1. Addressing Partial-Response or Non-Response
in the treatment of schizophrenia
Presentation to first episode schizophrenia treatment group
July 26, 2017
Erik Messamore, MD, PhD
Associate Professor of Psychiatry, Northeast Ohio Medical University
Medical Director, Best Practices for Schizophrenia Treatment (BeST) Center
Option 1

2. Best Practices in Schizophrenia Treatment (BeST) Center at NEOMED
The BeST Center’s mission:
Promote recovery and improve the lives of as many individuals with schizophrenia as quickly as possible
Accelerate the use and dissemination of effective treatments and best practices
Build capacity of local systems to deliver state-of-the-art care to people affected by schizophrenia and their families
The BeST Center offers:
Training
Consultation
Education and outreach activities
Services research and evaluation
The BeST Center was established:
Department of Psychiatry, Northeast Ohio Medical University in 2009
Supported by The Margaret Clark Morgan Foundation and other private foundations and governmental agencies

3. Rates of Non-response May be as low as 20% in first-episode cohorts
May be > 50% in other samples

4. General approach to treatment non-response
Review the validity or completeness of the diagnosis
Better accounted for by a different psychiatric diagnosis?
Are there unrecognized psychiatric comorbitities
Psychological factors
Persistent dysfunctional beliefs
Maladaptive personality characteristics
Unrecognized etiologically-relevant medical conditions
Present in 5% to 12% of cases not pre-screened for treatment resistance
Likely higher prevalence among treatment-resistant cases
Consider paradoxical medication effects
Medication-induced apathy (D2 antagonists, SSRI/SNRI)
Subjective akathisia
Cognitive impairment/slowing
Worsening of anxiety from SSRI/SNRI

5. General approach to treatment non-response
Consider substance use
Cannabis is associated with higher rates of treatment-resistance
Stimulants generally worsen psychosis; oppose antipsychotic target action
Caffeine antagonizes endogenous adenosine neurotransmission
Substance use desire may increase to self-medicate residual symptoms, or to combat prescribed medication side effects
Consider adherence, dose adequacy
LIA formulations can assure constancy of dosing
Adequacy of (oral or LAI) dosing can be assessed by:
Parkinsonism
Hyperprolactinemia
Laboratory testing
Generally signal excessive D2 antagonism; and call for dose reduction

6. Blood level test availability for antipsychotic medications
Generic Name
Trade Name
Blood levels test available?
Chlorpromazine
Thorazine
Yes
Fluphenazine
Prolixin
Haloperidol
Haldol
Loxapine
Loxitane No
Molindone
Moban
Perphenazine
Trilafon
Thiothixene
Navane
Trifluoperazine
Stelazine
Aripiprazole
Abilify; Maintena; Aristada
Asenapine
Saphris
Brexipiprazole
Rexulti
Cariprazine
Vraylar
Clozapine
Clozaril, Fazaclo
Lurasidone
Latuda
Iloperidone
Fanapt
Olanzapine
Zyprexa; Relprevv
Paliperidone (9-OH risperidone)
Invega, Sustenna, Trinza
Risperidone
Risperdal; Consta
Quetiapine
Seroquel
Ziprasidone
Geodon
Blood level testing is available for all LAI-formulated drugs

7. Assuming the right diagnosis and adequately-dosed medication…
Medication non-response

8. Medication non-response in a single-cause-of-schizophrenia worldview
Medications fail because illness severity exceeds therapeutic capacity of the drug.

9. The double life of medication
Agents of therapy
Interrogators of physiology
Every treatment is an implicit test of a pathophysiological hypothesis

10. Medication non-response in a many-causes-of-schizophrenia worldview
Medications fail because their targets are irrelevant to the dominant pathophysiology
Dopamine signaling biomarkers are normal in the majority of cases of treatment-resistant schizophrenia
Howes, O. D. & Kapur, S. A neurobiological hypothesis for the classification of schizophrenia: type A (hyperdopaminergic) and type B (normodopaminergic). Br J Psychiatry 205, 1–3 (2014).
Giving dopamine blockers to patients without excess dopamine thus won’t likely benefit them
Glutamate signaling distortion is the most likely abnormality in the treatment-resistant schizophrenia patient

11. Nothing compares to clozapine with respect to evidence base for success in treatment-resistant schizophrenia
J Clin Psychiatry. doi: /JCP.16f11328

12. Medications without primary action at D2 receptors that have been reported as possibly helpful in partially-responsive schizophrenia

13. Source: Correll et al., 2017

14. Source: Correll et al., 2017

15. Source: Correll et al., 2017

16. Summary 1 Medication non-response may arise from
Inaccurate diagnosis
Undetected medical, psychiatric, or substance use comorbidity
Paradoxical effect of a medication, or their combinations
Inadequate adherence/dose
Secondary to stress from environmental, social, psychological factors
Mismatch between medication’s pharmacological targets vs core etiology for the particular case of illness
Consider pharmacodynamics, mechanism of action of the failed agent when considering its replacement
Discontinue drugs with no clear benefit

17. Summary 2
Always maximize environmental, social, and psychological support
But more so in cases where biological interventions are inadequate