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Across the Spectrum:<br />
Managing First-episode and<br />
Relapsed Schizophrenia
Leslie Citrome, MD, MPH<br />
Clinical Professor of Psychiatry &<br />
Behavioral Sciences<br />
New York Medical College<br />
Valhalla, NY
Diana O. Perkins, MD, MPH<br />
Professor, Department of Psychiatry<br />
University of North Carolina at Chapel Hill<br />
Medical Director, Outreach and Support<br />
Intervention Services (OASIS)<br />
Chapel Hill, NC
Objectives<br />
• Examine diagnostic methodologies that assist in<br />
identifying first-episode schizophrenia so that the<br />
appropriate therapy can be administered early.<br />
• Assess therapeutic methods and modalities that<br />
assist providers and patients with improving<br />
adherence to schizophrenia treatment.<br />
• Evaluate the safety, efficacy, and tolerability of<br />
therapeutic advances that may improve outcomes<br />
in patients with first-episode or relapsed<br />
schizophrenia.
Outline<br />
• Achieving Appropriate and Timely Diagnosis<br />
– Symptomatic domains of schizophrenia and implications for treatment<br />
– DSM-5 and domain ratings<br />
– Diagnosis of early disease<br />
• Treatment of First-episode Schizophrenia and Reducing Relapse - New and<br />
Emerging Treatment Options<br />
– Treatment of first-episode schizophrenia<br />
– Review of the anticipated new second-generation antipsychotics<br />
– Compare and contrast new and older second-generation antipsychotics in reducing<br />
relapse<br />
• Adherence in Schizophrenia<br />
– Challenges of adherence in chronic illnesses<br />
– Strategies to improve adherence<br />
– Emerging therapies that may improve adherence<br />
– Emerging delivery and administration methods that may improve adherence
Outline<br />
• Achieving Appropriate and Timely<br />
Diagnosis<br />
– Symptomatic domains of schizophrenia and<br />
implications for treatment<br />
– DSM-5 and domain ratings<br />
– Diagnosis of early disease
When to Diagnose?<br />
Progressive Stages of Illness in Schizophrenia<br />
Premorbid<br />
Prodromal<br />
Onset/<br />
Deterioration<br />
Residual/Stable<br />
Healthy<br />
Margin of Prevention<br />
Worsening<br />
Severity of<br />
Signs and<br />
Symptoms<br />
Abnormal Brain<br />
Development<br />
Sensitization by dopamine (?)<br />
Excitatory neurotoxicity of glutamate (?)<br />
Neurochemical<br />
Dysregulation<br />
Neurodegeneration<br />
Gestation/Birth 10 Puberty 20 30 40 50<br />
Years<br />
Adapted from: Lieberman JA, et al. Biol Psychiatry. 2001;50(11):884-897.
When to Diagnose?<br />
Progressive Stages of Illness in Schizophrenia<br />
Premorbid<br />
Prodromal<br />
Onset/<br />
Deterioration<br />
Residual/Stable<br />
Healthy<br />
Margin of Prevention<br />
Worsening<br />
Severity of<br />
Signs and<br />
Symptoms<br />
Abnormal Brain<br />
Development<br />
Sensitization by dopamine (?)<br />
Excitatory neurotoxicity of glutamate (?)<br />
Neurochemical<br />
Dysregulation<br />
Neurodegeneration<br />
Gestation/Birth 10 Puberty 20 30 40 50<br />
Years<br />
Adapted from: Lieberman JA, et al. Biol Psychiatry. 2001;50(11):884-897.
When to Diagnose?<br />
Progressive Stages of Illness in Schizophrenia<br />
Premorbid<br />
Prodromal<br />
Onset/<br />
Deterioration<br />
Residual/Stable<br />
Healthy<br />
Margin of Prevention<br />
Worsening<br />
Severity of<br />
Signs and<br />
Symptoms<br />
Abnormal Brain<br />
Development<br />
Sensitization by dopamine (?)<br />
Excitatory neurotoxicity of glutamate (?)<br />
Neurochemical<br />
Dysregulation<br />
Neurodegeneration<br />
Gestation/Birth 10 Puberty 20 30 40 50<br />
Years<br />
Adapted from: Lieberman JA, et al. Biol Psychiatry. 2001;50(11):884-897.
