Course, Natural History and Prognosis Schizophrenia Schizophrenia is a heterogeneous disease with many dimensions Negative symptoms Positive symptoms Disorganization Dimensions underlying pathophysiology and treatment response Motor symptoms Cognitive deficits Mood symptoms Tandon R et al. Schizophr Res. 2009;110(1-3):123. Schizophrenia progression may lead to functional decline The majority of patients with schizophrenia experience recurring psychotic relapses, and clinical deterioration may occur in the context of these relapses: Mild The longer the period of untreated psychosis, the worse the prognosis

Premorbid Childhood Prodromal Adolescence to early adulthood Number of relapses may be related to greater deterioration Prodromal Psychotic Critical years Illness-driven decline in functioning plateaus Residual Symptoms, level of functioning Clinical deterioration begins here and occurs throughout the first 510 years before the first episode Severe Remainder of life

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 Lieberman JA, et al. Biol Psychiatry. 2001;50(11):884897. Typical Course of Schizophrenia Prodromal Phase Marked decrease in function Acute Phase (1 to 6 months) Psychotic symptoms begin Recuperative/ Recovery (several months) Positive symptoms; negative symptoms and impaired functioning remain Residual (several months or more) Some positive symptoms;

negative symptoms persist Some patients will remain chronically symptomatic despite adequate treatment over many years. American Psychiatric Association. Practice Guideline for the Treatment of Patients With Schizophrenia. 2nd ed. Arlington, VA: American Psychiatric Association; 2004. Relapses, characterized by acute psychotic exacerbation, can have a negative impact on psychosocial functioning In addition to the risk of self-harm and harm to others, relapse may have serious psychosocial implications: Cause distress to patients and families Jeopardize friendships and relationships Disrupt education or employment Diminish personal autonomy Contribute to stigma Add to the economic burden of treating schizophrenia x Emsley R, et al. Schizophr Res. 2013;148(13):117121.

Relapse and treatment Emergent adverse effects have substantial impact on patient quality of life Relapse has the highest impact on quality of life (lowest utility value) of the various health states measured: Stable schizophrenia 0.92 Stable schizophrenia with weight gain 0.83 Stable schizophrenia with hyperprolactinemia 0.82 Stable schizophrenia with diabetes 0.77 Stable schizophrenia with EPS Relapse 0.72 0.60 Mean utility score* EPS=extrapyramidal symptoms. *A time trade-off instrument was used to determine the importance of each health state. Higher scores represent the highest utility to the patient. Health state descriptions for each of the schizophrenia-related symptoms, adverse events, and relapse were developed using a combination of a literature review, patient interviews, and feedback, as well as feedback from volunteers to form the basis of the utility elicitation. Briggs A, et al. Health Qual Life Outcomes. 2008;6:105. Many patients experience symptoms that are not fully controlled with treatment

According to physician ratings, 4760% of patients experiencing positive symptoms that are not fully controlled following treatment and over 70% of patients experience only some, little or no control of negative symptoms, Negative symptoms Little or no control Positive symptoms Only some control Social withdrawal (n=3,491) Disordered thought (n=3,857) Impoverished thought (n=2,525) Bizarre behaviour (n=1,684) Blunted affect (n=2,487) Delusions (n=4,746) Apathy/avolition (n=1,737) Hallucinations (n=3,845) Anhedonia (n=1,549) Agitation (n=1883) Lethargy/fatigue (n=897) Aggression (n=1,413) 0

10 20 30 40 50 60 70 80 Percentage of patients with symptoms that are not fully controlled 90 100 Physicians rated the level of control with current treatment of each of the five most important symptoms in that patient. Rating categories were generally well controlled, some control and little or no control. 0 20 30

40 50 60 70 80 90 100 Percentage of patients with symptoms that are not fully controlled n-values indicate the number of patients with that leading symptom, out of a total cohort of 6,523 patients Lecrubier Y, et al. Eur Psychiatry. 2007;22(6):371379. 10 G A F m e a n s c o re Symptoms that are not fully controlled are significantly associated with impaired global functioning Patients in remission with residual symptoms featured significantly worse global functioning compared with the group without residual symptoms1 Residual symptoms in remitted patients with a schizophrenia spectrum disorder after acute inpatient treatment were highly prevalent (94%) Only 6% of patients in remission did not have a residual symptom at discharge from hospital 82

80 78 76 74 72 70 68 66 64 Global functioning 79.7 P=0.0003 69.6 GAF, Global Assessment of Functioning Patients with a diagnosis of schizophrenia, schizophreniform disorder, delusional disorder, or schizoaffective disorder. Residual symptoms were defined as the presence of any symptom, indicated by a PANSS item score >1 (at least borderline mentally ill), at the time of remission. Remission was defined using the consensus criteria by Andreasen2 as a PANSS score of 3 on each of the following items: delusions (P1), unusual thought contents (G9), hallucinatory behavior (P3), conceptual disorganization (P2), mannerism/posturing (G5), blunted affect (N1), social withdrawal (N4) and lack of spontaneity (N6) 1. Schennach R, et al. Eur Arch Psychiatry Clin Neurosci. 2015;265(2):10716. 2. Andreasen et al. Am J Psychiatry 2005;162(3):441449 C o r r e la tio n ( r ) w it h L ife S k ills P r o file D im e Disorganization, a common residual symptom,1 is associated with impaired community functioning Disorganization is a reliable predictor of several aspects of community functioning: 2 Total ...

