Managing First Episode Psychosis

Transcription

1 Managing First Episode Psychosis Abigail Donovan, M.D. Assistant Professor of Psychiatry, Harvard Medical School Director, First Episode and Early Psychosis Program MGH Schizophrenia Program Massachusetts General Hospital

2 Disclosures Neither I nor my spouse has a relevant financial relationship with a commercial interest to disclose.

3 Learning Objectives Recognize prodromal schizophrenia and understand options for intervention Understand key treatment goals for each phase of treatment of schizophrenia Understand interventions for comorbid health problems

4 Why do we care about schizophrenia anyway? Mental illnesses are the chronic diseases of the young Insel and Fenton, Arch Gen Psych 2005

5 Epidemiology of Schizophrenia Found in all cultures Lifetime prevalence of 1% Approx 72 million people affected worldwide Lifetime risk lower in females 1 Risk ratio males:females 1.42:1 Average age of onset years old Earlier in men, later in women 1. Aleman A et al. Arch Gen Psychiatry 2003;565

6 Psychosis in Boston

7 Definitions Childhood Onset (COS) Onset before age 13 Rare: <1% of all patients Very poor prognosis Cognitive delays are common 1 25% co-morbid ASD 2 High rate of false positives 2 25% re-diagnosed as bipolar Adolescent/Early Onset (EOS) Onset before age 18 ~ 30% of all FEP pts Compared to adult onset: Worse premorbid functioning Longer duration of untreated psychosis (DUP) More depression and SI Worse prognosis 1. Frangou, Front Hum Neurosci, 2010; Stayer C et al. JAACAP 2004:1026.

8 Genetics Overall heritability is 65-80% Many different genes implicated (>100 loci) 1 : COMT: catecholamine degradation, 22Q11DS MHC: immune and neurodevelopmental pathways NRXN1: regulation of neurotransmitters Key factor: advanced paternal age >45 yo: offspring have 2x risk for schizophrenia >50 yo: offspring have 3x risk for schizophrenia 1. PCG Nature 2014;

9 Environmental Factors Genetic vulnerability PLUS additional social and environmental factors lead to schizophrenia Environmental Factors Inflammation during gestation (viral exposure) 1 Starvation in prenatal period (Dutch Hunger Winter) Social Factors 2 Immigration Sexual trauma Bullying Major social stressors: losses, transitions 1. Canetta et al. Am J Psychiatry 2014; McGrath et al. Am J Psychiatry 2011;168;1235

10 Brain Changes MRI findings 1 : Increased ventricular volume Decreased hippocampal volume Decreased medial temporal lobe volume Decreased whole brain volume Brain abnormalities are present in drug naïve FEP patients 2 and to a lesser extent in prodromal patients 3 Antipsychotics may also cause mild volume loss 4,5 1.Guret al. Schizophr Bull, 2007; Ren. Am J Psychiatry 2013; Cerletti et al, Schizophr Bull 2012; Ho et al. Arch Gen Psych 2011; Lesh JAMA Psychiatry 2015;

11 Phases of illness *DUP Initiation of Antipsychotic 1-5 years 1-2 years* Positive Sx Negative Sx Prodromal Period Psychosis Post-Psychotic Period Based on Häfner, ABC Schizophreniestudie

12 Phases of treatment GOALS KEY QUESTION Prodromal Phase Acute Psychosis Prevent schizophrenia Keep DUP short Achieve early remission of symptoms Treat with antipsychotic? Which antipsychotic? What dose? When to switch? Post-psychotic Phase Achieve sustained remission Recovery and QOL Prevent morbidity Treat for how long? Courtesy of O. Freudenreich

13 Prodrome: Case example 15 year old boy, high school student, normal development In the past year, Grades have slipped from As to Cs He has not been seeing friends as much Not motivated to practice piano or basketball Mentioned to Mom that someone was following him MSE: engaged and cooperative, a little flat, +PI with insight

14 Prodrome Early prodrome symptoms are non-specific, thus frequently recognized retrospectively Social withdrawal Reduced concentration and attention: mimic ADHD Reduced drive and motivation Depression/Anxiety Poor hygiene Sleep disturbances Many teenagers will have these symptoms and not develop psychosis