How to Diagnose?<br />
Domains of Psychosis<br />
Disorganized<br />
Speech<br />
Abnormal<br />
Psychomotor<br />
Behavior<br />
Negative<br />
Symptoms<br />
Impaired<br />
Cognition<br />
Depression<br />
Hallucinations<br />
Mania<br />
Delusions<br />
In DSM-5, severity for psychosis is rated quantitatively from 0 (not present) to 4 (present<br />
and severe) on delusions, hallucinations, disorganized speech, abnormal psychomotor<br />
behavior, and negative symptoms, plus other domains are available to rate as needed.<br />
Heckers S, et al. Schizophr Res. 2013;150(1):11-14.
How to Diagnose?<br />
Domains of Psychosis<br />
Disorganized<br />
Speech<br />
Abnormal<br />
Psychomotor<br />
Behavior<br />
Negative<br />
Symptoms<br />
Impaired<br />
Cognition<br />
Depression<br />
MAY SEE<br />
THESE<br />
SYMPTOMS<br />
FIRST<br />
Hallucinations<br />
Mania<br />
Delusions<br />
In DSM-5, severity for psychosis is rated quantitatively from 0 (not present) to 4 (present<br />
and severe) on delusions, hallucinations, disorganized speech, abnormal psychomotor<br />
behavior, and negative symptoms, plus other domains are available to rate as needed.<br />
Heckers S, et al. Schizophr Res. 2013;150(1):11-14.
Treatment of First-episode Schizophrenia and<br />
Reducing Relapse:<br />
New and Emerging Treatment Options<br />
• Treatment of first-episode schizophrenia<br />
• Review of the anticipated new secondgeneration<br />
antipsychotics<br />
• Compare and contrast new and older<br />
second-generation antipsychotics in<br />
reducing relapse
Treatment of First-episode<br />
Schizophrenia<br />
Diana Perkins, MD, MPH<br />
Professor, Department of Psychiatry<br />
University of North Carolina at Chapel Hill<br />
Medical Director, Outreach and Support Intervention<br />
Services (OASIS)<br />
Chapel Hill, NC
Stage-based Interventions<br />
Acute Psychosis<br />
• Treatment goals:<br />
– Establish therapeutic alliance<br />
– Psychosis remission<br />
• Treatment modalities<br />
– Antipsychotic monotherapy<br />
§ Low dose<br />
§ Encourage use of LAI once efficacy and tolerability established<br />
§ Clozapine after 2 to 3 efficacy failure<br />
– Individual supportive psychotherapy<br />
– Family therapy
Stage-based Interventions<br />
Early Recovery<br />
• Metabolic adverse effects<br />
– Monitor: weight, lipids, A1C<br />
– Prevent:<br />
§ Lifestyle counseling<br />
§ Pharmacological: Metformin 500 to 2000 mg daily<br />
• Hyperprolactinemia-related adverse effects<br />
(bone demineralization, hypogonadism)<br />
– Monitor<br />
§ Measure prolactin in risperidone, paliperidone, and typical<br />
antipsychotic treated patients<br />
– Prevent<br />
§ Pharmacological: aripiprazole, bromocriptine<br />
Ajmal A, et al. Psychosomatics. 2014;55:29-36; Kelly DL, et al. BMC Psychiatry. 2013;13:214; Mizuno Y, et al. Schizophrenia<br />
Bull. 2014;40:1385-1403.
Stage-based Interventions<br />
Early Recovery<br />
• Treat-to-Target:<br />
– Negative symptoms: Primary versus secondary<br />
– Anxiety/poor stress tolerability<br />
• Treatment modalities<br />
– Antipsychotic dose adjustment<br />
– Individual psychotherapy with focus on functional<br />
recovery, improved stress tolerability<br />
– Complimentary treatments:<br />
§ N-acetyl-cysteine<br />
§ L-theanine
N-Acetyl Cysteine: Clinical Trial<br />
• Rationale<br />
– N-acetyl cysteine is a glutathione<br />
precursor, oral administration<br />
increases glutathione levels<br />
• Subjects: 140 subjects with<br />
schizophrenia<br />
• Design: 24-week, randomized,<br />
double-blind, placebocontrolled<br />
augmentation on<br />
current antipsychotic<br />
• Treatment: 1000 mg BID N-<br />
acetyl cysteine<br />
• Outcomes: N-acetyl cysteine<br />
augmentation is associated<br />
with reduced total (P = .009),<br />
negative (P = .028), and<br />
general psychopathology<br />
10<br />
9<br />
8<br />
7<br />
6<br />
5<br />
4<br />
3<br />
2<br />
1<br />
0<br />
NAC<br />
PANSS<br />
Total<br />
Placebo<br />
PANSS<br />
Positive<br />
PANSS<br />
Negative<br />
Berk M, et al. Biol Psychiatry. 2008;64(5):361-368.