Non-turbu... 0 Social co... Communica... Responsib... Self... -0.07 -0.25 * -0.31 -0.37 ** -0.37 ** -0.47 *** * p<0.05. **p<0.01. Scales were scored so that higher scores indicated better community functioning. Disorganization was defined using the PANSS P2 item (conceptual disorganization). Schennach R, et al. Eur Arch Psychiatry Clin Neurosci. 2015;265(2):107 16.

Norman RM, et al. Am J Psychiatry. 1999;156(3):4005. Positive symptoms of schizophrenia are inversely correlated with ability to function Positive symptoms impair functional capacity and are associated with reductions in real-world performance measures via a correlation with depression: Positive symptoms Functional capacity 0.27 * 0.21* 0.28 * Depres sion *p<0.05. N=78 Interpersonal Skills Prediction Model fit: =8.22, df=9, p=0.52; comparative fit index=0.99. Community Activities Prediction Model fit: =10.37, df=9, p=0.32; comparative fit index=0.99 Work Skills Prediction Model fit: =10.08, df=10, p=0.43; comparative fit index=0.99. Bowie CR, et al. Am J Psychiatry. 2006;163(3):41825. -0.13 0.20*

Interpersonal skills Community activities Work skills Primary negative symptoms of schizophrenia can impact domains of functioning directly1 Even in those with positive symptoms that respond or remit, patients may remain functionally impaired because of negative symptoms and cognitive deficits2 r= 0.42*** Primary Primary negative negative symptoms symptoms ***p<0.001 r= 0.24*** r= 0.30*** Interpersonal Interpersonal relations relations (social) (social) Use

Use of of common common objects objects and and activities activities (recreational) (recreational) Instrumental Instrumental role role functioning functioning (vocational) (vocational) Primary negative symptoms were assessed using the negative symptom factor score from the Positive and Negative Syndrome Scale (PANSS). Functional status was assessed using the HeinrichsCarpenter Quality of Life Scale (QLS). 1. Fervaha G, et al. Eur Psychiatry. 2014;29(7):44955. 2. Lehman AF, et al. [APA Practice Guidelines] 2010. Take home points Functioning is complex and multifactorial, and a variety of factors contribute to functional impairment in patients with schizophrenia Symptoms that are not fully controlled are significantly associated with impaired global functioning Current treatment guidelines include optimizing functioning and quality of life as important treatment goals Schizophrenia Is a Progressive and Cyclical Disease Characterized by Multiple Psychotic Relapses

Following a relapse, patients often fail to recover to the same degree 1 Premorbid Prodromal Onset Healthy Deterioration Chronic/residual Worsening Severity of Signs and Symptoms Birth 10 20 30 Age, years2 40 50 60 Although the majority of patients with schizophrenia exhibit a severe pattern of deterioration, different degrees of severity and temporal sequences do occur 1 1 2

Lieberman JA et al. Biol Psychiatry. 2001;50(11):884-897. Lewis DA, Lieberman JA. Neuron. 2000;28(2):325-334. Early, Continuous Treatment of Schizophrenia Improves Treatment Outcomes Symptom Remission and Recovery Categories Patients Meeting Criteria for Any 6 Months, % Patients Meeting Criteria for All 12 Months, % No hospitalizations 100 83 Symptom remission* 36 22 Disorganization symptoms 93 82 Reality distortion

65 48 Negative symptoms 55 40 Good functional outcome 25 7 Social functioning 60 40 Work functioning 38 10 10 1 Recovery * Symptom remission criteria that include 3 symptom groups: reality distortion (positive), negative

symptoms, and disorganization rated as mild or less for a duration of 6 months. Combined social and work functioning used to define good functional outcome. Requires no hospitalizations, good or adequate social and work functioning, and symptom ratings of mild or less for a period of 1 year. Ventura J et al. Schizophr Res. 2011;132(1):18-23. Poor Treatment Outcomes Early in the Course of Schizophrenia Led to Measurable Neurological Damage Adapted from Lieberman J et al. Biol Psychiatry. 2001;49(6):487-499. A Variety of Symptom Clusters Contribute to Functional Impairment Positive symptoms1,2 Delusions Disorganized thought Disorganized speech Hallucinations Negative symptoms1 Flat or blunted affect and emotion Poverty of speech (alogia) Inability to experience pleasure (anhedonia) Lack of desire to form relationships (asociality) Lack of motivation (avolition) Lack of insight2 Functional impairment2 Ability to work Coping with self care Establishing social relationships

