Presentation on theme: "Schizophrenia: An overview of diagnosis and treatment"— Presentation transcript:
1Schizophrenia: An overview of diagnosis and treatment This slide presentation briefly reviews clinical features of schizophrenia, its costs, and considerations in selection of therapy.The role of ZYPREXA for the treatment of schizophrenia is described through a summary of the clinical studies documenting the efficacy and safety of ZYPREXA as a first-line therapy for treatment of schizophrenia.
2Epidemiology of Schizophrenia A disease process with multiple signs and symptoms involving thoughts, perceptions, emotions, and behavior1Most catastrophic mental illness1,2Peak incidence in males at 15 to 25 years of age and in females at 25 to 35 years of age1Global incidence: 1% in all societies3Course of illness is extremely variable, often chronic, and sometimes episodic1Florid symptoms may diminish with age, although years of dysfunction are rarely overcome1Schizophrenia is a disease process.1The peak incidence of schizophrenia occurs in young adults.1It rarely strikes before puberty.It is likely that both genetic and environmental factors play a role in the development of schizophrenia.1The clinical course of schizophrenia is variable, but often chronic.Years of disability associated with schizophrenia are rarely overcome.1Positive symptoms may diminish with age, but negative symptoms tend to persist.1
3Epidemiology of Schizophrenia Associated with heavy emotional burden4Often requires long-term caregiving450% of patients exhibit comorbid substance abuseEconomic impact22% of all mental illness costs in the United States5Annual direct and indirect costs estimated at $65 billion (1991)5Annual treatment costs may range from $10,000 to $70,000 per patient6-9Schizophrenia is associated with considerable indirect and direct costs:The annual direct and indirect costs of schizophrenia in the United States are an estimated $32.5 billion.5Direct costs include physicians’ bills, drugs, nursing home care, and services of mental health organizations and professionals.Indirect costs include morbidity, premature mortality, costs incurred by the criminal justice system, and family care giving.The annual per-patient treatment costs of schizophrenia may be $10,000 to $70,
4Behavioral Symptoms Positive Symptoms Negative Symptoms Mood DelusionsHallucinationsDisorganized speechSuspiciousnessExaggerated thoughtsNegative SymptomsAffective flatteningAlogia / AvolitionAnhedoniaSocial withdrawalMoodDepressionManiaAnxiety / AggressionCognitionAttention / MemoryOrganized ThinkingJudgment / InsightPositive symptoms: Delusions, hallucinations, suspiciousness and conceptual disorganizationNegative symptoms: Flat affect, lack of motivation, social withdrawalAlogia= decrease in speechAvolition= decrease in activitiesAnhedonia= decrease in ability to experience pleasureHostile behavior: Anger, belligerenceCognitive symptoms: Poor attention, disorganized thinking, lack of judgment and insight. Executive functioning …. Daily living skills
5Impact of Mood Symptoms Depressive symptoms present in up to 65% of patientsAffect all other core symptomsAffect all outcomes, including complianceHigher suicide rate40% Attempt / 10% CompletionDepressive and anxious symptoms:Are observed in up to 65% of patients with schizophrenia.10Affect core symptoms of schizophrenia.10Are associated with a higher suicide rate.11
6Interplay of Depressive and Other Symptoms of Illness in Schizophrenia Clinical IssuesInterplay of Depressive and Other Symptoms of Illness in SchizophreniaNegative SymptomsIllness Related SymptomsPositive SymptomsCognitive DysfunctionMood SymptomsEPSDepressive symptoms associated with schizophrenia:Affect both positive and negative symptoms.Are interrelated with:Cognitive dysfunctionFunctional impairmentEPSProlactin effectsProlactin EffectsFunctional ImpairmentMedication Related Side Effects