N-Acetyl Cysteine: Clinical Trial<br />
• Rationale<br />
– N-acetyl cysteine is a glutathione<br />
precursor, oral administration increases<br />
glutathione levels<br />
• Subjects: 42 subjects with<br />
schizophrenia, acutely psychotic<br />
• Design: 8-week, randomized,<br />
double-blind, placebo-controlled<br />
augmentation on current<br />
antipsychotic<br />
• Treatment: 1000 mg BID N-acetyl<br />
cysteine<br />
• Outcomes: N-acetyl cysteine<br />
augmentation is associated with<br />
reduced total (P = .006), negative<br />
(P = .001), and general<br />
psychopathology (P = .005), not for<br />
positive symptoms (P = .42)<br />
– No adverse effects were reported<br />
Farokhnia et al. Clinical Neuropharmacology 2013;36:185-192<br />
60<br />
50<br />
40<br />
30<br />
20<br />
10<br />
0<br />
PANSS<br />
Total<br />
NAC<br />
Placebo<br />
PANSS<br />
Positive<br />
PANSS<br />
Negative
L-Theanine: Clinical Trial<br />
• Rationale<br />
– L-theanine biologically active amino acid<br />
in tea<br />
– High affinity kainate, AMPA, NMDA<br />
receptors<br />
– Has anti-oxidant effects<br />
– Reduces stress response<br />
• Subjects: 60 subjects with schizophrenia<br />
• Design: 8-week, randomized, doubleblind,<br />
placebo-controlled augmentation<br />
on current antipsychotic<br />
• Treatment: 400 mg/day L-theanine<br />
• Outcomes: L-theanine augmentation<br />
associated with reduced positive<br />
symptoms (P = .004, and general<br />
psychopathology (P
Recently Approved<br />
Antipsychotics
Cariprazine: Clinical Trial<br />
• Rationale<br />
– D2 partial agonist: selective impact on<br />
dopamine system<br />
– D3 partial agonist: potential impact on<br />
negative symptoms and cognition<br />
• Subjects: 439 subjects with<br />
schizophrenia<br />
• Design: 6-week, randomized, doubleblind,<br />
placebo-controlled trial<br />
• Treatment: 3 to 6 mg, 6 to 9 mg dosing<br />
• Outcomes:<br />
– Placebo vs 3 to 6 mg dose: total P=.003,<br />
positive P=.003, and negative symptoms<br />
(P=.15)<br />
– Placebo vs 6 to 9 mg dose total P
Brexpiprazole: Clinical Trial<br />
• Rationale<br />
– D2 partial agonist: selective impact on<br />
dopamine system<br />
• Subjects: 636 subjects with<br />
schizophrenia<br />
• Design: 6-week, randomized, doubleblind,<br />
placebo-controlled trial<br />
• Treatment: 0.25 mg, 2 mg, 4 mg<br />
dosing<br />
• Outcomes:<br />
– Placebo vs 2 mg dose: total P=.0006,<br />
positive P=.003, and negative<br />
symptoms (P=.0007)<br />
– Placebo vs 4 mg dose total P
Paliperidone Palmitate versus Placebo for<br />
Relapse Prevention<br />
• N=506, Study compared once/3-mo formulation) versus placebo<br />
• First time to relapse significantly favored paliperidone palmitate versus<br />
placebo (HR=3.45; 95% CI, P
Relapse Prevention<br />
• Relapse<br />
– Most patients will relapse if antipsychotics are discontinued<br />
– Interferes with normal psychosocial development<br />
– Interferes with educational and vocational achievements<br />
– Risk of harm to self, others, or property higher during active psychosis<br />
– Risk of involuntary hospitalization increases<br />
– Prognosis may be negatively impacted<br />
• Some people have worse schizophrenia than others<br />
– 10% to 15% highly treatment resistant<br />
– 10% to 15% benign course<br />
• Treatment approach<br />
– Collaborative, informed decision making<br />
– Relapse prevention planning and monitoring<br />
– Early recognition and intervention if symptoms return
Meta-analysis: Relapse Rates<br />
First Generation versus Second Generation<br />
• Subjects: 23 studies, n=4504 with schizophrenia<br />
• Study duration: ≥3 months<br />
• Outcomes:<br />
• Risk of relapse higher in persons treated with first<br />
generation versus second generation<br />
