Treatment of Patients with First- Episode Psychosis S. Charles - - PowerPoint PPT Presentation

Multidisciplinary Approach to Treatment of Patients with First- Episode Psychosis

• S. Charles Schulz, MD

Professor Emeritus Psychiatrist, PrairieCare

Disclosure Information

May 16, 2016

• S. Charles Schulz, MD

Disclosure of Relevant Financial Relationships

I have the following financial relationships to disclose:

• Grant/research support from:

NIMH, Myriad/RBM, Otsuka

• Consultant for:

FORUM, Lundbeck, Merck Manual

Disclosure of Off-Label and/or Investigative Uses

I will be discussing off label use and/or investigational use in my presentation and identify those issues.

Introduction

• In the last two decades there has been significant literature

about First Episode Schizophrenia and the significance of Duration of Untreated Psychosis (DUP).

• Recent work at NIMH has led to greater recognition of the

needs of first episode patients and reducing the DUP – a federal government allocation has been made to states.

• Recent assessment in this area reported the average length of

time to first treatment at 78 weeks.

First Episode Psychosis An Integrated Care Model

Care Coordinator Medical Director

Identify & Treat Prodrome Reduce DUP Evaluation of 1st Episode Medication Treatment (In- and Out- Patient Family Psychoeduca- tion & Support Cognitive Behavioral Treatment (CBT) Day Treatment & Neurocognitive Remediation

Sikich L, Efficacy of atypical antipsychotics in early-onset schizophrenia and other psychotic

• disorders. J Clin Psychiatry, 2008; 69[suppl 4]:21-25.

Initial Medial Work-up of First Episode Psychosis

Freudenreich, et al., Early Intervention in Psychiatry 3:10-8; 2009

• The phrase “First Episode Psychosis” leads to the need for a careful

initial evaluation to lead to an accurate assessment in the psychosis domain.

• Family input to the initial assessment is crucial for the patient and

begins support of families – also don’t forget siblings.

• Leading university programs have work up strategies to make sure

the illness is not caused by a medical issue – e.g. Wilson’s disease.

• Some programs encourage neuropsychological assessment to assist

in approving functional outcomes and identifying specific cognitive issues.

Normal Control vs Child High Risk HVLT-R t-score Group Mean Comparison

42 44 46 48 50 52 54 56 Baseline Exit NC CHR

• a. Baseline Independent Samples t-test (2-tailed)*: p=0.095, t=-1.75, df=25
• b. Exit Independent Samples t-test (2-tailed): p=0.155, t=-1.48, df=20

*Baseline Independent Samples t-test Ho ≠ Ha p<0.05 (sig.1-tailed), t=-1.75, df=25

Overgard S. et al., ICOSR, March 2015

Long-chain Omega-3 Fatty Acids for Indicated Prevention of Psychotic Disorders: A Randomized, Placebo-controlled Trial

• Introduction: The authors note the usefulness of omega-3 fatty acids for

psychiatric illness and lack of side-effects. They aimed to assess the compound in sub-threshold psychosis.

• Methods: RCT in 81 subjects at ultra-high risk of psychotic disorder – 81

subjects were enrolled in this 12 month study.

• Results: 76/81 subjects completed the trial. In the omega-3 group, 2/41

converted to psychosis while 11/40 converted in the control group. Of note is that symptoms were reduced.

• Conclusions: The authors note a reduction of conversion to a psychotic

disorder and note omega-3 was safe.

Amminger et al., Arch Gen Psychiatry, 2010;67(2): 146-54.

The Neurapro-E Study: A Multicenter RCT of Omega-3 Fatty Acids and Cognitive-Behavioural Case Management for Patients at Ultra High Risk of Schizophrenia and Other Psychotic Disorders

• Background: The authors note previous studies have examined strategies

to prevent psychosis in prodromal subjects. They conducted a large study

• f omega-3 polyunsaturated fatty acids.
• Methods: The design was a double-blind and placebo-controlled study of

6 months duration. They included case management.

• Results: Impressively, the study included 304 subjects and 78% stayed in

the trial for 6 months. At the ICOSR meeting, the authors note no difference between omega-3 and placebo, but many were prevented from progressing in the overall intervention.

McGorry P et al., The Neurapro-E Study….Abstracts for the 15th International Congress

• n Schizophrenia Research (ICOSR), March 2015 Colorado Springs, CO, USA

Discussion Points

• Can the Prodrome be accurately identified using symptoms,

biomarkers, family history (or genes)?

