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Understanding the Course of Schizophrenia: Symptoms, Prognosis, and Treatment Response

This course explores the heterogeneous nature of schizophrenia, including its positive and negative symptoms, underlying pathophysiology, and treatment response. It also examines the progression of the disease and the impact on functional decline and prognosis.

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Understanding the Course of Schizophrenia: Symptoms, Prognosis, and Treatment Response

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  1. Course, Natural History and Prognosis Schizophrenia

  2. Course of Schizophrenia

  3. Schizophrenia is a heterogeneous disease with many dimensions Negative symptoms Disorganization Positive symptoms Dimensions underlying pathophysiology and treatment response Motor symptoms Cognitive deficits Mood symptoms Tandon R, et al. Schizophr Res. 2009;110(1-3):1–23.

  4. Schizophrenia: A broad range of symptoms Positive symptomsExcess or distortion of normal functions2 • Delusions1 • Hallucinations1 • Disorganised thought/speech1 • Grossly disorganised or catatonic behaviour1 Negative symptomsDecline in or loss of normal functions2 • 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 Cognitive symptomsKey component of schizophrenia3 • 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. APA. 2013. APA. 2000. Wilk et al. Neuropsychology. 2005;19(6):778–786.

  5. 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: Premorbid Prodromal Psychotic Residual Healthy Onset Clinical deterioration begins here and occurs throughout the first 5–10 years before the first episode Worsening level of functioningseverity ofsigns andsymptoms The longer the period of untreated psychosis, the worse the prognosis Number of relapses may be related to greater deterioration Illness-driven decline in functioning plateaus Age, years2 Birth 10 20 30 40 50 60 Adolescence to early adulthood Remainder of life Critical years Childhood 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):884-897.

  6. Typical Course of Schizophrenia Recuperative/Recovery(several months) Residual(several months or more) Acute Phase(≈1 to 6 months) Prodromal Phase Marked decrease in function Psychotic symptoms begin Positive symptoms; negative symptoms and impaired functioning remain 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.

  7. Many patients experience symptoms that are not fully controlled with treatment According to physician ratings, 47–60% 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, Little or no control Negative symptoms Positive symptoms Only some control 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”. Percentage of patients with symptoms that are not fully controlled 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):371–379.

  8. 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 withthe group without residual symptoms1 Residual symptoms in remitted patients with a schizophrenia spectrum disorder after acute inpatient treatment were highly prevalent (94%) P=0.0003 Only 6% of patients in remission did not have a residual symptom at discharge from hospital 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 ClinNeurosci. 2015;265(2):107–16. 2. Andreasen et al. Am J Psychiatry. 2005;162(3):441–449.

  9. Disorganization, a common residual symptom,1 is associated with impaired community functioning Disorganization is a reliable predictor of several aspects of community functioning:2 * ** ** *** * 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 ClinNeurosci. 2015;265(2):107–16. Norman RM, et al. Am J Psychiatry. 1999;156(3):400–5.

  10. 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 Interpersonalskills -0.27* Functional capacity -0.21* Depression Community activities -0.13 0.28* -0.20* Work skills *p<0.05. N=78 Interpersonal Skills Prediction Model fit: ²=8.22, df=9, p=0.52; comparative fit index=0.99. Community Activities Prediction Model fit: ²=10.37, df=9, p=0.32; comparative fit index=0.99 Work Skills Prediction Model fit: ²=10.08, df=10, p=0.43; comparative fit index=0.99. Bowie CR, et al. Am J Psychiatry. 2006;163(3):418–25.

  11. 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*** Interpersonalrelations (social) Primary negative symptoms r = –0.24*** Use of common objects and activities (recreational) r = –0.30*** ***p<0.001 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 Heinrichs–Carpenter Quality of Life Scale (QLS). Instrumental role functioning (vocational) Fervaha G, et al. Eur Psychiatry. 2014;29(7):449–55. Lehman AF, et al. [APA Practice Guidelines] 2010.

  12. 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

  13. Prognosis

  14. Schizophrenia Is a Progressive and Cyclical Disease Characterized by Multiple Psychotic Relapses Following a relapse, patients often fail to recover to the same degree1 Premorbid Prodromal Healthy Onset Deterioration Worsening level of functioningseverity ofsigns andsymptoms Chronic/residual Birth 10 20 30 40 50 60 Age, years2 Although the majority of patients with schizophrenia exhibit a severe pattern of deterioration, different degrees of severity and temporal sequences do occur1 Lieberman JA, et al. Biol Psychiatry. 2001;50(11):884-897. Lewis DA, Lieberman JA. Neuron. 2000;28(2):325-334.

