PH AntiPsychotics and Mood Stabilizers.docx

PHARMACOTHERAPY OF PSYCHIATRIC DISORDERS 2/14 & 2/15/23 James Beaulieu, PharmD [email protected] Learning Objectives By the end of this lecture, students should be able to: Recognize class medication side effects Select a medication based on patient comorbidities Differentiate between typi...

PHARMACOTHERAPY OF PSYCHIATRIC DISORDERS 2/14 & 2/15/23 James Beaulieu, PharmD [email protected] Learning Objectives By the end of this lecture, students should be able to: Recognize class medication side effects Select a medication based on patient comorbidities Differentiate between typical and atypical antipsychotics Manage drug interactions 2 Antipsychotics Indications Schizophrenia Acute agitation associated with psychosis Bipolar Disorder Psychotic Depression Refractory Anxiety/Obsessive-Compulsive Disorder Refractory Eating Disorders Low doses for delirium (not FDA approved) Efficacy can be seen with first dose Improvements can be seen for up to 4-6 weeks after starting antipsychotics Quick Recap: Schizophrenia Overall: imbalance of dopamine Positive symptoms  Hallucinations (auditory), delusions, disordered thought process, bizarre behaviors  Result of excess dopamine in the mesolimbic pathway Negative symptoms  Social withdrawal, blunted response, anhedonia  Low dopamine in the mesocortical pathway Biochemistry is different between these two symptom types, so treatment will be different Life span is 10 years shorter due to metabolic syndrome of medications Dopamine Hypothesis of Schizophrenia Goal: restore normal dopamine function  + symptoms: ↑DA receptor binding in mesolimbic pathway - symptoms: ↓ DA receptor binding in mesocortical pathway Hypothesis % binding directly correlates with efficacy Blocking > 65% D2 receptors = clinical response Blocking > 80% D2 receptors = EPS All antipsychotics work by blocking the dopamine type 2 (D2) receptors in the brain Poor efficacy for negative symptoms Positive and Negative Symptoms Battle of the Generations 1st generation: Typical Tightly bound to DA receptor; dissociate slowly = ↑ EPS Increased tardive dyskinesia in early typical trials Used haldol doses >20mg 80% D2 receptor binding achieved at 2 – 5mg Lower potency = more anticholinergic, orthostasis, sedation Use limited by lack of efficacy in negative symptoms and side effects 2nd generation: Atypical “Atypical” because higher 5HT:DA ratio than typical Increased efficacy for negative symptoms Decreased EPS Bind and dissociate quickly CATIE trial shows atypicals are no better than typicals for positive symptoms Serotonin Hypothesis of Schizophrenia Serotonin may explain reduction of negative symptoms (5HT2A- receptor) with atypicals and not with typicals All atypical antipsychotics act as 5HT2A receptor antagonists Stimulation of 5HT2A reduces DA release Antipsychotics: Overview Antipsychotics reduce positive symptoms vs. placebo in ~ 70% patients Meta-analysis showed small reduction in negative symptoms with atypicals, antidepressants No efficacy seen with typical antipsychotics for negative Titrate very slowly; avoid high doses upfront Maximum effects seen ~ 26 weeks Some data suggests earlier treatment for first episode = more favorable long term outcomes 25 – 50% adherent patients experience relapse within 2 years vs 85% placebo Antipsychotics: First Generation Generic Name Brand Name Usual Dosage Range (mg/d) Manufacturer’s Maximum Dose (mg/d) chlorpromazine Thorazine 100-800 2000 fluphenazine Prolixin 2-20 40 haloperidol Haldol 2-20 100 perphenazine Trilafon 10-64 64 RED: high potency; GREEN: moderate potency; BLUE: low potency High potency: EPS, dystonia Low potency: more anticholinergic, antihistaminergic, alpha-1 antagonism All have risk of QTc prolongation Typical Antipsychotics M1 Dopamine Antagonist H1 Extrapyramidal Side Effects α1 Dystonic reactions Tardive Dyskinesia Neuroleptic malignant Anticholinergic Dry mouth Blurred vision Cognitive Conventional 1G antipsychotic drug D2 syndrome Alpha-1 Blockade Orthostatic hypotension impairment QTc prolongation Urinary retention Histamine Antagonist Sedation Hunger Atypical Antipsychotics Atypical Antipsychotics Less receptor antagonism vs. typicals = less side effects Metabolic Syndrome Glucose dysregulation Weight gain Hyperlipidemia January 