• Are there ways to specify the direction of Prodromal

symptoms in order to apply specific treatments?

• Is there adequate data to recommend treatment approaches

to the Prodrome?

• In other branches of medicine, there are concerns of over

diagnosis of early stages of illness. How can such concerns be dealt with in the Prodrome?

First Episode Psychosis An Integrated Care Model

Care Coordinator Medical Director

Identify & Treat Prodrome Reduce DUP Evaluation of 1st Episode Medication Treatment (In- and Out- Patient Family Psychoeduca- tion & Support Cognitive Behavioral Treatment (CBT) Day Treatment & Neurocognitive Remediation

Cognitive Deficits in Recent-Onset and Chronic Schizophrenia

Sponheim S.R., Jung R.E., Seidman L.J., Mesholam-Gately R., Manoach D.S., O’Leary D.S., Ho B.C., Andreasen N.C., Lauriello J., Schulz S.C. Cognitive Deficits in Recent-Onset and Chronic Schizophrenia. Journal of Psychiatric Research 2010;(44)7:421-428

Relationship between Duration of Untreated Psychosis and Outcome in First Episode Schizophrenia: A Critical Review and Meta-analysis

Perkins DO et al., Am J Psychiatry 2005;162:1785-1804

First Episode Psychosis An Integrated Care Model

Care Coordinator Medical Director

Identify & Treat Prodrome Reduce DUP Evaluation of 1st Episode Medication Treatment (In- and Out- Patient Family Psychoeduca- tion & Support Cognitive Behavioral Treatment (CBT) Day Treatment & Neurocognitive Remediation

An MRI Study of Adolescent Patients with Either Schizophrenia or Bipolar Disorder as Compared to Healthy Control Subjects

Friedman L. et al., Biological Psychiatry, 1999

Alterations in Patterns of Gyrification in Children and Adolescents with Schizophrenia

White et al., (2003) Biological Psychiatry

Cortical Folding Defects as Markers of Poor Treatment Response in First Episode Psychosis

• Importance: Authors noted no reliable predictors to distinguish first episode

psychosis patient’s treatment response. They assessed gyrification.

• Participants: Total subjects = 126

First Episode = 80 Controls = 46 Patients received 12 weeks of treatment.

• Results:
• Patients had hypogyria compared to controls.
• Nonresponders had hypogyria on both insula areas, left frontal and right

temporal regions.

• Seen in both affective and non-affective psychosis.
• Conclusions: Gyrification may be a useful predictor. Early neurodevelopmental

issues may predict unfavorable prognosis.

Palaniyappan L et al., JAMA Psychiatry online Aug 14, 2013.

Clusters Showing Differences in Gyrification Among Responders, Nonresponders, and Controls. No clusters showed significant results in the opposite directions to the contrasts shown in the

• Figure. All clusters are displayed on a

reconstructed average white matter surface (fsaverage in FreeSurfer software) and survived multiple testing using Monte- Carlo simulation with a cluster inclusion criterion of P = .05. The left hemisphere is

• n the left side of the image, and the right

hemisphere is on the right side. The exact values of clusterwise probability for the clusters are presented in Table 2.

JAMA Psychiatry. 2013;70(10):1031-1040.

Cortical Folding Defects as Markers of Poor Treatment Response in First Episode Psychosis

Changes in Resting State Connectivity Following Treatment in First Episode Schizophrenia

• Background: Resting state fMRI used to describe disrupted connectivity of

brain functional networks. Further there are changes alterations pre and post treatment in schizophrenia.

• Methods: Twelve subjects with schizophrenia who had suffered first episode

and did not have previous medication treatment had an image on a 3T MRI

• scanner. The subjects received antipsychotic medication and then a second
• scan. They received PANSS interviews at the time of both scans. They received

second generation antipsychotic treatment.

• Results: The data was prepared with the relation of symptom measures and

network organization. Treatment was 10 weeks. There was a statistical correlation of positive symptoms and change in diversity of connectivity.

• Discussion: This technique can assist in pathophysiology of treatment. It can

help in assessing individual treatment.

Schulz SC et al., SIRS Poster, 2012.