Cognitive impairment1 Episodic memory Inappropriate affect Executive function Working memory Tandon R et al. Schizophr Res. 2009;110(1-3):1-23. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision. Washington, DC: American Psychiatric Association; 2000. 1 2 Some Patients With Schizophrenia May Achieve Recovery With Effective Treatment In a 3-year observational study, adults with schizophrenia (N=6642) achieved 1: Long-lasting symptomatic remission* 33 Long-lasting adequate quality of life 27 Long-lasting functional remission Achieved recovery, defined as all 3 of the above 0 13 4 5

10 15 20 25 30 35 Patients, % Employment, independent living, social activity, and medication adherence were all significantly associated with achieving recovery 1 62% of patients at the end of a 10-year follow-up study were rated as having a poor outcome 2 Poor outcome was defined as substantial historical and recent mental illness and unemployment or an unnatural cause of death * Defined as <4 in the CGI-SCH positive, negative, cognitive, and overall severity score, plus no inpatient admission for 24 months. Defined as 70 on the EuroQoL5 dimensions visual analogue scale (EQ-5D VAS) for 24 months. Defined as employed/student, plus independent living, plus active social interactions for 24 months. CGI-SCH=Clinical Global Impression-Schizophrenia scale. 1 Novick D et al. Schizophr Res. 2009;108(1-3):223-230. 2 White C et al. Psychol Med. 2009;39(9):1447-1456. M ean Total Score Patients With Schizophrenia Who Achieved Symptomatic Remission Had Significantly Better Personal and Social Functioning

P=0.001 P<0.001 80 70 67.1 Patients in remission (n=23) Patients not in remission (n=53) 65.9 60 51.9 50 51 40 30 20 10 0 GAF Score GAF=Global Assessment of Functioning scale; PSP=Personal and Social Performance scale. Brissos S et al. Schizophr Res. 2011;129(2-3):133-136. PSP Total Score

Mean WHOQOL Score Patients With Schizophrenia Who Achieved Symptomatic Remission Had Significantly Better Self-Reported Quality of Life P=0.009 P=0.013 P=0.023 P=0.009 Patients in remission (n=23) Patients not in remission (n=53) 80 70 60 70.4 68.7 56.4 59.8 65.7 62.5 50.5 50

54.4 40 30 20 10 0 Physical Domain Psychological Domain WHOQOL=World Health Organization Quality of Life measure. Brissos S et al. Schizophr Res. 2011;129(2-3):133-136. Social Domain Environmental Domain 3.5 Patients in remission (n=23) Patients not in remission (n=53) P=0.003 3.0 2.5 3 2.0 1.5

M e an P A N SS It e m G 6 Sco re (D e p r e ssio n ) M e an PAN SS Ite m G1 2 Score (Insight) Symptomatic Remission in Schizophrenia Led to Significantly Better Insight and Fewer Depressive Symptoms 2 2.5 1.5 2 1.0 1 0.5 0.5 PANSS=Positive and Negative Syndrome Scale; a trademark of Multi-Health Systems, Inc. Brissos S et al. Schizophr Res. 2011;129(2-3):133-136. Patients in remission (n=23) Patients not in remission (n=53) 2.0 1.0

0 P=0.013 0 Excess mortality in severe mental illness1 Serious mental illness (including schizophrenia) confers: 2025 year reduction of life expectancy 40% excess mortality through suicide 60% excess mortality due to natural causes including2: Cardiovascular diseases Digestive diseases Infectious diseases Respiratory diseases 1. Tiihonen J, et al. Lancet 2009;374:6207. 2. Saha S et al. Arch Gen Psychiatry. 2007;64(10):1123-1131. Schizophrenia: A broad range of symptoms Positive symptoms Excess or distortion of normal functions2 Negative symptoms Decline in or loss of normal functions2 Cognitive symptoms Key component of schizophrenia3

Delusions1 Hallucinations1 Disorganised thought/speech1 Grossly disorganised or catatonic behaviour1 Alogia1 (Poverty of speech ) Avolition1 (Lack of motivation ) Anhedonia1 (Inability to experience pleasure) Asociality1 (Lack of desire to form relationships) Diminished emotional expression1 Attention1 Episodic memory1 Executive functions (including language function)1 Working memory1

Processing speed1 Inappropriate Affect1 Inhibitory capacity1 Mood symptoms, e.g., depression, anxiety, anger, hostility, aggression are common1 Catatonia: Motor abnormalities Repetitive, complex gestures. Usually of the fingers or hands . Excitable, wild flailing of limbs. 1. APA. 2013; 2. APA. 2000; 3. Wilk et al. Neuropsychology 2005;19(6):778786; C u m u la tiv e r e la p s e r a te (% ) Relapse is common in schizophrenia Cumulative relapse rates in schizophrenia, by year following recovery from the first episode1 100 80 60 40 20 0 1 2 (104 patients at risk of relapse) First relapse 3 4 5