7Causes of Psychosis Dopamine Hypothesis Neurotransmitter Interaction Structural AbnormalitiesPrenatal or Perinatal Trauma
8Brain PathwaysFrom:Risch SC. Pathophysiology of schizophrenia and the role of newer antipsychotics. Pharmacotherapy 1996;15(1 pt 2):12S
10Dopamine Activity Overview Psychotic Symptoms:Caused by too much Dopamine activity in the limbic systemExtrapyramidal Symptoms:Not enough Dopamine activity
11Efficacy = Dopamine Blockade All Anti-psychotic medications MUST:BLOCK DOPAMINE RECEPTORSFor Superior Efficacy:SELECTIVE DOPAMINE BLOCKINGDegree of dopamine blockingActivity in selective areas of the brain (A9, A10)
12Degree of BlockadeAgent must block 50% of D2 receptors to begin controlling positive symptomsBlocking > 70% of D2 receptors may cause dose-dependant EPSPUBLISHED DATA SHOWS:Zyprexa & Clozaril50-60% D2 BlockadeRisperdal & Haldol80-90% D2 Blockade
13Selective Dopamine Blockade A-10 (Mesolimbic) PATHWAYThe "Efficacy Pathway"ZYPREXA is theorized to have strong activity hereA-9 (Nigral Striatal) PATHWAYThe "EPS Pathway"Typicals and Risperdal are theorized to be more active here (vs.. A-10)A-10 = GOODA-9 = BAD
14Patient Care The "Team Approach" PharmacologicPsychiatristPsychiatric Nurse / DONPsychologistMedical DirectorPrimary care physicianPhysician Assistant (PA)Nurse Practitioner (NP)Consultant / Clinical PharmacistCase Manager / Social workerFamily and friendsPsychologicalRehabilitationPsychosocial
15Considerations in Choosing Antipsychotics: Acute vs.Continuation Time to response: significant response may take 4 to 5 weeks of therapy with conventional agents12Symptom control/level of function: persistence of positive, negative, cognitive, or affective symptoms may indicate need to switchIncidence of adverse effects: EPS/TD, sedation, cognitive impairment, hypotension, sexual dysfunction (Risks vs. Benefits)Cost of therapy, including acquisition price and cost of necessary adjunctive meds or inpatient treatmentAvailable formulations: Dosing FlexibilityPrevious experience with an agent or classOBJECTIVES OF THERAPY:Acute/inpatient goals: Initial control of acute psychotic symptoms beginning week 1 (positive symptoms, agitation, hostile behavior, mood symptoms)Outpatient goals: Maintain and improve clinical effect over time, Improvement in negative symptoms, Improve depression-anxiety symptoms, Patient acceptance of therapy (minimize adverse effects such as EPS, prolactin effects)Several factors contribute to the ultimate choice of antipsychotic agent:Onset of action and whether rapid control of symptoms is neededEfficacy in symptom control, including positive and negative symptoms as well as mood, cognition, and behavioral symptomsSide effect profileTotal cost of therapyFormulations and their suitability for the individual patientClinician’s and patient’s past experience with a particular medication
16Chemical Structures Clozapine Olanzapine Quetiapine Haloperidol OHNNONONNNClNNNNNSSCH3HHClozapineOlanzapineQuetiapineCH3NNHOClOFNNNewer antipsychotic agents have been developed in an attempt to retain positive aspects of older agents, while minimizing drawbacks.In general, atypicals have 2 major advantages compared with typical antipsychotics:Efficacy in both positive and negative symptomsLower potential for certain side effects, including extrapyramidal side effectsONHaloperidolRisperidoneOF
17Receptor Binding Profiles OlanzapineClozapineHaloperidolAripiprazoleD1D2D45-HT2A5-HT2CMusca1RisperidoneQuetiapineZiprasidonea2H1Bymaster FP, et al. Neuropsychopharmacology. 1996;14(2):87-96.Schotte A, et al. Psychopharmacology (Berl). 1996;124(1-2):57-73.