2017 CMS requirement Inpatient psychiatric hospitals to report the % of patients discharge on an antipsychotic with a complete metabolic panel completed within the past 12 months Lipid panel BMI Blood glucose or HgbA1c Atypical Antipsychotic Dosing Generic Name Pearls clozapine 1st line for treatment-refractory schizophrenia (requires 2 failed agents) Agranulocytosis Myocarditis Drooling High risk: Weight gain Low risk: EPS, hyperprolactinemia 1A2 substrate risperidone High risk: EPS/hyperprolactinemia Reach effective doses quickly Low risk: metabolic syndrome/weight gain Orthostasis, dizziness olanzapine Greatest risk of weight gain quetiapine Low doses used off label for delirium Active metabolite has anxiolytic properties QTC prolongation Atypical Antipsychotic Dosing Generic Name Pearls ziprasidone Most QTC prolongation has limited use aripiprazole Partial DA agonist May have least metabolic syndrome May have least EPS Long half life ~72 hours Slow titration if switching agents paliperidone Metabolite of risperidone iloperidone Not commonly used in practice Weight gain, xerostomia, orthostatic hypotension lurasidone Poorly absorbed; needs to be eaten with at least 350 calories asenapine Sublingual Transdermal Patch Long Acting Injectables Poor adherence to oral formulations IM LAI showed reduction in morbidity for schizophrenia Seen as attempt to impose treatment on patients LAI bypass first pass metabolism by the liver Higher proportion of drug available centrally Allows the use of lowest effective dose Advantages Avoidance of daily administration Transparency of adherence Reduced risk of unintentional or intentional overdose More consistent absorption Disadvantages Some LAI require refrigeration Less dose adjustment flexibility Pain at injection site Burden of travel to outpatient clinics or home visits for administration Stigma Long Acting Injectables Available formulations Fluphenazine every 4 weeks Haloperidol every 4 weeks Aripiprazole every 4 – 6 weeks Olanzapine every 2 – 4 weeks Risperidone every 2 weeks Paliperidone every 1 – 3 months ($7,000) Check package insert PO to IM conversion Some require overlap of oral and IM Some require taper Different schedule for each product Clozapine Treatment resistant schizophrenia or unable to tolerate side effects History; agranulocytosis 1 – 2% Autoimmune reaction; not dose related Myocarditis REMs program Q1week WBC counts x 6 months Twice monthly WBC x 6 months Monthly > 1 year Must be registered Use in treatment resistant schizophrenia (failed 3 trials) in Kane 1988: 30% improved in 4 weeks Recalled in Finland due to deaths Some patients in US >20 years of clozapine treatment Antipsychotics 2 Extrapyramidal Symptoms (EPS) and Tardive Dyskinesia (TD) EPS and TD both refer to centrally mediated musculoskeletal side effects of antipsychotics EPS occurs as a result of blocking too many dopamine receptors  Akathisia  Dystonia  Tremor  Parkinsonian movements-“cogwheeling” or shuffling gait TD occurs as a result of long term dopamine receptor blockade, rarely occurs after short term treatment  Facial grimacing  Tongue protrusion  Lip smacking  Repetitive eye blinking  Repetitive, but not rhythmic, irregular 21 contractions of arms, legs, head or neck Extrapyramidal Symptoms (EPS) and Tardive Dyskinesia (TD) EPS is reversible TD is permanent Medication dose adjustments Treatment with:  Benztropine  increases dopamine activity  Centrally acting beta blockers (propranolol) relieve symptoms Treatments for TD yield minimal relief 22 Neuroleptic Malignant Syndrome Rare; Idiosyncratic Excessive DA blockade can lead to excessive glutamate release Onset: 4 – 14 days Evolves over 1 – 3 days Symptoms: Fever Encephalopathy Vital sign instability Elevated CPK Rigidity Typicals > atypicals (?) Treatment options Dantrolene – prevents catabolic processes Bromocriptine – DA agonist Diazepam – relaxes muscle Overview: Atypical Antipsychotics Goal: restore normal dopamine function  + symptoms: ↑DA receptor binding in mesolimbic pathway - symptoms: ↓ DA receptor binding in mesocortical pathway Atypicals may provide better outcomes than typicals for negative symptoms Metabolic syndrome is a common side effect of antipsychotics Patients receiving clozapine must be enrolled in a REMs program 24 [email protected]