Stoner - Read-Only

1 9/4/181 Steven C. Stoner , , BCPPC hair and Clinical Professor UMKC School of PharmacyDivision of Pharmacy Practice and AdministrationObjectives Recognize basic symptomatology associated with schizophrenia. Identify mechanisms of action of first and second-generation antipsychotic medication as well as recognize their pharmacodynamic differences. Define proper therapeutic drug monitoring procedures when using antipsychotic and Conflict of Interest Steve Stoner is on the advisory board for Alkermes Pharmaceuticals and a speaker for NeurocrinePharmaceuticals. 9/4/182 Epidemiology of Schizophrenia Onset - late teens to mid 30s Lifetime prevalence No gender or racial differences in prevalence Women later onset then men Socioeconomic class First-degree relativeAmerican Psychiatric Association: DSM-5.

2 Arlington, VA, American Psychiatric Association Mortality Suicide attempts estimated 20-50% Completed suicide estimated at 10% normal mortality for chronic illness Medical mortality 6x normal cardiac deaths 5x normal respiratory illnessSiris SG. Suicide and schizophrenia, J Psychopharmacol2001; 15 DC et al. Medical morbidity and mortality in schizophrenia: guidelines for psychiatrists. J ClinPsychiatry2005; 66: Psychiatric Association: DSM-5. Arlington, VA, American Psychiatric Association and Symptoms of Schizophrenia Positive symptoms hallucinations, delusions, paranoia Negative symptoms (withdrawn, alogia) Cognitive symptoms (confusion, memory loss) Mood symptoms Social and occupational dysfunction Unable to work or go to school9/4/183 Natural Course of Disease Prodromalphase Social withdrawal First psychotic break Usually occurs during a time of large amounts of stress Several episodes of positive symptoms with continuous negative symptomatology Decreased positive symptoms but continuous negative symptoms Occurs with increasing ageWhen Does it Happen?

3 Causes Genetic: 108 potential loci have been identified Autoimmune Molecular (alterations in D2 and Glutamate receptors) Environmental Poor maternal care Obstetric complications Stressors ToxinsNature 20149/4/184 Dopamine Hypothesisof SchizophreniaHyperactivity:positive symptomsMesolimbic pathwayNigrostriatal pathway (part of EP system)Tuberoinfundibular pathway(inhibits prolactin release)Mesocortical pathwayHypoactivity:negative symptomsPathophysiologyRegion of the Brain/Dopamine TractDopamine Level in SchizophreniaSymptomatologyPrefrontal Cortex/MesocorticalDecreaseNegative symptomsBasal ganglia/MesolimbicIncreasePositive symptomsSubstantianigra/Nigrostriatal(A9 area)NeutralEPS side effectsHypothalamus/Tuberoi nfundi bul arNeutralProlactinregulationAntipsychoti c Medication Goals Use a team approach to: Address safety and medical issues Prevent adverse events Decrease positive, negative and cognitive symptoms Integrate into communityHow would we measure each of these?

4 9/4/185 Antipsychotic Medication Goals: Reality Safety Medication Adherence Medical issues / adverse effects 50% patients obese 75% smokers 10% diabetic 20% hypertensive Decrease positive symptoms Integrate into community Decrease negative and cognitive symptomsOutcomes Good prognosis Later onset Acute onset Married Good support systems Predominate positive symptoms Poor prognosis Earlier onset Insidious onset Family history Poor support system Negative symptoms No remission in 3 years Multiple relapsesEstimated 35% relapse in 2 years and 74% relapse within 5 yearsKanaharaN, et al. PLOSONE, June 2013; 8(6) to Choose an Antipsychotic? History of response Efficacy Adverse effect profile Drug interactions Dosing Monitoring / adherence issues Concurrent medical /psych history Cost9/4/186 What Differentiates First from Second Generation?

5 Minimal EPS at clinically effective propensity to cause TD with long-term both the negative and positive antagonism leads to increase in dopamine in prefrontal cortex (improvement in negative symptoms)Typical Antipsychotics Low potency chlorpromazine (Thorazine ) thioridazine (Mellaril ) Intermediate potency perphenazine(Trilafon ) loxapine(Loxitane ) High potency haloperidol (Haldol ) fluphenazine (Prolixin )Typical (Traditional) Antipsychotics All EQUALLY effective at EQUIVALENT doses 400 to 800 chlorpromazine equivalents is a good antipsychotic dose Differences: Potency of the drugs Side effect profiles9/4/187 Potency: Chlorpromazine EquivalencesAgentmgChlorpromazine100 Thioridazine100 Loxapine10 Perphenazine8 Trifluoperazine5 Thiothixine4 Fluphenazine2 Haloperidol2 Typical Antipsychotic Side Ef fectsMedicationSedation, Anticholinergic,OrthostasisEPSLow PotencyHigherLowerthioridazinechlorproma zineIntermediate PotencyperphenazineloxapineHigh PotencyhaloperidolfluphenazineLowerHighe rExtrapyramidal Side Effects (EPS) Caused by postsynaptic dopamine receptor blockage in the basal ganglia Acute DystonicReaction Pseudoparkinsonism Akathisia Ta r d i v e d y s k i n e s i a ( T D )