18Anti-Psychotic Side Effects: Extrapyramidal Symptoms (EPS)Akathisia: Severe inner restlessnessDystonia: Involuntary muscle spasmsParkinsonism: Rigidity of the muscles, Tremor, Shuffling of feet"It can be argued that EPS are the most troublesome side effects…a major reason why patients discontinue their drug therapy"**Source: Casey DE. International Clinical Psychopharmacology. 1997;12 (suppl 1):S19-S27
19Anti-Psychotic Side Effects: TD (Tardive Dyskinesia)Involuntary muscle movements of the face, body and/or trunkOften Irreversible: Patient is disfigured, "looks like a psych patient"Typicals carry 5% risk of developing TD per year of exposure85% risk after 25 years of continuous exposure*Source: Casey DE. International Clinical Psychopharmacology. 1997;12 (suppl 1):S19-S27
20Anti-Psychotic Side Effects: Prolactin Related Side-EffectsShort TermAmenorrheaGalactorreaGynecomastiaSexual DysfunctionLong TermIncreased risk for OsteoporosisIncreased risk for Breast Cancer
21Other Limitations of Conventional Anti-Psychotics: Extrapyramidal symptoms (EPS)Tardive dyskinesia (TD)Prolactin elevationSedationQTc prolongationCognitive impairmentOrthostatic hypotensionCompliance / RelapseConventional antipsychotics may carry a substantial list of limitations both in terms of side effect profile as well as the potential for poor compliance and inadequate response.Among the most troublesome side effects of conventional antipsychotics are EPS, tardive dyskinesia, and cardiovascular toxicity.According to IMS Health data, conventional antipsychotics account for more than half of all antipsychotics currently prescribed by PCPs.
22Typical Antipsychotics Haldol, Mellaril, Thorazine, Prolixin, etc. Perceived AdvantagesPerceived DisadvantagesAvailable since the mid - '50sProven positive symptom efficacyFormulations:Short acting ( I.M.)Long acting (Depot)Generics available ($)Incomplete symptom efficacy (compared to atypicals)NegativeMoodCognitionHigh incidence of EPSIncreased risk for TDProlactin-related side effects
23The Bipolar patient...“My thoughts ran with lightning-like rapidity from one subject to another. All the problems of the universe came crowding in my mind, demanding instant discussion and solution--- mental telepathy, hypnotism, women’s right, all the problems of medical science, religion and politicsMonths later……...
24Bipolar Patient cont…..“I seem to be in a perpetual fog and darkness. I cannot get my mind to work. Instead of associations clicking into place, everything is an inextricable jumble. I could not feel more ignorant, undecided or inefficient. It is appallingly difficult to concentrate, and writing is a pain and grief to me”
25Classifications of Bipolar Bipolar I1 or more manic or mixed episodesMay be followed by 1 or more depressive episodesBipolar II1 or more depressive episodesaccompanied by at least 1 hypomanic episodemania not severe enough to cause “marked impairment”
26Subtypes: Rapid Cycling 4 or more mood episodes in 1 yearOccurs in 12-20% of bipolar patientsOccurs later in the illnessDifficult to treatMore common in womenInducible by antidepressantsUpon Treatment, more susceptible to pole flipping.
27Symptom Domains in Bipolar I Disorder Manic Mood and BehaviorDysphoric Mood and BehaviorEuphoriaGrandiosityPressured SpeechImpulsivityExcessive LibidoRecklessnessDiminished Need for SleepDepressionAnxietyIrritabilityHostilityViolence or SuicideCognitive SymptomsRacing ThoughtsDistractibilityPoor InsightDisorganizationInattentivenessConfusionPsychotic SymptomsDelusionsHallucinationsSensory Hyperactivity
28Symptom Descriptors for Bipolar Manic Episodesinflated self-esteem or grandiositydecreased need for sleepexcessive talkativenessracing thoughtsdistractibilityincreased physical activitypursuit of pleasurable but risky activitiespsychotic featuresDepressive Episodesdepressed mooddiminished interests or pleasurefatigueworthlessness or guiltpoor concentrationsuicidal thoughtsIncrease or decrease in:weight/appetitephysical activitysleep
29Classifications of Bipolar Depressive EpisodeManic EpisodeBIPOLAR IMixedEpisodeMood WithinNormal RangeRapidCyclingHypomanicEpisodeBIPOLAR IISubtypes of BipolarClassifications of Bipolar