Years after recovery from previous episode 1. Robinson et al. Arch Gen Psychiatry 1999;56:241247; 2. Csernansky & Schuchart. CNS Drugs 2002;16(7):473484; 3. Kane. J Clin Psychiatry 2007;68(Suppl 14):2730; 4. Lewis & Lieberman. Neuron 2000;28:325344; 5. Levander et al. Acta Psychiatr Scand 2001;104(Suppl 408):6574; 6. Briggs et al. Health Qual Life Outcomes 2008;6:105 About 82% of patients with schizophrenia or schizoaffective disorder experienced 1 relapse over 5 years1 Relapse can cause: Rehospitalisation2 Slow and incomplete recovery3 Treatment-resistant illness3 Persistent symptoms4 Progressive cognitive decline5 Increasing difficulty to regain previous level of functioning3 Reduced quality of life6 Multiple factors increase the risk of relapse The risk of relapse following treatment for first-episode psychosis was significantly increased by:1,2 Non-adherence to medication Treatment resistance Persistent substance use Carers criticism Poorer pre-morbid adjustment Improving medication adherence, and relapse prevention, are key components of the management of schizophrenia1,3 Findings from a systematic review and meta-analysis of 29 longitudinal studies 1,2 1. Emsley et al. BMC Psychiatry 2013;13:50;

2. Alvarez-Jimenez et al. Schizophr Res 2012;139(13):116128; 3. Kane. J Clin Psychiatry 2007;68(Suppl 14):2730 Relapses negatively affect the disease trajectory and outcome 82% of the patients relapse within 5 years following recovery from the first psychotic episode1 Relapses lead to: Slow or incomplete remission/recovery2 Treatment-resistant illness and increased difficulty regaining previous level of functioning2 Only 7% - 9% of patients, who have failed to respond adequately to 2 adequate antipsychotic treatments, will improve to subsequent treatments3 1. Robinson et al. Arch Gen Psychiatry 1999;56:241247. 2. Kane. J Clin Psychiatry 2007;68(Suppl 14):2730. 3. Kinon et al. Psychopharmacol. Bull, 29, 309-314. Brain imaging and relapse 5-year longitudinal study of MRI whole brain scans1 96 patients with schizophrenia and 113 matched healthy controls Excessive decreases in grey matter density occurred in the left superior frontal area, left superior temporal gyrus, right caudate nucleus, and right thalamus as compared to healthy individuals1,2 Number of hospitalisations was significantly associated with a larger decrease in grey matter1,2 Suggests an association between number of relapses and degree of morphological brain change2 1. van Haren et al. Neuropsychopharmacology 2007;32(10):20572066; 2. Emsley et al. Schizophr Res 2013;148(13):117121 D a y s to re m is s io n Days to remission after each relapse

140 130 120 100 76.5 80 60 47 40 20 0 First Lieberman et al, J Clin Psychiatry1996;57:59. Second Third Impact of Relapse on Patients With Schizophrenia Short- and Long-term Consequences of Relapse Are Substantial to Patients Increased risk of recurrent psychotic

Cumulative deterioration in functioning episodes Short-term Interruptions in antipsychotic therapy Long-term Hospitalizations Nasrallah HA, Lasser R. J Psychopharmacol. 2006;20(6 suppl):57-61. Diminished ability to maintain employment or relationships M e a n C h a n g e i n P A N S S F o l l o w i n g 3 2 W e e k s o f M e d i c a ti o n Relapse May Reduce Patient Response to Medication Following relapse, 14 of 97 (14.4%) patients who initially responded favorably to antipsychotic therapy failed to respond to medication again Prior to relapse (n=14) Following relapse (n=14) 20 10 7

0 -10 -20 -18.2 PANSS=Positive and Negative Syndrome Scale, a trademark of Multi-Health Systems, Inc. Emsley R et al. Schizophr Res. 2012;138(1):29-34. Relapse Can Decrease Patient Functioning 59 P<0.05 57.8 58 Score 57 56 55 54 53 52.6 52 51 50 GAF

GAF=Global Assessment of Functioning. Almond S et al. Br J Psychiatry. 2004;184:346-351. Relapse (n=77) No relapse (n=68) Impact of Early Intervention for Patients With Schizophrenia 100 75 Pati e nts W ith Favorable Course of Illne ss, %2 Patients Relapsed Within 1 Year, %1 Shorter Duration of Psychosis Led to Improved Outcomes in Patients With First-Episode Schizophrenia P=0.025 30 50 15 25 0 0 DUI=duration of untreated illness; DUP=duration of untreated psychosis. 1