antipsychotics (P=.0007), Number-needed-totreat<br />
= 17 (95% CI: 10-50)<br />
• Lower rates with second versus first generation:<br />
• Relapse at 3, 6, 12 months (P=.04, P
Not All First-episode Patients Relapse<br />
• 207 persons with first-episode<br />
schizophrenia<br />
100<br />
• 24 had only a single episode in<br />
7.5 years<br />
75<br />
• Predictors* of a single episode<br />
included shorter duration of<br />
untreated psychosis and more<br />
rapid time to response to<br />
medication<br />
50<br />
25<br />
• Single-episode patients all<br />
stopped taking antipsychotic<br />
medication during follow-up<br />
period**<br />
0<br />
Single Episode<br />
Multiple Episode<br />
*Including only predictors that survived adjustment for multiple testing; **Personal communication Alvarez-Jimenez<br />
Alvarez-Jimenez M, et al. Schizophr Res. 2011;125:236-246.<br />
26
Are Some Patients<br />
Harmed by Antipsychotics?<br />
• Subjects: 7-year follow-up of 128 subjects, 103 agreed<br />
to participate<br />
• Following initial remission, half randomized to dose<br />
reduction, half to maintenance treatment<br />
• ~10% on typical antipsychotic<br />
• Outcomes<br />
• DR group had less overall exposure to<br />
antipsychotics<br />
• Relapse rates similar, most patients in both groups<br />
had trial off of antipsychotic<br />
• Symptom remission at 7 years similar in both<br />
groups<br />
• Functional remission* 46% DR vs 20% MT (P=.01)<br />
• Full recovery 40% DR vs 18% MT (P=.004)<br />
• 8 DR and 3 MT did not relapse after stopping<br />
antipsychotics<br />
Wunderink L, et al. JAMA Psychiatry. 2013 Sep;70(9):913-20.<br />
Cumulative Survival<br />
0.9<br />
0.6<br />
0.3<br />
0<br />
DR MT<br />
500 Days 3000 Days<br />
Time to Relapse from t6, d<br />
*Groningen Social Disability Schedule
Do Antipsychotics Contribute to<br />
Gray Matter Loss?<br />
All Antipsychotics, size of circle reflects relative sample size in study.<br />
P=0.028<br />
Mean Daily Antipsychotic Dose Administered During Scan Interval<br />
(chlorpromazine equivalents)<br />
Image used with permission. Vita A, et al. Biol Psychiatry. 2015;78(6):403-412.<br />
28
Do Antipsychotics Contribute to<br />
Gray Matter Loss?<br />
Any treatment with “typical” antipsychotics, size of circle reflects relative sample size in study.<br />
P=0.003<br />
Mean Daily Antipsychotic Dose Administered During Scan Interval<br />
(chlorpromazine equivalents)<br />
Image used with permission. Vita A, et al. Biol Psychiatry. 2015;78(6):403-412.<br />
29
Do Antipsychotics Contribute to<br />
Gray Matter Loss?<br />
Only treated with “atypical” antipsychotics, size of circle reflects relative sample size in study.<br />
clozapine olanzapine quetiapine risperidone ziprasidone multiple-atypicals<br />
P=0.003<br />
Mean Daily Antipsychotic Dose Administered During Scan Interval<br />
(chlorpromazine equivalents)<br />
Image used with permission. Vita A, et al. Biol Psychiatry. 2015;78(6):403-412.<br />
30
Outline<br />
• Adherence in Schizophrenia<br />
– Challenges of adherence in chronic illnesses<br />
– Strategies to improve adherence<br />
– Emerging therapies that may improve<br />
adherence<br />
– Emerging delivery and administration methods<br />
that may improve adherence
Scope of the Adherence Problem<br />
§ Medication adherence is poor across physical<br />
and psychiatric disorders 1<br />
§<br />
Medication adherence is particularly poor in persistent<br />
disorders where treatments are designed to prevent symptom<br />
onset or recurrence, and the consequences of stopping<br />
treatment are delayed<br />
§ ~75% of patients with schizophrenia become<br />
nonadherent within 2 years of hospital<br />
discharge 2<br />
1<br />
Nose A, et al. Psychol Med. 2003;33:1149-1160. 2 Weiden PJ, et al. Psychiatry Serv. 1995;46:1049-1054.
