not severity of global psychopathology, positive symptoms, or neurocognitive functioning.[Perkins et al., 2005] Reference: Perkins DO, Gu H, Boteva K, Lieberman JA. Relationship between duration of untreated psychosis and outcome in first-episode schizophrenia: a critical review and meta-analysis. Am J Psychiatry 2005; 162 (10): 1785–1804. 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

Association between DUP and treatment response
Global psychopathology Positive symptoms Negative symptoms Functioning Effect size: Positive, significant 4 studies 5 studies 7 studies 4 studies Studies with positive effect size (Hedge’s gu >0.0) Studies with negative effect size (Hedge’s gu ≤0.0) This critical review searched for literature concerning duration of untreated psychosis published up to 2004, finding 43 publications that were carried over into the meta-analysis.[Perkins et al., 2005] Whilst a shorter duration of untreated psychosis was associated with greater response to antipsychotic treatment (as measured by severity of global psychopathology, positive symptoms, negative symptoms, and functional outcomes), duration of untreated psychosis was associated only with the severity of negative symptoms – not severity of global psychopathology, positive symptoms, or neurocognitive functioning.[Perkins et al., 2005] Reference: Perkins DO, Gu H, Boteva K, Lieberman JA. Relationship between duration of untreated psychosis and outcome in first-episode schizophrenia: a critical review and meta-analysis. Am J Psychiatry 2005; 162 (10): 1785–1804. 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

Patients with long DUP were less likely to achieve remission
Odds of no remission in the long versus short DUP groups Odds ratio (95% CI) Definition(s) of remission 6-month follow-up 3.55 (2.03–6.18) No positive symptoms on PANSS >3, or GAF Total >62, or variant of WHO life chart method 12-month follow-up 2.75 (1.14–6.64) Variant of WHO life chart method, or all global SAPS items <2 24-month follow-up 2.72 (1.20–6.17) Variant of WHO life chart method 269-month follow-up 2.42 (1.51–3.86) No symptoms at interview This systematic review aimed to establish whether the duration of untreated psychosis is associated with prognosis in patients with schizophrenia.[Marshall et al., 2005] A total of 26 studies were identified that reported the relationship between duration of untreated psychosis and outcome, in prospective cohorts of patients with schizophrenia, recruited during their first episode of psychosis.[Marshall et al., 2005] The results demonstrate a convincing, albeit modest, association between the duration of untreated psychosis and a range of clinical outcomes, including remission.[Marshall et al., 2005] The authors are keen to point out that the association does not prove a direct cause – it does not prove that untreated psychosis causes poor outcomes.[Marshall et al., 2005] Rather, the two factors could be related via a third variable.[Marshall et al., 2005] Reference: Marshall M, Lewis S, Lockwood A, et al. Association between duration of untreated psychosis and outcome in cohorts of first-episode patients: a systematic review. Arch Gen Psychiatry 2005; 62 (9): 975–983. 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

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 Several retrospective analyses have examined the interplay between the duration of untreated illness and subsequent treatment effectiveness in patients with schizophrenia.[Owens et al., 2010; Primavera et al., 2012] One study reanalysed the data from the Northwick Park Study of First Episodes in the context of duration of untreated illness, finding a correlation between the duration of untreated illness and relapse rates.[Owens et al., 2010] Another study analysed clinical records of a cohort of 80 patients with schizophrenia, tabulating outcome variables such as number of hospitalisations, attempted suicide, course of illness, and GAF (Global Assessment of Functioning) scores.[Primavera et al., 2012] A shorter duration of untreated psychosis was linked to favourable course of illness, even in the very long term.[Primavera et al., 2012] References: Owens DC, Johnstone EC, Miller P, et al. Duration of untreated illness and outcome in schizophrenia: test of predictions in relation to relapse risk. Br J Psychiatry 2010; 196 (4): 296–301. Primavera D, Bandecchi C, Lepori T, et al. Does duration of untreated psychosis predict very long term outcome of schizophrenic disorders? Results of a retrospective study. Ann Gen Psychiatry 2012; 11 (1): 21. 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