15 What is the risk of conversion? PACE N=416 UHR patients followed for 15 years Highest rate of conversion in first 2 years: 20% Total conversion rate: % (comparable to 2 other studies) 0 PACE=Personal Assessment and Crisis Evaluation 1. Nelson et al. JAMA Psychiatry 2013; Yearly Transition Rate Yearly Transition Rate

16 Prevention? 3 RCT: Risperidone + CBT 1, CBT alone 2, Olanzapine 3 All interventions delayed onset of psychosis during treatment period, but did not prevent psychosis during follow up As soon as patients stopped treatment, they developed psychosis at equal rates No indication to use antipsychotic medication 1.McGorry et al. Arch Gen Psychiatry 2002; Morrison et al. Schizophr Bull 2007; McGlashan et al. Am J Psychiatry 2006;790-9.

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18 Omega g/d of omega-3 or placebo for 12 weeks, then 40 weeks of monitoring During active tx, sig. fewer conversions in omega-3 group After monitoring: Only 1 add l omega-3 pt converted Overall transition rate: 5% vs. 28% Omega 3 1. Amminger et al. Arch Gen Psychiatry 2010; Placebo 5% 28% P=0.007

19 Omega 3 Long term follow up Median 6.7 years Transition rate: 9.8% vs. 40% Protective effects of Omega 3 intervention were sustained long term Omega 3 Placebo 9.8% 40% P= Amminger et al. Nature Comms 2015;1-7.

20 How do we treat the prodome? Omega 3 may be beneficial and have little downside Results need to be replicated Psychosocial treatments may be beneficial and have little to no adverse effects We can also modify risk factors for progression

21 Cannabis Individual level: earlier age at onset Age at onset is years earlier in cannabis users Population level Frequent cannabis use in adolescents doubles risk of schizophrenia 3 Actively discourage cannabis use in youth 1. Dekker et al. Psychol Med 2012; Large et al. Arch Gen Psychiatry 2011; Moore et al. Lancet 2007;

22 Acute Psychosis: Case Example 18 yo, freshman in college, no formal psych history Stopped attending class due to poor concentration, grades now Ds Smoking cannabis daily Not socializing at all, rarely leaves dorm room Told parents he was hearing voices MSE: disheveled and malodorous, guarded, not engaged, self dialoging but denies hallucinations

23 DSM 5: Schizophrenia Two Criterion A symptoms for one month: Delusions Hallucinations Disorganized speech Disorganized behavior Negative symptoms One must be a core symptom Functional decline Total duration of symptoms: 6 months

24 Cognition Cognitive performance is 1-2 SD below age matched controls 1 Affected areas include: attention, executive fxn, memory, processing speed, social cognition 2 Cognitive decline is nearly universal, present before the onset of psychosis, and worsens during the illness 3 Chronic impairment is specific to schizophrenianot seen in bipolar disorder or depression 4 1. Keefe et al. Schizophr Bull 2007; Nuechterlein KH et al. Schizophr Res 2004; Kahn et al. JAMA Psych 2013; Meier et al. Am J Psychiatry 2014;

25 Cognition Antipsychotic treatment leads to very small improvements in cognitive subtests 1 Cognitive function is a critical determinant of global functional outcome 2 1.Frazier et al. JAACAP 2012; Kahn et al. JAMA Psychiatry 2013;

26 Medical Work Up Labs: Diagnostic testing: Chem 10 MRI CBC EEG LFTs TSH Good neuro exam B12/Folate ESR ANA Anti-treponemal antibodies/hiv Ceruloplasmin Toxicology screens Additional labs/testing as indicated by presentation Courtesy of O. Freudenreich

27 Anti-NMDAR Encephalitis Auto-antibodies are produced against the NMDA receptor, causing neurologic and psychiatric symptoms, including psychosis Definitive diagnosis is made by testing CSF for anti-nmdar antibodies 1 testing CSF: 100% sensitive testing serum: 85% sensitive 55% of pts have prodromal flu-like symptoms 2 1. Gresa-Arribas et al. Lancet 2014; Armangue et al. J Pediatr 2013;850-

28 Anti-NMDAR Encephalitis Subsequent symptoms include: Movement disorders: dyskinesias, choreoathetosis (84% of children 1 ) Seizures (77% of children 1 ) Decreased level of consciousness Autonomic instability (86% of children 1 ) Psych sx s: mood symptoms, agitation, bizarre behavior, AH/VH, delusions 1.Jones et al. Neuroimag Clin N Am 2013;

29 In FEP, when to test? Psychotic symptoms, plus: Movement disorders Seizures Autonomic instability Altered consciousness Will any patients be missed? Cohort Study: only 0.9% of patients have a purely psychiatric presentation 1 All patients had an abnormal MRI and/or EEG 1. Kayser MS JAMA Neurol 2013;

30 Acute Psychosis: Treatment Questions When do you start treatment? Which antipsychotic is first-line treatment? What dose do you use? How long do you treat before you switch? How long do you treat the first episode?