Association of Changes in Network Organization with Change in Clinical Symptoms in First Episode Schizophrenia Patients Following 10 Weeks of Treatment

Changes in Resting State Connectivity Following Treatment in First Episode Schizophrenia S.Charles Schulz, Shauna M Overgaard, Chen DaChun, Xue-Dong Yang, Thomas R Kosten, Xiang Yang Zhang, Kelvin O Lim, SIRS, 2012

Neuropsychologic Test Results

• f Adolescents

First Episode Psychosis An Integrated Care Model

Care Coordinator Medical Director

Identify & Treat Prodrome Reduce DUP Evaluation of 1st Episode Medication Treatment (In- and Out- Patient Family Psychoeduca- tion & Support Cognitive Behavioral Treatment (CBT) Day Treatment & Neurocognitive Remediation

Risperidone and haloperidol in first-episode psychosis: a long-term randomized trial.

• Objective: In first-episode psychosis there is significant importance to reduce

relapse and to affect the willingness to accept treatment.

• Method: In a long lasting trial (median treatment length 206d), first episode

subjects were randomized to risperidone (mean 3.3 mg) or haloperidone (2.9 mg.)

• Results: Using the PANSS measure the investigators saw significant improvement

for both groups, but no differences. In the long study - relapse in the risperidone group at 466 days and for haloperidol at 205 days. Regarding side-effects, the haloperiodol group had more extra pyramidal symptoms (EPS.) There was more increased prolactin in the risperidone group. Less weight gain in the haloperidol group in the early phase.

• Conclusions: There were significant decreases in symptoms for a large number of
• patients. Longer response for risperidone and less movement disorder.

Schooler N et al., Risperidone and haloperido in first-episode psychosis… Am J Psychiatry, 2005 May;162(5):947-53.

Efficacy and Tolerability of Olanzapine, Quetiapine, and Risperidone in the Treatment of Early Psychosis: A Randomized, Double-Blind 52-Week Comparison

McEvoy JP, et al., Am J Psychiatry 2007; 164:1050-1060

Long-Acting Injectable Risperidone for Relapse Prevention and Control of Breakthrough Symptoms After a Recent First Episode of Schizophrenia A Randomized Clinical Trial

• Objective: To compare efficacy of long-acting injectable to oral

formulation – early course of schizophrenia

• Methods: A randomized trial of 86 patients who are recent onset
• schizophrenia. Half of each group received either cognitive

behavior therapy or healthy-behaviors training.

• Results: The authors note that 3 subjects refused LAI. Psychosis

exacerbation and/or relapse was significantly lower in the LAI group (5% v. 33%; p=0.01). There were no statistically significant differences between the psychosocial treatments.

• Conclusion: The authors comment on advantages of LAI in the first

episode group.

Subotnik KL et al., JAMA Psychiatry, Aug 2015;72(8):822-29.

Long-Acting Injectable Risperidone for Relapse Prevention and Control of Breakthrough Symptoms After a Recent First Episode

• f Schizophrenia

A Randomized Clinical Trial

JAMA Psychiatry. 2015;72(8):822-829. doi:10.1001/jamapsychiatry.2015.0270

Prescription practices in the treatment of first-episode schizophrenia spectrum disorders: data from the national RAISE-ETP study

• Introduction: As part of the RAISE study to address treatment in First Episode

patients, the authors assessed the medication treatments of the young subjects.

• Methods: The authors note an assessment of the treatment for the First Episode

patients – 404 participants.

• Results: As a goal of this report, the authors noted 159 (39.4%) of subjects might

have done better with standard RAISE approaches. – 8.8% - doses were higher than recommended – 32.1% - on olanzapine-many on high doses – 23.3% - on more than 1 antipsychotic – 36.5% - on an added antidepressant without any explanation – 10.1% - on psychiatric meds, but not antipsychotic – 1.2% - on stimulants

• Conclusions: Service delivery factors need to address this issue to improve
• utcomes.

Robinson DG et al., Prescription practices in the treatment of first-episode schizophrenia spectrum disorders…. Am J Psychiatry. 2015 Mar 1;172(3):237-48

Early Use of Clozapine for Poorly Responding First-Episode Psychosis

• The investigators noted that a subgroup of first-episode patients

have ongoing psychotic symptoms

• Patients in the CAMH program followed a medication algorithm.