30Epidemiology of Bipolar Disorder Psychotic symptoms occur in 47-75% of all patients at some point in the disease cycle2/3 of bipolar episodes present as depressionNo differences in race or gender50% have a family historyWomen with postpartum depression at higher riskSymptoms usually first appear between the ages of 15-24Prevalence rates from 1.2% - 1.6%• Prevalence is similar between men and women• Women appear more likely to be depressed at the first episode and more likely to develop rapid cycling47-75% of pts hospitalized with bipolar disorder experience psychotic symptoms*Compared to an 18% rate for those without bipolar
31Effect on Social Functioning Ability to work declines in 66% of patientsSocial functioning declines in 50% of patientsRepresents a high divorce rate60% suffer from substance abuse issuesMay be self medicatingMasks illness in early stagesPredictor of early onset (before age of 20)Significant impact on expected life span and personal health
32Morbidity of Bipolar Disorder Recurrent illness in 85-95% of patientsFunctional recovery often lags behind symptomatic and syndrome recoveryRecurrent episodes may lead to progressive deterioration in functioningNumber of episodes may affect subsequent treatment response and prognosisPatients with Bipolar Disorder usually suffer long-term disruption of their lives.Symptomatic episodes can persist for months or longer if not treated
33Mortality in Bipolar Disorder 25%-50% attempt suicideSuicide completion rate ~19%50% suicidal ideation in mixed maniaBipolar Disorder is a high mortality illness % of patients attempt at least once.Studies estimate that at least 11% kill themselves, this is 25X the rate of the general populationeffective treatment of Bipolar Disorder can literally be life- saving.Other features that may carry higher suicide risk include:presence of psychosisFirst onset of illnessRapid cyclingRecent switch in mood state
34Schizophrenia vs. Bipolar Schizophrenia BipolarThinking Disorder which can affect moodPrimarily a mood disorder that can affect thinking & judgmentSchizophrenia is primarily a thought disorder which can effect mood whereas Bipolar disorder is primarily a mood disorder which can effect thought. Schizoaffective disorder falls in-between the two.Psychotic disorderAffective Disorder
35Contrasts of Schizophrenia and Bipolar Disorder Key SimilaritiesGenerally treated by psychiatristsPsychotic symptoms are frequent during maniaAntipsychotics were drugs of choice through 1960slithium as a "mood stabilizer"Awareness of TD risk (greater risk in bipolar ?)High utilization of health care systemProblems with treatment complianceKey DifferencesDifferent core symptomsDifferent courses of illnessBipolar patients are less consistently "sick" and outcomes get closer to "well”Bipolar patients are more likely to commit suicideTreatment paradigmstherapeutic settingtreatment goalsmedication choicesWhile some similarities exist, mostly a different patient population with different treatment paradigms
36Related Disease Outcomes level offunctioningThis slide looks at the differences of progression of schizophrenia , schizoaffective disorder and bipolar disorder.Patients with bipolar are able to get back to a higher level of functioning, close or at the level prior to and episode, where as patients with schizophrenia experience a slow steady downward drift.Patients with schizoaffective disorder are similar to patients with bipolar disorder in that they do experience some improvement during asymptotic periods, yet outcomes do deteriorate over time.Bipolar Schizoaffective SchizophreniaSchizoaffective: has features of both schizophrenia and mood disorders. Best diagnosis for patients whose clinical syndrome would be distorted if it were considered as only schizophrenia or only a mood disorder. (Kaolin and Sadock, 1996)
37Diagnosis of Bipolar Disorder High rates of misdiagnosis - Important to determine longitudinal courseMay be diagnosed as unipolar depressionMay be mischaracterized as adolescent behaviorMay be masked by substance abuseA psychiatrist is most often the one who ultimately makes the correct diagnosisInvolvement from various members of the health care team(Psychologist, Psych Nurse, etc.)84% of Bipolar Patients are initially diagnosed with something else.