  15. Early, Continuous Treatment of Schizophrenia Improves Treatment Outcomes * 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.

  16. Poor Treatment Outcomes Early in the Course of Schizophrenia Led to Measurable Neurological Damage AdaptedfromLieberman J, et al. Biol Psychiatry. 2001;49(6):487-499.

  17. A Variety of Symptom Clusters Contribute to Functional Impairment Positive symptoms1,2 Delusions Disorganizedthought Disorganized speech Hallucinations Lack of insight2 Functional impairment2 Ability to work Coping with self care Establishing social relationships Negative symptoms1 Flatorbluntedaffectand emotion Poverty of speech (alogia) Inability to experiencepleasure (anhedonia) Lack of desire to form relationships (asociality) Lack of motivation (avolition) Cognitive impairment1 Episodic memory Inappropriate affect Executive function Working memory 1Tandon R, et al. Schizophr Res. 2009;110(1-3):1-23. 2 American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision. Washington, DC: American Psychiatric Association; 2000.

  18. Some Patients With Schizophrenia May Achieve Recovery With Effective Treatment In a 3-year observational study, adults with schizophrenia (N=6642) achieved1: • Employment, independent living, social activity, and medication adherence were all significantly associated with achieving recovery1 • 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. Novick D, et al. Schizophr Res. 2009;108(1-3):223-230. White C, et al. Psychol Med. 2009;39(9):1447-1456.

  19. Patients With Schizophrenia Who Achieved Symptomatic Remission Had Significantly Better Personal and Social Functioning P=0.001 P<0.001 GAF=Global Assessment of Functioning scale; PSP=Personal and Social Performance scale. Brissos S et al. Schizophr Res. 2011;129(2-3):133-136.

  20. 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 WHOQOL=World Health Organization Quality of Life measure. Brissos S, et al. Schizophr Res. 2011;129(2-3):133-136.

  21. Symptomatic Remission in Schizophrenia Led to Significantly Better Insight and Fewer Depressive Symptoms 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 2.5 2.0 1.5 1.0 0.5 0 P=0.013 P=0.003 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.

  22. Excess mortality in severe mental illness1 • Serious mental illness (including schizophrenia) confers: • 20–25 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;374:620–7. 2. Saha S et al. Arch Gen Psychiatry. 2007;64(10):1123-1131.

  23. Relapse

  24. Relapse is common in schizophrenia Cumulative relapse rates in schizophrenia, by year following recovery from the first episode1 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 (104 patients at risk of relapse) Years after recovery from previous episode 1. Robinson et al. Arch Gen Psychiatry. 1999;56:241–247; 2. Csernansky & Schuchart. CNS Drugs. 2002;16(7):473–484; 3. Kane. J Clin Psychiatry. 2007;68(Suppl 14):27–30; 4. Lewis & Lieberman. Neuron. 2000;28:325–344; 5. Levander et al. Acta Psychiatr Scand. 2001;104(Suppl 408):65–74; 6. Briggs et al. Health Qual Life Outcomes. 2008;6:105

  25. 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 1. Emsley et al. BMC Psychiatry 2013;13:50; 2. Alvarez-Jimenez et al. Schizophr Res 2012;139(1–3):116–128; 3. Kane. J Clin Psychiatry 2007;68(Suppl 14):27–30 Findings from a systematic review and meta-analysis of 29 longitudinal studies1,2

  26. 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(1–3):117–121.

  27. 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;56:241–247. 2. Kane J. J Clin Psychiatry. 2007;68(Suppl 14):27–30. 3. Kinon et al. Psychopharmacol Bull. 29, 309-314.

  28. Relapse and treatment – Emergent adverse effects have substantial impact on patient’s quality of life Relapse has the highest impact on quality of life (lowest utility value) of the various health states measured: 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.

  29. 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):2057–2066.2. Emsley et al. Schizophr Res. 2013;148(1–3):117–121.