Owens DC et al. Br J Psychiatry. 2010;196(4):296-301. 2 Primavera D et al. Ann Gen Psychiatry. 2012;11(1):21 Patients With First-Episode Schizophrenia Are at an Increased Risk of Nonadherence Only 45% of all patients with first-episode schizophrenia continue their initial medication for longer than 30 days1 Patients with first-episode schizophrenia who discontinued antipsychotic therapy had a nearly 5-fold increase in the risk of relapse2 1 2 Tiihonen J et al. Am J Psychiatry. 2011;168(6):603-609. Robinson D et al. Arch Gen Psychiatry. 1999;56(3):241-247. Continuous Maintenance Treatment Led to Decreased Deterioration in Symptoms During the Second Year Following Diagnosis * Increase 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 scale; PANSS=Positive and Negative Syndrome Scale, a trademark of Multi-Health Systems, Inc.; Gaebel W et al; for the German Study Group on First-Episode Schizophrenia. J Clin Psychiatry. 2011;72(2):205-218. Supportive Relationships Can Improve Long-term Adherence and Reduce Relapse Risk in Patients With Schizophrenia Family Involvement and Better Patient Insight May Improve Patient Adherence Patients with early-episode schizophrenia who were significantly more adherent 6 months after hospital discharge: Were more aware of their illness and need for medication Had more positive perceptions of doctorpatient trust in the therapeutic alliance Had better perceived family involvement in treatment and had more positive family

attitudes toward medication Had more positive attitudes toward medication Baloush-Kleinman V et al. Schizophr Res. 2011;130(1-3):176-181. Instrumental Family Support* Predicts Higher Medication Usage in Patients With Schizophrenia A logistic regression analysis was conducted to assess if family factors, including the independent dimensions of expressed emotion (EE) and family support variables, would predict usage of psychiatric medications Higher levels of instrumental family support were associated with greater likelihood of medication usage Only family instrumental support significantly predicted medication usage (odds ratio = 4.8, P=0.05) * Instrumental support was operationalized as the total number of statements that illustrated family caregiver task-oriented assistance, such as completion of errands; eg, I helped him fill out an employment application. Ramrez Garca JI et al. Soc Psychiatry Psychiatr Epidemiol. 2006;41(8):624-631. Mean PANSS Score Mean GAF Score Family-Supervised Treatment Led to Significant Improvement in Symptoms and Functioning PANSS total score 65 60 GAF score 105

Intervention (n=55) Treatement as usual (n=55) 100 95 90 55 85 80 50 Intervention (n=55) Treatment as usual (n=55) 45 P=0.003 40 0 3 6 9 12 75

70 65 P=0.008 60 0 Months Intervention involved supervised treatment in outpatients for schizophrenia (STOPS). GAF=global assessment of functioning; PANSS=Positive and Negative Syndrome Scale, a trademark of Multi-Health Systems, Inc. Farooq S et al. Br J Psychiatry. 2011;199(6):467-472. 3 6 Months 9 12 The Value of a Support System In a post hoc analysis of data from the CATIE trial, 89% of patients with a supportive family improved, compared with only 39% of those lacking a supportive family With support systemn=27 Without support systemn=23 no change or worsening; 11.00%

improved; 89.00% improved; 39.00% no change or worsening; 61.00% Patients with a supportive family were about twice as likely to remain in treatment for the duration of the study CATIE=Clinical Antipsychotic Trials of Intervention Effectiveness. Glick ID et al. J Clin Psychopharmacol. 2011;31(1):82-85. Involving Patients in Their Own Care Increases Knowledge About Their Disease P=0.03 85 80 K n o w le d g e B e fo r e D isch ar g e * P e r ce ive d In vo lv e m e n t CO M RADE Patients who were provided information about treatment options and asked to write down medication preferences perceived a higher level of treatment involvement and demonstrated significantly more knowledge P=0.01 18 16

75 14 70 12 65 10 Intervention _x000d_(n=49)Control _x000d_(n=58) Intervention _x000d_(n=49)Control _x000d_(n=58) * Knowledge was assessed with a 7-item questionnaire about the patients disease and its treatment. COMRADE=Combined Outcome Measure for Risk Communication and Treatment Decision Making Effectiveness. Hamann J et al. Acta Psychiatr Scand. 2006;114(4):265-273. M e a n N u m b e r o f C lin ic ia n S t a t e m e n t s o f E m p a t h y M e a n N u m b e r o f P a ti e n t S t a t e m e n t s C o n t r ib u ti n g t Simple Techniques Improve the Communication Between Patients and Clinicians P<0.05 P<0.03 1.5 300

1 250 200 0.5 150 100 50 0 Intervention _x000d_(n=24)Control _x000d_(n=26) 0 Intervention _x000d_(n=24)Control _x000d_(n=26) Steinwachs DM et al. Psychiatr Serv. 2011;62(11):1296-1302. A Strong Therapeutic Alliance and High Patient Insight Was Significantly Correlated With Adherence to Medication Medication Adherence Rating Scale (MARS) Total Score Medication Adherence Behavior Attitude Toward Taking Medication Negative Side Effects SUMD subscore (patient insight)