76% of the 123 patients who agreed to try clozapine were compared to those who refused

• The clozapine treated group had a 19-point reduction in BPRS

scores (from 53.5 to 34.5), while the other patients had a 2-point increase

• The authors noted reluctance to use clozapine early in the illness

and suggested that clozapine may have an important role in early- stage patients

CAMH = Centre for Addiction and Mental Health; BPRS = Brief Psychiatric Rating Scale. Agid O, et al. J Clin Psychopharmacol. 2007;27(4):369-373.

Response Rates for Antipsychotic Trials 1 and 2 (Olanzapine or Risperidone) followed by Trial 3 (Clozapine)

Agid O et al., J Clin Psychiatry. 2011;72(11):1439-1444.

First Episode Psychosis An Integrated Care Model

Care Coordinator Medical Director

Identify & Treat Prodrome Reduce DUP Evaluation of 1st Episode Medication Treatment (In- and Out- Patient Family Psychoeduca- tion & Support Cognitive Behavioral Treatment (CBT) Day Treatment & Neurocognitive Remediation

First Episode Family Psychoeducation

• Week 1: To introduce terms – e.g. psychosis,
• schizophrenia. To begin discussion of causes of psychotic
• illness. How diagnosis is made.
• Week 2: Introduce psychological issues. Discuss Cognitive

Behavior Therapy. Communication issues with the family member with the illness.

• Week 3: Look at biological background and talk about

medications.

First Episode Family Psychoeducation

• Week 4: Address symptoms such as hallucinations and

delusions – including ways to deal with them. Issues with jobs.

• Week 5: Discuss the issue of insight and how to deal with

the challenging issue.

• Week 6: Discussion of plans to avoid relapse – includes
• pen communication and issues of adherence.

First Episode Psychosis An Integrated Care Model

Care Coordinator Medical Director

Identify & Treat Prodrome Reduce DUP Evaluation of 1st Episode Medication Treatment (In- and Out- Patient Family Psychoeduca- tion & Support Cognitive Behavioral Treatment (CBT) Day Treatment & Neurocognitive Remediation

Cognitive Behavior Therapy for Psychosis

• Can be adapted for First Episode – individual or group.
• Clinician provides information about psychosis and

relation of symptoms to stress.

• This can reduce embarrassment.
• Next steps are ABC:
• Antecedents to psychosis
• Beliefs
• Emotional and Cognitive consequences

Mueser KT, Deavers F, Penn DL, Cassisi JE. Psychosocial Treatments for

• Schizophrenia. Annu. Rev. Clin. Psychol. 2013.9:465-497.

First Episode Psychosis An Integrated Care Model

Care Coordinator Medical Director

Identify & Treat Prodrome Reduce DUP Evaluation of 1st Episode Medication Treatment (In- and Out- Patient Family Psychoeduca- tion & Support Cognitive Behavioral Treatment (CBT) Day Treatment & Neurocognitive Remediation

MCCB Domain and Composite Scores Pre and Post Cognitive Remediation

Murray A. et al., ICOSR, March 2015

Scores from the BPRS Pre and Post Cognitive Remediation

Murray A. et al., ICOSR, March 2015

Cognitive Remediation Therapy

• To assist in improving cognition, computer

programs were developed to especially address sustained attention and working memory

• At University of Minnesota, such a program was

applied to patients with schizophrenia and

• utcomes measured by fMRI. Not only did

performance improve, but regional metabolism increased

Haut, Lim and MacDonald. (2010) Prefrontal Cortical Changes Following Cognitive Training in Patients with Chronic schizophrenia: Effects of Practice, Generalization, and

• Specificity. Neuropsychopharmacology. 35: 1850-1859

Aerobic Exercise Improved Cognitive Performance

Joe Ventura, Ph D, UCLA – Washington, DC Conference April 6, 2016 - SIRS

• First Episode subjects with schizophrenia (16) were

assigned to cognitive remediation – 4 hrs/wk

• Seven of the group were given 4 hrs/wk of aerobic

exercise while 9 had brain training. The subjects who exercised had better cognitive outcome.

• A second study of longer length shows very good
• utcome.

Conclusions

• Studies of the early stages of schizophrenia have added

significant understanding of the neuroscience of the illness and to strategies for treatment.

• Even though there are continuities in neuropsychological

and imaging studies, there are differences in psychopharmacology which require attention.

• Psychosocial treatments are crucial for outcome in young

people – for example family therapies. Further, neurocognitive remediation has significant potential.