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

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

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

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

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

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

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

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

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

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

Nothing compares to clozapine with respect to evidence base for success in treatment-resistant schizophrenia J Clin Psychiatry. doi: 10.4088/JCP.16f11328

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

Source: Correll et al., 2017

Source: Correll et al., 2017

Source: Correll et al., 2017

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

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