0.54* 0.46 0.45 0.19 4PAS (therapeutic alliance) 0.66* 0.45 0.52* 0.48 Patient insight and therapeutic alliance were significantly correlated with medication adherence (P<0.0001) * P<0.001. P<0.01. 4PAS=4-Point Ordinal Alliance Scale; SUMD=Scale to Assess Unawareness of Mental Disorder. Misdrahi D et al. Nord J Psychiatry. 2012;66(1):49-54. High Prevalence of Nonadherence to Medication Among Patients With Schizophrenia N o n ad h e r e n t P ati e n t s,* % 2 N o n ad h e re n t P ati e n t s,* % 1

Rates of Medication Nonadherence in Chronic Nonpsychiatric Conditions and Schizophrenia Nonpsychiatric conditions 100 75 Schizophrenia 100 75 60 50 50 25 25 0 0 Hypertension Seizure disorders Hypercholesterolemia Type 2 diabetes Osteoporosis

Hypothyroidism N=706,032.1 * Defined as having a medication possession ratio (MPR) <80% during a 1-year study. 1 Briesacher BA et al. Pharmacotherapy. 2008;28(4):437-443. 2 Byerly M et al. Psychiatry Res. 2005;133(2-3):129-133. Gout Few Patients With Schizophrenia Take Their Medication as Prescribed 24.00% Nonadherent 41.00% Partially adherent Excess fillers 16.00% Adherent 19.00% MPR=medication possession ratio. Gilmer TP et al. Am J Psychiatry. 2004;161(4):692-699. Clinicians Overestimated Patient Adherence to Medication 100 90 80

70 60 50 40 30 20 10 0 Nonadherent Adherent Patients, % Patients, % Adherent 84% 52% 6 5 0% 4 0% 3 Clinician Rating Scale Score (Measure of Adherence)

MEMS=medication event monitoring system. Byerly M et al. Psychiatry Res. 2005;133(2-3):129-133. 0% 2 0% 1 100 90 80 70 60 50 40 30 20 10 0 Nonadherent 72% 60% 48% 20% 12% 4% <90% <80%

<70% <50% <30% <10% Actual Daily Adherence Based on MEM Clinicians Overestimate Medication Usage in Their Patients With Schizophrenia Patients, % What portion of patients take >80% of their doses? 50 40 30 20 10 0 N=47. * Please indicate the proportion of patients with schizophrenia you believe to be adherent, based on your reading of the treatment literature. What proportion of your patients with schizophrenia are adherent? Kane JM et al; Expert Consensus Panel for Optimizing Pharmacologic Treatment of Psychotic Disorders. J Clin Psychiatry. 2003;64(suppl 12):52-94. Proportion of patients based on the literature* Proportion of their own patients Risk Factors for Nonadherence

in Patients With Schizophrenia Adherence Is a Multidimensional Phenomenon The 5 Dimensions of Adherence Health care system/ HCT factors Social/economic factors Disease-related factors Treatment-related factors Patient-related factors HCT=health care team. Adherence to long-term therapies: evidence for action. World Health Organization Web site. Published 2003. Accessed March 6, 2013. Cognitive deficits Co-occurring substance abuse Belief medications are no longer needed Attitude toward medication Partial or lack of efficacy Unresolved symptoms: negative

and/or positive Velligan DI et al; Expert Consensus Panel on Adherence Problems in Serious and Persistent Mental Illness. J Clin Psychiatry. 2009;70(suppl 4):1-48. Practical problems: transportation, financial situation Homelessness Lack of daily routines Stigma toward mental illness and medication Social Fear of potential side effects Complexity of regimen Environmental Poor insight Treatment Patient Specific Factors Influence Adherence Lack of social support Therapeutic alliance Beliefs of significant

others toward mental illness and medication Barriers to Medication Adherence in Patients With Schizophrenia Difficulty with Regimen Lack of trust in Provider Denial of Illness Afraid of Medication Lack of Social Support Memory Problems Other Barriers (Homelessness, Substance Abuse) Adverse Drug Reactions Stigma 0 10 20 30 40 Patients Reporting Barriers, % Hudson TJ et al. J Clin Psychiatry. 2004;65:211-216. 50 60 Predictors for Nonadherence in First-Episode Patients With Schizophrenia

60 First-episode patients with schizophrenia or schizophreniform disorder were assessed over a 4-year period. After 6 months, adherence was assessed using the Compliance Interview, and nonadherence was defined as 0% to 74% adherence over the preceding 3 months. 20 Patients (33%) were nonadherent with medication Predictors of Nonadherence Total positive symptom score (P<0.01) Alcohol misuse (P=0.01) Lack of insight (P=0.04) Drug misuse (P=0.04) Kamali M et al. Eur Psychiatry. 2006;21(1):29-33. Patients With Schizophrenia Are Commonly Unaware of Signs and Symptoms Associated With Their Disease Patients Unaware of Signs and Symptoms, % Hallucinations Delusions Thought Disorder Blunt Affect Anhedonia Asociality 0 10 20 30