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 32.3% 42.4% Risk ratio: (95% CI: 0.61, 0.90), p=0.003 versus Early intervention Treatment as usual This was a systematic literature review of publications comparing early intervention studies with treatment as usual, in patients with first-episode psychosis, or early phase schizophrenia.[Correll et al., 2018] Early intervention studies were defined as meeting the needs of people with early-phase psychosis – a multimodal treatment program, including several psychosocial and psychopharmacological interventions, provided from one team, in a coordinated and integrated fashion.[Correll et al., 2018] Of an initial selection of 8,935 records, 10 studies were included in the final meta-analysis.[Correll et al., 2018] From the difference highlighted by the meta-analysis, the authors conclude that early intervention programmes are clearly superior to treatment as usual across a range of clinical outcomes, including hospitalisation, symptoms, and patient functioning.[Correll et al., 2018] Reference: Correll CU, Galling B, Pawar A, 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 (6): 555–565. Adapted from: Correll et al. JAMA Psychiatry 2018;75(6):555–565

Summary

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 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 The limitations of current treatments, e.g., the adverse-event burden, can be frustrating for all involved and can decrease quality of life Agents with different pharmacological profiles may avoid the current treatment compromises, and help patients with schizophrenia to function at their optimal level Improved patient functioning and improved quality of life are important treatment goals at all stages of schizophrenia management.1,2 Functional impairment may be the result of an insufficient treatment effect.3 Sedating or activating adverse events can prevent patients from functioning at their optimal level and can negatively impact their quality of life.4-7 The adverse events associated with current treatments are often seen as a necessary compromise for continued symptom control.8-10 The limitations of current treatments, e.g., the adverse event burden, can be frustrating for all involved and can decrease quality of life.11-14 References: 1. Hasan A, Falkai P, Wobrock T, et al.; WFSBP Task force on Treatment Guidelines for Schizophrenia. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of schizophrenia, part 2: update 2012 on the long-term treatment of schizophrenia and management of antipsychotic-induced side effects. World J Biol Psychiatry 2013; 14 (1): 2–44. 2. Lehman AF, Lieberman JA, Dixon LB, et al. Practice guideline for the treatment of patients with schizophrenia, second edition. Am J Psychiatry 2004; 161 (Suppl. 2): 1–56. 3. Schennach R, Riedel M, Obermeier M, et al. What are residual symptoms in schizophrenia spectrum disorder? Clinical description and 1-year persistence within a naturalistic trial. Eur Arch Psychiatry Clin Neurosci 2015; 265 (2): 107–116. 4. Bobes J, Garcia-Portilla MP, Bascaran MT, et al. Quality of life in schizophrenic patients. Dialogues Clin Neurosci 2007; 9 (2): 215–226. 5. Kane JM, Sharif ZA. Atypical antipsychotics: sedation versus efficacy. J Clin Psychiatry 2008; (69 Suppl. 1): 18–31. 6. Loebel AD, Siu CO, Cucchiaro JB, et al. Daytime sleepiness associated with lurasidone and quetiapine XR: results from a randomized double-blind, placebo-controlled trial in patients with schizophrenia. CNS Spectr 2014; 19 (2): 197–205. 7. Hofer A, Kemmler G, Eder U, et al. Quality of life in schizophrenia: the impact of psychopathology, attitude toward medication, and side effects. J Clin Psychiatry 2004; 65 (7): 932–939. 8. 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 (9896): 951–962. 9. Barnes TR; Schizophrenia Consensus Group of British Association for Psychopharmacology. Evidence-based guidelines for the pharmacological treatment of schizophrenia: recommendations from the British Association for Psychopharmacology. J Psychopharmacol 2011; 25 (5): 567–620. 10. Abidi S, Bhaskara SM. From chlorpromazine to clozapine – antipsychotic adverse effects and the clinician’s dilemma. Can J Psychiatry 2003; 48 (11): 749–755. 11. Awad AG, Voruganti LN. The burden of schizophrenia on caregivers: a review. Pharmacoeconomics 2008; 26 (2): 149–162. 12. Naber D, Kasper S. The importance of treatment acceptability to patients. Int J Psychiatry Clin Pract 2000; 4 (1): 25–34. 13. National Alliance on Mental Illness (NAMI). Schizophrenia: public attitudes, personal needs: views from people living with schizophrenia, caregivers, and the general public. Arlington, VA: NAMI, 2008. 14. Tsang HW, Tam PK, Chan F, Cheung WM. Sources of burdens on families of individuals with mental illness. Int J Rehabil Res 2003; 26 (2): 123–130. For references, please see slide notes

Treatment principles Schizophrenia.

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