Exam 1 - Antipsychotics

Question 1

Dopamine

Produced in the Ventra Tegmental Area(Reward Pathway)

Associated with reward and pleasure
Involves 4 major pathways

Mesolimbic Pathway “reward/pleasure”

Associated with positive symptoms of schizophrenia (i.e. hallucinations, delusions etc)

However, excess DA in this pathway will produce positive psychotic sx (even in people abusing substances which increase DA and other disorders with psychosis)

Question 2

Note: Dopamine inhibits prolactin.

Question 3

Dopamine

Mesocortical Pathway

Associated with the negative symptoms of Schizophrenia (i.e. cognition, affect, apathy, behavior etc.)

It is believed that negative sx are related to a deficit of dopamine in this particular pathway

FGA can induce negative and cognitive symptoms as they block DA

Question 4

Dopamine

Tuberoinfundibular Pathway

When functioning normally, the neurons in this pathway are active and INHIBIT prolactin release

Sx of elevated prolactin levels: galactorrhea, amenorrhea, possible sexual dysfunction

Question 5

Note: Dopamine inhibits prolactin.

Therefore, blockade of dopamine= ↓DA= ↑ Prolactin

Question 6

Dopamine

Nigrostriatal Pathway

Blockade of DA in this pathway produces increased motor movements

Deficient DA in this pathway causes movement disorders
e.g. EPS (Pseudo parkinsonism, Akathisia, dystonia & TD)

Question 7

Question 8

Neurotransmitters in schizophrenia

↑Dopamine in the mesolimbic area

↓Dopamine activity in the Mesocortical area

↓Serotonin (down regulation) in the frontal cortex

Question 9

Most patients experience prodromal phase so symptoms before their first psychotic break (i.e. negative symptoms, cognitive deficits and social awkwardness (2-3 years before psychotic break)

10+% incidence with one parent with schizophrenia and 35+% with both parents with schizophrenia.

Antipsychotic polypharmacy can increase the risk ofor re-hospitalization, diabetes, EPS, sedation, seizures, metabolic effects, mortality and sudden cardiac death.

Question 10

Red part

Antipsychotic polypharmacy can increase the risk ofor re-hospitalization, diabetes, EPS, sedation, seizures, metabolic effects, mortality and sudden cardiac death.

Question 11

Psychotic Disorders:

Brief Psychotic Disorder

Schizophreniform disorder

Schizophrenia

Schizoaffective disorder (Bipolar type or depressive type)

Question 12

Antipsychotics (Up to 6-8 weeks for response)

Etiology:

Impaired neuronal communication

↑ DA in mesolimbic pathway = positive symptoms

↓ DA in mesocortical pathway = negative symptoms

Excessive Glutamate

↓ GABA

↓ 5HT

NOTE: Majority of patients require lifelong medication.

Indication(s): Schizophrenia, schizoaffective disorder, depression w/ psychotic features, bipolar w/ psychotic features,

Question 13

Positive Symptoms of Schizo/Psychotic disorders:

Delusions

Conceptual disorganization

Excitement

Grandiosity

Hostility

Hallucinations

Question 14

Negative Symptoms of Schizo/Psychotic disorders:

Affects (generally flat, constricted)

Alogia (relative absence of speech

Avolition/Apathy ( lack of emotions, initiative)

Attention (poor or lacking)

Anhedonia (absence of pleasure/motivation

Asociality- withdrawal from normal social contact

Cognitive Symptoms

Question 15

Manifestation of Positive Symptoms of Schizo/Psychotic disorders:

Delusions

Hallucinations

Conceptual disorganization

Hostility

Grandiosity

Question 16

Manifestation of Negative Symptoms of Schizo/Psychotic disorders:

Affect (generally flat, constricted)

Alogia (relative absence of speech)

Avolition/Apathy(lack of emotion enthusiasm)

Attention (poor or lacking)

Anhedonia (absence of pleasure)