40 50 60 57.4% of patients with schizophrenia showed a moderate to severe lack of awareness of having a mental disorder Amador XF et al. Arch Gen Psychiatry. 1994;51(10):826-836. P a ti e n t s D e m o n s t r a ti n g P o o r In s ig h t , % ,* Poor Insight Was Associated With Nonadherence P<0.001 60 P<0.001 Adherent (n=202) P<0.001 40 20 0 * Poor insight was defined as a score 3 on each of the respective dimensions of the SUMD scale. SAIQ=Self-Appraisal of Illness Questionnaire; SUMD=Scale to Assess Unawareness of Mental Disease.

Dassa D et al. Aust N Z J Psychiatry. 2010;44(10):921-928. Nonadherent (n=89) Poor Insight Was Associated With Nonadherence 5 Adherent (n=26) Nonadherent (n=32) GAS 4 P<0.01 P<0.05 3 2.7 2.4 2 1.5 1.7 1 0 Lack of Feeling of Illness GAS=Global Assessment Scale. Bartk G et al. Acta Psychiatr Scand. 1988;77(1):74-76.

Lack of Insight Into Illness 16 P=0.013 12 10.3 Mean BIS Mean BIS Poor Insight in Schizophrenia Is a Well-Established Risk Factor for Relapse and Rehospitalization 16 P=0.001 12 10.2 8.8 8.1 8 8 4 4

0 0 Rehospitalized (n=84) Relapsed (n=120) Nonrelapsed (n=116) Not rehospitalized (n=152) The rate of relapse in patients with the best insight scores was 39% of the rate among patients with the worst insight scores BIS=Birchwood Insight Scale, rated from 0 to 16. Drake RJ et al. J Clin Psychiatry. 2007;68(1):81-86. Insight Varies Over Time Model of the etiology and implications of insight components over time Awareness of need for treatment Higher likelihood of treatment adherence and recovery Attitudes toward illness Awareness of consequences Depression, functional strategies

Reasoning biases Relabeling of symptoms as mental illness Neuropsychologica l deficits Awareness of symptoms Lincoln TM et al. Schizophr Bull. 2007;33(6):1324-1342. Time Attitudes toward treatment Implications Etiology Societal, cultural, and religious norms; prior experiences; mood Lower likelihood of dysfunctional coping strategies and acting on symptoms

Consequences of Nonadherence to Antipsychotics in Patients With Schizophrenia Poor Adherence Negatively Impacts Patient Outcomes Hospitalizations Hospitalizations were higher among those who did not adhere to antipsychotics (17.1% vs 29.6%; P<0.05)1 Length of stay Partially adherent patients had more total days hospitalized vs adherent patients (32.0 vs 8.8 days; P<0.05)1 Number of suicide attempts Suicide attempts were more frequent among patients who did not adhere to antipsychotic treatment (1% vs 0%; P=0.004)2 Number of episodes Nonadherent patients had a higher rate of >4 annualized episodes vs adherent patients (23% vs 10%; P<0.001)2 Recovery* Adherent patients are more likely to achieve recovery (OR: 2.25; CI, 1.45-3.51)3 Relapse rate Nonadherent patients are more likely to relapse vs adherent patients (OR: 10.27; CI, 2.59-40.67)4 * Defined as simultaneously achieving long-lasting symptomatic and functional remission and an

adequate quality of life for a minimum period of 24 months and maintained until the 36-month visit. CI=confidence interval; OR=odds ratio. 1 Ascher-Svanum H et al. BMC Res Notes. 2009;2:6. 2 Ahn J et al. Value Health. 2008;11(1):48-56. 3 Novick D et al. Schizophr Res. 2009;108(1-3):223-230. 4 Morken G et al. BMC Psychiatry. 2008;8:32. Nonadherent Patients With First-Episode Psychosis Were More Likely to Relapse 1.0 Adherence (n=92) Nonadherence (n=48) Fraction Survival (Patients Not Relapsed) 0.8 0.6 0.4 0.2 0.0 0 12 24 Months Caseiro O et al. J Psychiatr Res. 2012;46(8):1099-1105. 36

Nonadherence Predicts Relapse in Patients With Recent-Onset Schizophrenia Proportion Not Relapsed 1.0 0.9 Adherent (n=65) 0.8 Nonadherent* (n=35) 0.7 0.6 0.5 0.4 0.3 0.2 0 31 151 271 391 511 Days in Study Missing as little as 25% of the prescribed dosage over a period of 2 weeks significantly raised the risk of psychotic symptom return