  30. Days to remission after eachrelapse Lieberman J, et al. J ClinPsychiatry. 1996;57:5–9.

  31. Impact of Relapse on Patients With Schizophrenia

  32. Short- and Long-term Consequences of Relapse Are Substantial to Patients Increased risk of recurrent psychotic episodes Cumulative deterioration in functioning Short-term Long-term Interruptions in antipsychotic therapy Hospitalizations Diminished ability to maintain employment or relationships Nasrallah HA, Lasser R. J Psychopharmacol. 2006;20(6 suppl):57-61.

  33. 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 PANSS™=Positive and Negative Syndrome Scale, a trademark of Multi-Health Systems, Inc. Emsley R, et al. Schizophr Res. 2012;138(1):29-34.

  34. Relapse Can Decrease Patient Functioning P<0.05 GAF=Global Assessment of Functioning. Almond S, et al. Br J Psychiatry. 2004;184:346-351.

  35. Impact of Early Intervention for Patients With Schizophrenia

  36. Shorter Duration of Psychosis Led to Improved Outcomes in Patients With First-Episode Schizophrenia P=0.025 DUI=duration of untreated illness; DUP=duration of untreated psychosis. Owens DC, et al. Br J Psychiatry. 2010;196(4):296-301. Primavera D, et al. Ann Gen Psychiatry. 2012;11(1):21.

  37. Patients With First-Episode Schizophrenia Areat 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 1Tiihonen J, et al. Am J Psychiatry. 2011;168(6):603-609. 2 Robinson D, et al. Arch Gen Psychiatry. 1999;56(3):241-247.

  38. 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 SyndromeScale, a trademark of Multi-Health Systems, Inc.; Gaebel W, et al. J ClinPsychiatry. 2011;72(2):205-218.

  39. Supportive Relationships Can Improve Long-term Adherence and Reduce Relapse Risk in Patients With Schizophrenia

  40. 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 doctor–patient 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.

  41. 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 wasoperationalized as the total number of statements thatillustratedfamilycaregiver ‘‘task-oriented’’ assistance, such as completion of errands; e.g., ‘‘I helpedhimfill out an employmentapplication.’’ Ramírez García JI, et al. SocPsychiatryPsychiatrEpidemiol. 2006;41(8):624-631.

  42. Family-Supervised Treatment Led to Significant Improvement in Symptoms and Functioning PANSS™ total score GAF score P=0.003 P=0.008 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.

  43. 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 Patients with a supportivefamilywereabouttwice as likelyto remain in treatment for the duration of the study CATIE=Clinical Antipsychotic Trials of Intervention Effectiveness. Glick ID, et al. J ClinPsychopharmacol. 2011;31(1):82-85.

  44. Involving Patients in Their Own Care Increases Knowledge About Their Disease 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=0.03 P=0.01 * Knowledge was assessed with a 7-item questionnaire about the patient’s disease and its treatment. COMRADE=Combined Outcome Measure for Risk Communication and Treatment Decision Making Effectiveness. Hamann J et al. ActaPsychiatr Scand. 2006;114(4):265-273.

  45. Simple Techniques Improve the Communication Between Patients and Clinicians P<0.05 P<0.03 Steinwachs DM et al. Psychiatr Serv. 2011;62(11):1296-1302.

  46. A Strong Therapeutic Alliance and High Patient Insight Was Significantly Correlated With Adherence to Medication 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 AssessUnawareness of Mental Disorder. Misdrahi D et al. Nord J Psychiatry. 2012;66(1):49-54.

  47. High Prevalence of Nonadherence to Medication Among Patients With Schizophrenia

  48. Rates of Medication Nonadherence in Chronic Nonpsychiatric Conditions and Schizophrenia Nonpsychiatric conditions Schizophrenia N=706,032.1 * Defined as having a medicationpossession ratio (MPR) <80% during a 1-year study. Briesacher BA, et al. Pharmacotherapy. 2008;28(4):437-443. Byerly M, et al. Psychiatry Res. 2005;133(2-3):129-133.

  49. Few Patients With Schizophrenia Take Their Medication as Prescribed MPR=medicationpossession ratio. Gilmer TP et al. Am J Psychiatry. 2004;161(4):692-699.

  50. Clinicians Overestimated Patient Adherence to Medication Adherent Nonadherent Adherent Nonadherent Clinician Rating Scale Score (Measure of Adherence) MEMS=medication event monitoring system. Byerly M et al. Psychiatry Res. 2005;133(2-3):129-133.

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