31 Treat ASAP Minimize duration of untreated psychosis (DUP) Early intervention is associated with: Improved clinical outcomes at 2 years 1 and 5 years 2 Higher GAF, improved social functioning, fewer symptoms at 20 years 3 Early intervention increases the chances of achieving initial remission 4 1. Melle et al. Arch Gen Psych 2008; Larsen et al. Psychol Med 2011; Cechnicki et al. Psych Res 2014; Fraguas et al. Schizophr Res 2014;

32 What antipsychotic to use? Café Trial 1 SGAs only Olanzapine, quetiapine and risperidone had comparable efficacy EUFEST 2 FGAs and SGAs Haloperidol, quetiapine, ziprasidone, amisulpride, olanzapine had comparable efficacy SGA s were more well tolerated: 33-53% vs 72% FGA discontinuation rate TEOSS 3 FGAs and SGAs, children only Molindone, olanzapine, risperidone had comparable efficacy and comparable discontinuation Olanzapine had significant weight gain 1.McEvoy et al. Am J Psychiatry 2007; Kahn et al. Lancet 2008; Sikich et al. Am J Psychiatry 2008;

33 Newer Antipsychotic Medications Paliperidone: 3-12 mg QD, approved yo Active metabolite of risperidone, similar SE profile Lurasidone: mg QD, w/ food, not approved in children Akathisia, less weight gain, more EPS? Asenapine: mg BID SL, approved for bipolar only Sedation, EPS, weight gain Iloperidone: 1-12 mg BID, not approved in children Sedation, weight gain Brexpiprazole: 2-4mg QD, not approved in children Partial D2 agonist, akathisia, weight gain

34 Cloz Olanz Risp Palip Halo Quet Aripip Asen Luras Ilo Comparative Efficacy Meta-Analysis Meta-analysis, 15 antipsychotics: FGAs, SGAs, Clozapine 1 Clozapine was significantly more effective Olanzapine and risperidone were more effective than most (small effect size); all others had similar efficacy Haloperidol had highest all cause discontinuation Medication Efficacy 1.Leucht et al. Lancet, 2013;

35 Bottom Line Because SGAs have similar efficacy, but are better tolerated than FGAs, start with an SGA Given that efficacy is generally similar between SGAs, consider different side effect profiles and individual patient vulnerabilities to make initial choice

36 What dose to use? First-episode patients are more responsive to medication FEP patients require lower doses of antipsychotics than multi-episode patients First-episode patients are more sensitive to side effects than multi-episode patients 1. Robinson et al. Schizophr Bull 2005;

37 What dose to use? FEP patients respond to lower doses of antipsychotics 1,2 Haloperidol Aripiprazole Olanzapine Risperidone Quetiapine FEP Daily Target Dose 2.1 mg 10 mg 11.7 mg 2.4mg 500 mg 1. Lieberman, Schooler, 2005

38 When to switch antipsychotics? Clinical improvement is slow Positive symptoms take weeks to resolve Negative symptoms take months/years (if they resolve at all) AACAP Guidelines: After 6 weeks, if there are insufficient effects while using adequate dosages, consider switching Patients without even minimal improvement at week 2 are unlikely to have later response 1 2 weeks of a therapeutic dose 1. Leucht et al. Am J Psychiatry, 2015;

39 Clozapine 20% of FEP patients will not respond to FGAs or SGAs Patients with 2 failed trials should be offered clozapine The only antipsychotic agent for which there is established superiority over other agents For tx refractory schizophrenia, clozapine is more beneficial than haloperidol and high dose olanzapine (66% vs 33%) 1 Clozapine can be used in adolescents, but adolescents are more sensitive to its side effects, especially 2 : akathesia (15% vs 3%) neutropenia (6% vs 1%) 1. Kumra, Biol Psychiatry 2008; Sporn, et al. JAACAP 2007;