Clinical Consequences of<br />
Nonadherence Are Severe<br />
• ~50% of patients who discontinue/do not take<br />
antipsychotics will relapse within 3 to 10<br />
months 1,2<br />
• Relapse rates are much higher in nonadherent<br />
patients 3<br />
§ 69% of patients with poor adherence relapsed compared<br />
with 18% of patients with good adherence (NNT=2)<br />
1<br />
Blackwell B. Clin Pharmacol Therapy. 1972;13:841-848. 2 Hirsch SR, et al. Schizophrenia. Oxford,<br />
England: Blackwell Science; 1995:443-468. 3Morken G, et al. BMC Psychiatry. 2008;8:32.
Partial Adherence Increases the<br />
Rate of Rehospitalization<br />
Patients Rehospitalized, %<br />
25<br />
20<br />
15<br />
10<br />
5<br />
0<br />
6<br />
12<br />
0 1-10<br />
16<br />
11-30 >30<br />
22<br />
Maximum Therapy Gap, Days within 1 year<br />
Weiden PJ, et al. Psychiatr Serv. 2004;55:886-891.
Suicide Attempts Increase<br />
When Therapy Is Interrupted<br />
100<br />
Suicide Attempt Rate/<br />
1000 person/y<br />
80<br />
60<br />
40<br />
20<br />
20<br />
72<br />
Age/gender-adjusted<br />
relative risk increased<br />
4.2 times (95% CI:<br />
1.7-10.1)<br />
0<br />
No Interruption<br />
n=399<br />
≥30-day Interruption<br />
n=204<br />
Data obtained from drug-dispensing and hospital discharge records (Netherlands) for<br />
schizophrenic patients (sample size, 603) in database (N=865,000) with drug interruption and<br />
≥30-day gap in treatment. Risk estimates were controlled for differences in age and gender.<br />
Herings RM, et al. Pharmacoepidemiol Drug Saf. 2003;112:423-424.
Hazard Ratio<br />
Stopping Medication Is the Most Powerful<br />
Predictor of First-episode Relapse<br />
6<br />
5<br />
4<br />
3<br />
2<br />
1<br />
0<br />
4.89<br />
First<br />
Relapse<br />
4.57<br />
Second<br />
Relapse<br />
Sample of 104 first-episode schizophrenia patients<br />
who responded to treatment of their index episode but<br />
were at risk for relapse.<br />
• Relapse risk is 5 times<br />
higher after a first-episode<br />
patient stops antipsychotic<br />
medication 1<br />
• Predictors of nonadherence<br />
in first year:<br />
– Early adolescent premorbid<br />
adjustment (P
Unfortunately,<br />
We Overestimate Adherence<br />
– Nonadherence viewed as failure → consistent bias to<br />
overestimate adherence/underestimate nonadherence<br />
– We assume lack of adequate response as “treatmentresistance”<br />
and lack of efficacy for the antipsychotic for<br />
that patient<br />
§ This is a possible explanation for high dosing of antipsychotics,<br />
polypharmacy with other antipsychotics and combination<br />
treatment with anticonvulsants<br />
♦ This is a no-win cycle: adherence is even more of a challenge<br />
with complex regimens<br />
Velligan DI, et al. Psychiatr Serv. 2007;58(9):1187-1192.