* Nonadherence was defined as adherence with <50% of the prescribed medication dose for at least 2 weeks. All sources of information were considered in categorizing medication adherence. Typically, patient self-report and clinician judgments were available at each rating point, pill counts were available every 12 weeks, and plasma levels were assayed every 4 weeks. Subotnik KL et al. Am J Psychiatry. 2011;168(3):286292. Nonadherence Led to Worsened Symptoms and Decreased Functioning in Patients With Schizophrenia Measure Mean (SD) Adherent* (n=381) Nonadherent* (n=201) P Value Total -26.84 (19.66) -22.57 (21.20) 0.002 Positive factor -10.61 (8.07) -8.70 (8.75) 0.002 Negative factor

-5.59 (5.65) -4.79 (6.13) 0.058 Disorganized thought factor -4.41 (4.13) -3.84 (4.01) 0.035 Hostility factor -2.60 (3.04) -1.87 (3.61) <0.001 Depression factor -3.62 (3.43) -3.23 (3.57) 0.017 -1.14 (1.05) -0.96 (1.13)

0.05 12.14 (13.57) 9.54 (12.20) 0.036 -5.0 (6.91) -4.29 (7.93) 0.004 8.55 (18.81) 6.06 (18.19) 0.15 PANSS score CGI-S score GAF score MADRS total score QLS total score * Medication nonadherence was defined as not taking the full dose of medication as prescribed and was determined based on a daily pill count for each patient. CGI-S=Clinical Global Impression-Severity of Illness scale; GAF=Global Assessment of Functioning; MADRS=Montgomery-sberg Depression Rating Scale; PANSS=Positive and Negative Syndrome Scale, a trademark of Multi-Health Systems, Inc.; QLS=Quality of Life scale; SD=standard deviation. Lindenmayer JP et al. J Clin Psychiatry. 2009;70(7):990-996. Nonadherence to Antipsychotics and Relapse Are Associated With a High Health Care Burden

Annual health care costs are 2 to 3 times higher for patients who have had a recent relapse1,2 Adherence to antipsychotic therapy could save a Medicaid system $106 million in inpatient costs3 Loss of neuroleptic efficacy accounted for ~60% of hospitalization costs, while nonadherence was predicted to account for ~40%4 1 2 3 4 Hong J et al. Prog Neuropsychopharmacol Biol Psychiatry. 2009;33(5):835-841. Ascher-Svanum H et al. BMC Psychiatry. 2010;10:2. Marcus SC, Olfson M. Schizophr Bull. 2008;34(1):173-180. Weiden PJ, Olfson M. Schizophr Bull. 1995;21(3):419-249. Hospitalization Costs due to Patient Nonadherence Gilmer et al, 2004 Variables Svarstad et al, 2001 0MPR0.49 0.5MPR0.79 Refill gap 3 months US population in 2005, millions

296.4 296.4 296.4 Prevalence rate of schizophrenia 0.01 0.01 0.01 Nonadherence rate 0.24 0.16 0.19 Hospitalization rate for nonadherent patients 0.35 0.24 0.33 $3413 $2689

$3421 0.14 0.14 0.19 Annual hospitalization costs for adherent patients $1025 $1025 $1799 Hospital costs per day in 2005 $1658 $1658 $1658 Hospital costs per day in the study year of the corresponding studies $1096 $1096 $528 Subtotal, millions $1122

$357 $1392 Nonadherence measure and cut-off level Annual hospitalization costs for nonadherent patients Hospitalization rate for adherent patients Total, millions MPR=medication possession ratio. Sun SX et al. Curr Med Res Opin. 2007;23(10):2305-2312. $1479 $1392 P s y c h ia tr ic H o s p ita liz a tio n R a te Nonadherent Patients Were More Likely to Be Hospitalized 40 35 30 25 20 15 10 5 0 Nonadherent

* P<0.001 compared to adherent patients. Gilmer TP et al. Am J Psychiatr. 2004;161(4):692-699. Partially Adherent Adherent Excess Medication Filler Partial Adherence and Nonadherence Led to Increased Hospitalization 32 Time spent hospitalized * * * 8.8 17.6 Time, days 29.6 * 17.1 Rate % 30.6

Rate of hospitalization Adherent (n=1758) Partially adherent (n=36) Nonadherent (n=216) Adherent was defined as an MPR 80%, partially adherent was defined as an MPR 60% and <80%, and nonadherent was defined as an MPR <60%. * P<0.05 vs adherent. MPR=medication possession ratio. Ascher-Svanum H et al. BMC Res Notes. 2009;2:6. Adheren t (n=1758 ) Partially adherent (n=36) Nonadherent (n=216) Pa ti e nts H ospita lize d, % Nonadherent Patients Were More Likely to Be Hospitalized

P<0.001 25 20 15 10 5 0 Nonadherent Nonadherent was defined as an MPR <70%. MPR=medication possession ratio. Weiden PJ et al. Psychiatr Serv. 2004;55(8):886-891. Adherent

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