40 How long to treat? AACAP Guidelines 2013 Most individuals need long term treatment and are at significant risk of relapse if medication is discontinued Maintain medication at the lowest effective dose to minimize adverse events After prolonged remission, a small number of individuals may be able to discontinue medication Change from 2001 guidelines- emphasized intermittent treatment or discontinuation

41 Relapse off Medication 3 year, open label trial 1 All FEP patients, stable for 2 years All patients underwent gradual medication taper Relapse rates: 79% at 1 year 97% at 3 years Recurrence Rate (%) 94% 97% 79% 12 months 24 months 36 months Recurrence Rate (%) 1. Emsley et al. J Clin Psychiatry, 2012;e541-e547

42 Maintenance Treatment Strongly encourage long term treatment at the lowest effective dose Most patients ask for a trial off medication They will do it with or without you After 1-2 years of stability, after significant discussion of risks, consider gradual taper, with close monitoring Multi-episode patients will need indefinite maintenance treatment

43 All about meds? RAISE Study Comprehensive tx vs. usual care Comprehensive tx: Med management, individual therapy, family psycho-ed, supp employment/ed Outcomes: Time in treatment, functioning, QLS, PANSS, depression, hospitalizations Quality of Life Score P= Kane et al. AJP in Advance 2015 doi:

44 Prognosis Short-term prognosis: Most (80%) achieve short term symptomatic remission 1 Long-term prognosis: Less than 40% maintain remission for >6 months 2 Relapse rate is very high (>82% during first 5 yrs) 3 Functional prognosis at 7 years 4 : 36% of patients are employed 22% of patients are employed and socially connected 14% are employed, socially connected & symptomatically remitted 1. Lieberman et al. J Clin Psychiatry 1993; Gaebel et al. Schizophr Res 2014; Robinson et al. Arch Gen Psychiatry 1999; Henry et al. J Clin Psych 2010;

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46 Morbidity and Mortality Schizophrenia is associated with a 20 year decrease in life expectancy 1 and a 4 fold increase in mortality 2 Premature mortality is due to cardiovascular dz, respiratory dz, infections and cancers 3 Even in FEP, cardiac and metabolic abnormalities are present early on 4 Related to underlying illness, unhealthy lifestyle, antipsychotic meds, inadequate medical care 1. Druss et al. Med Care 2011; Revier at al. J Nerv Ment Dis 2015; Olfson et al. JAMA Psychiatry 2015; Correll et al. JAMA Psychiatry 2014;

47 Antipsychotics and Weight Gain Children may be particularly prone to weight gain Naturalistic study: At 12 weeks, antipsychotic naïve youth gained 1 : 4.4 kg on aripiprazole 5.3 kg on risperidone 6.1 kg on quetiapine 8.5 kg on olanzapine 1. Correll et al. JAMA 2009;

48 Monitoring Baseline: BMI Fasting glucose, lipids, BP Family history of obesity, DM, CVD, HTN BMI: check at 4, 8, 12 weeks, every 3 months after Fasting glucose, lipids, BP: check at 3 months, then annually if normal Intervene for abnormalities!

49 Metformin N=148 patients with schizophrenia 1 Randomized to metformin 1,000 mg BID or placebo All patients received diet and exercise counseling 1. Jarksog et al. Am J Psychiatry, 2013;

50 Behavioral weight loss interventions 2 studies of behavioral weight loss interventions in patients with SMI 1,2 Diet and nutrition education, ind weight management, group exercise sessions Both studies demonstrated significant weight loss in intervention groups 1. Daumit et al. N Engl J Med, 2013; Green et al. Am J Psychiatry 2015;71-81

51 Summary Recognizing and intervening in the prodrome Omega 3 fatty acids Key treatment goals for each phase of the first episode Treat early with low doses of SGAs Encourage maintenance treatment for most patients Monitor and treat comorbid physical health conditions

52 Acknowledgements MGH Schizophrenia Program Oliver Freudenreich, MD Daphne Holt, MD, PhD Cori Cather, PhD John Tyson, MD Hannah Brown, MD Yosh Kaneko, MD THANK YOU!