We Can Identify<br />
Risk Factors for Nonadherence<br />
These Can Differ for Each Patient<br />
Patient-related 1<br />
• Poor insight<br />
• Negative attitude<br />
toward medication<br />
• Prior nonadherence<br />
• Substance abuse<br />
• Cognitive impairment<br />
Treatment-related 1<br />
• Adverse effects<br />
• Lack of efficacy/<br />
continued symptoms<br />
Environment/Relationshiprelated<br />
1<br />
• Lack of family/social support<br />
• Problems with therapeutic alliance<br />
• Practical problems<br />
(financial, transportation, etc.)<br />
Societal-related 2<br />
• Stigma attached to illness<br />
• Stigma caused by medication<br />
adverse effects<br />
1. Velligan DI, et al. J Clin Psychiatry. 2009;70(suppl 4):1-46.<br />
2. Lee S, et al. Soc Sci Med. 2006;62(7):1685-1696.
Reverberations from Adverse Effects<br />
How Patient and Clinician Responses May Differ<br />
Adverse effect<br />
appears<br />
Influencing patient response<br />
Subjective<br />
Distress<br />
Objective<br />
Severity<br />
Influencing clinician response<br />
Adherence<br />
Impact<br />
Safety and Risk<br />
Weiden PJ, et al. J Clin Psychiatry. 2007;68(suppl 6):14-23.
It Is Nice to Have Choices<br />
– Different antipsychotics, each with their own tolerability profiles<br />
– Different formulations, each with their own advantages and<br />
disadvantages<br />
§ Regular capsules and tablets<br />
§ Liquid concentrates/oral suspensions<br />
§ Orally disintegrating tablets (swallowed)<br />
§ Orally disintegrating tablets (sublingual administration)<br />
§ Inhaled powders (use in agitation only)<br />
§ Fast-acting intramuscular antipsychotics (use in agitation)<br />
§ Long-acting intramuscular antipsychotics (acute or maintenance<br />
treatment)<br />
§ Long-acting oral antipsychotics?
Long-acting Injectable Antipsychotics Lower<br />
Risk of Rehospitalization After First<br />
Hospitalization for Schizophrenia<br />
Any depot injection compared with equivalent oral formulation<br />
Adjusted<br />
Hazard Ratio<br />
Rehospitalization<br />
95% CI P<br />
0.36 0.17-0.75 .0007<br />
Tiihonen J, et al. Am J Psychiatry. 2011;168:603-609.
Long-acting Injectable Antipsychotics Lower<br />
Risk of Rehospitalization After First<br />
Hospitalization for Schizophrenia<br />
Any depot injection compared with equivalent oral formulation<br />
Adjusted<br />
Hazard Ratio<br />
Rehospitalization<br />
95% CI P<br />
0.36 0.17-0.75 .0007<br />
Tiihonen J, et al. Am J Psychiatry. 2011;168:603-609.
Impact of Collaborative Care<br />
• Recovery of a normal life in the community<br />
• Reduce impairments, disabilities, and handicaps<br />
• Active family involvement<br />
• Build on patients’ strengths, interests, and<br />
capabilities<br />
• Integrate + coordinate services<br />
• Requires time, patience, and resilience<br />
Individualization of treatment is a<br />
fundamental pillar of rehabilitation.<br />
Littrell KH, et al. Psychiatr Ann. 1998;28(7):371-377.
Treatment Is a Dynamic Process<br />
• Switches offer both opportunity and risk<br />
• A medication does not have to be perfect<br />
– Does it relieve symptoms well enough?<br />
– Is it tolerated well enough?<br />
– Is the patient willing to take it?<br />
• Shared decision-making: Getting the patient to “buy in” is<br />
key in promoting adherence<br />
– Individuals have their own preferences and values regarding<br />
which symptoms are important to them<br />
– Individuals have their own preferences and values regarding<br />
which tolerability issues are important to them
Choosing an Antipsychotic:<br />
Switch or Stay?<br />
• Past history of efficacy of drug response<br />
• Nature of psychiatric condition, acuity<br />
• Target signs and symptoms<br />
• Patient preference, history of adherence<br />
• Need for special monitoring<br />
• Amenable to other interventions to address tolerability?<br />
– Diet, exercise, and statins for obesity and dyslipidemia<br />
– Beta-blockers for akathisia<br />
– Anticholinergic medications for EPS
Thank you for your participation!<br />
Please remember to take the posttest to<br />
receive CME credit for this activity.
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