38Olanzapine Data Suggest Effects Across Multiple Neurotransmitter Systems Olanzapine ActionRelevance to BipolarDopamineDirect DA receptor antagonistDA antagonists reduce psychotic symptomsSerotoninMultiple, balanced 5HT receptor antagonist5HT may affect mood, violence, suicideAcetylcholineIndirect Ach agonistCholinomimetics may reduce mania, improve cognitionWhile knowledge is not conclusive regarding the mechanism of action,Zyprexa's effect on several neurotransmitter systems corresponds to those postulated to be beneficial to Bipolar DisorderBlockade of Dopamine helps to reduce psychotic symptoms, but may also have anti-manic properties and help with mood-stabilization.Serotonin (particularly the 5HT2 antagonism may suggest antidepressant/ antianxiety potential)GABA= Gamma-Amino Butyrate , a primary inhibitory neurotransmitter, found to inhibit dopamine secreting neurons.Glutamate the brains most prevalent neurotransmitter.. Some evidence that lithium and valproic acid enhance glutamate as well . Role is not understood.GABAIndirect GABA agonistMay help reduce manic symptomsGlutamateModulates and stabilizes glutamate transmissionMay help regulate mood stability
39Current Treatment Paradigm for Psychiatrists (For psychosis associated with acute mania)A/PM/SA/PMaintenance TreatmentMOOD STABILIZERA/DFor recurrent psychotic featuresFor recurrent depressivefeaturesA/DM/SAntipsychotics are currently not considered a standardtherapy for long term treatment of bipolar
40Attributes of Ideal Mood Stabilizer for Mania Rapid efficacy for maniaFavorable cognitive effectsTreats psychotic symptoms of maniaLong-term usefulnessBroad efficacy (e.g., mixed, rapid cycling)Safe & well-toleratedReduces depressive elements in maniaEase of useAdapted from Keck Jr. PE, McElroy SL. In: Nathan PE, Gorman JM, eds. A Guide to Treatment that Works. New York: Oxford University Press, 1997
41Young Mania Rating Scale (Y-MRS) Elevated moodHypersexualityIrritabilityRacing thoughts / flight of ideasDisruptive behaviorIncreased activityDecreased sleepAbnormal thought contentRapid/pressured speechInappropriate appearancePoor insightY-MRS scale widely used in mania trials to quantitate the 11 symptoms listed on the slide. This scale captures most of the core manic symptoms11 items are scored 0-4 or 0-8, min score = 0 ; max score =60To be eligible to enroll in study, a Y-MRS as at least 20 was required, This would correlate to a moderately severe score , that reflects a general need for hospitalization.Response was defined as a greater than or equal to 50%v improvement in the Y-MRS scoreEuthymia was defined prior to the study as a Y-MRS score < 12. This definition was also used in the studies for Lithium and Valproic Acid.Y-MRS was the primary efficacy variable for both studies
42Psychosis in Bipolar Disorder Prevalence55% of patients had at least one psychotic symptom by clinician evaluation90% of patients had at least one psychotic symptom by self-reportMore common in mania than in depressionStabilized bipolar patients with history of psychotic features have relapse rates two to three times those without history of psychosisOver half of acutely manic patients have psychotic features, most commonly delusions.Psychotic symptoms are likely to reoccur in subsequent manic episodesPatients with psychotic symptoms appear capable of full recovery, there are studies that suggest they are less able to sustain remission and may relapse more sooner than stabilized manic pts who were free of psychosisGoodwin FK, Jamison KR, 1990; Keck Jr. PE et al, 1998; Pope HG, Lipinski JF, 1978; Tohen et al, 1990
43Reasons for Non-Compliance Symptoms of the illnessPatients don't want to “lose the high”Feelings of GrandiosityBlood monitoringStigma of a medicationFear of taking an “antipsychotic”Unwanted Side EffectsHigher functioning pts - more sensitive?Co-morbid substance abuseConsidered the most consistent predictor of poor compliancePartial efficacyMultiple daily dosingMore unique tobipolar disorderStigma: Bipolar Consumers: I can be a contributing member of society, Family Members: stigma gets in the way of resourcesInsight into Illness: Bipolar Consumers: Denial, Enjoy Mania, Family Member: Denial of affect on their family"The System“: lack access to medication, multiple MD switches: impacts med changesIn lithium treatment studies, 18-53% of subjects are non-compliant with medications*Patient survey reveals that cognitive dulling (memory problems) is the side effect most likely to provoke drug discontinuation against medical advice*Olanzapine does not worsen and may improve cognitive functioning in mania
44Symptom Domains in Bipolar I Disorder Manic Mood and BehaviorDysphoric Mood and BehaviorEuphoriaGrandiosityPressured SpeechImpulsivityExcessive LibidoRecklessnessDiminished Need for SleepDepressionAnxietyIrritabilityHostilityViolence or SuicideCognitive SymptomsRacing ThoughtsDistractibilityPoor InsightDisorganizationInattentivenessConfusionPsychotic SymptomsDelusionsHallucinationsSensory Hyperactivity