6 9/4/188 Acute DystonicReaction Bizarre involuntary tonic contractions of skeletal muscles Usually appear with 24-96 hours Commonly involve muscles in the face, head, and neck May also involve muscles in the back, arms, and legs Common with high potency typicals Treatment: diphenhydramine 25-50 mg IM or slow IV infusion benztropine2 mg IMPseudoparkinsonism Appears within first month after initiation of antipsychotic (90% within 3 months) Signs and symptoms: pill-rolling tremor, stiffness/cogwheel rigidity, mask-like facies, drooling, akinesia/bradykinesia, shuffling gait, stooped posture Related to dose and increases with age Treatment: Decrease dose or change to atypical Antiparkinsonianagents benztropine 2-8 mg/day trihexyphenidyl2-8 mg/day amantadine 100-300 mg/dayAkathisia Strong subjective feeling of inner restlessness or discomfort May be mistaken for agitation or worsening psychosis 90% develop with in 3 months Treatment.

7 Propranolol30- 120 mg/day (drug of choice) benzodiazepines Anticholinergics not as effective as other agents Decrease dose or change drug 9/4/189 TardiveDyskinesia Involuntary movements thought to be caused by supersensitivityof dopamine receptors Face tics, grimacing, blinking Oral musculature lip puckering, sucking, pouting, chewing, cheek puffing, tongue writhing or tremor, tongue protrusion Limb toe tapping or tremor, wrist flexion, myoclonicjerks, writhing Neck/truncal- torticollisTardive Dyskinesia Prevalence 15-20% Risks include: Age, female gender, affective disorders, diabetes Large doses, long duration of tx Treatment: VMAT2 Inhibitors: valbenazineor deutetrabenazine Discontinue drug or change to agent least likely to contribute to EPS Commonly irreversible, may be reversible if diagnosed early Prevention Use lowest possible dose Abnormal Involuntary Movement Scale (AIMS) at baseline and q 6 monthsNeuroleptic Malignant Syndrome (NMS) Incidence approximately to % Onset within 10 days of drug initiation Signs and symptoms include: 1.

8 Fever 2. rigidity (lead pipe) 3. mental status changes 4. autonomic disturbance (BP changes, tachycardia, diaphoresis, incontinence) 5. elevated CPK, WBC, occasionally LFTs Mortality rate - 10% (50% in patients with myoglobinemiaand renal failure)9/4/1810 NMS Treatment 1. Discontinue antipsychotic 2. Primarily supportive therapy 3. Drug therapy: dantroleneIV mg/Kg/day IV - 10 mg po tid amantadine100mg qd- tid Wait at least 2 weeks before restarting AP sOther Adverse Effects Allergic - most common, a maculopapularrash on the face, neck, or upper extremities Photosensitivity reactions - warn against prolonged sun exposure Long term skin changes - pigmentation of skin Antiadrenergic Orthostatic hypotension Increased risk with Low Potency FGA s Anticholinergic Dry mouth, constipation, blurred vision, urinary retention, tachycardia Cardiovascular Q-T and P-R prolongation, flattened T waves, S-T depression Increased risk with thioridazine, chlorpromazine.

9 And mesoridazineOther Adverse Effects Neurologic Sedation Decreases seizure threshold Metabolic Weight gain, hyperglycemia, hyperlipidemia Hypothalamic Amenorrhea, galactorrhea, infertility, and gynecomastia9/4/1811 Other Side Effects Hepatic: cholestaticjaundice Hematologic Agranaulocytosis, leukocytosis, eosinophilia, thrombpcytopenia Ophthalmologic: retinitis pigmentosa Limited dosing of thioridazineto 800 mg/dayAripiprazole Abilify , AbilifyMaintena , Aristada and AristadaInitio Schizophrenia, bipolar, adjunct therapy for MDD, autism associated irritability, Tourette s disorder Oral tablet, IM, ODT, Oral Solution, LAI MOA: 5-HT2A Antagonist, Partial Agonist at D2 and 5-HT1A Substrate.

10 3A4, 2D6 Long acting injection dose (AbilifyMaintena ) is 300 to 400 mg IM every 28 days (cross cover with PO antipsychotic first 14 days) Long acting injection dose (Aristada ) 441 mg, 662 mg, or 882 mg given monthly OR 882 mg dose given every 6 weeks OR1,064 mg dose given every 2 months (cross cover with oral aripiprazole for first 21 days) AristadaInitio given at 675 mg injection along with one 30 mg po dose of aripiprazole (Aristada is to be given in conjunction, inject in different location)Abilify, AbilifyMaintena, Aristada, AristadaInitio Package Inserts accessed August Rexulti Schizophrenia, adjunct therapy for MDD MOA: 5-HT2A Antagonist, Partial Agonist at D2 and 5-HT1A Immediate-release tablet Substrate: 3A4, 2D6 Being studied in PTSD and agitation and aggression with dementia (off-label ) Side Effects: weight gain, akathisaRexultiPackage Insert accessed August Saphris Indicated for Schizophrenia and Bipolar Mania MOA: Antagonist at D2 and 5-HT2A Substrate: 1A2 Inhibitor: 2D6 ODT (high first pass metabolism), avoid eating and drinking for 10 minutes Side Effects: oral hypoesthesia, akathisia, somnolence, dizziness, EPSS aphrispackage insert accessed August Vraylar FDA Indicated for schizophrenia and bipolar mania MOA: partia