Question 17

Antipsychotics: overview

Not just used for psychosis or schizophrenia

Used for mania and depression in bipolar d/o

Augmentation for mood

Off-label for many disorders including mood, anxiety, PTSD

Question 18

Typical/1st Generation /Neuroleptics /Coventional

Introduced in the 1950’s

Block D2 receptors

Effective for positive symptoms

Can worsen negative symptoms secondary to ↓DA in the Mesocortical pathway

Long-acting forms available (Decanoate)

Question 19

Atypical/2nd Generation

First line treatment

Fewer neurological S/E

Effective for both positive and negative symptoms

Serotonin-Dopamine antagonist (D2/5HT2A)

Can cause EPS but at a lower risk

↓ incidence of Tardive dyskinesia

Metabolic side effects : Weight gain, HLD, hyperglycemia, Diabetes, HTN, Cardiac and respiratory S/E

Some Antihistaminic, antiadrenergic and antimuscarinic effects

Elevated Liver function tests (LFTs)- check yearly

QTC Prolongation

Question 20

Atypical/2nd Generation Antipsychotics are first line treatment.

Question 21

NOTE: Antipsychotics can take up to 6-8 weeks for response

Question 22

Factors affecting choice of antipsychotic medication

Side effect profile

Available route of administration (e.g. liquid vs. disintegrating forms)

Patient’s medical hx

Current medications

Preference

Question 23

Low Potency Typical (1st Generation Antipsychotics)

Low affinity to DA receptors= ↑doses required

High incidence of antiadrenergic, anticholinergic and antihistaminic s/e

Lower risk of EPS

More lethal in overdose d/t QTC prolongation
e.g. Thorazine, Mellaril

Recap: Low potency= Low EPS= High antiadrenergic, anticholinergic and antihistaminic s/e

Question 24

High Potency Typical (1st Generation Antipsychotics)

Greater affinity to DA receptors= ↓doses needed

Less incidence of antiadrenergic, anticholinergic and antihistaminic s/e

Greater risk of EPS
e.g. Haldol, Prolixin, Stelazine

Recap: High potency= High EPS= Low antiadrenergic, anticholinergic and antihistaminic s/e

Question 25

Typical Antipsychotics Chlorpromazine (Thorazine) Can cause blue-gray skin discoloration and corneal/lens deposits Causes orthostatic hypotension Also used for N/V and intractable hiccups Comes in po and IM formulation (effective for agitation in emergencies

Question 26

Typical Antipsychotics Thioridazine (Mellaril) Associated with retinitis pigmentosa

Question 27

Typical Antipsychotics Loxapine (Loxitane) Higher risk of seizures

Question 28

Typical Antipsychotics Haloperidol (Haldol) Can be given PO/IM/IV; Decanoate (LAI) Given in Acute agitation or psychosis

Question 29

Typical Antipsychotics Fluphenazine PO/IM; Decanoate (LAI) available

Question 30

Typical Antipsychotics Trifluoperazine (Stelazine) Approved for nonpsychotic anxiety

Question 31

Side Effects of Typical Antipsychotics (blockade of histamine, acetylcholine, alpha 1 and other receptors) High antiadrenergic, anticholinergic and antihistaminic s/e (e.g. sedation, weight gain) Elevated liver enzymes, jaundice Seizures – all antipsychotics lower the seizure threshold Orthostatic hypotension QTC prolongation – obtain baseline EKG Sexual dysfunction Rashes, photosensitivity Elevated liver enzymes, EPS (Akathisia, dystonia, Parkinsonism) **Hyperprolactinemia (decreased libido, galactorrhea, gynecomastia, impotence, amenorrhea) Tardive dyskinesia Neuroleptic Malignant Syndrome(FALTERED)

Question 32

Muscarinic cholinergic blocking Conventional antipsychotics also block M1-cholinergic receptors Side effects: blurred vision, dry mouth, constipation, cognitive blunting, urinary retention Antipsychotics that have weaker anticholinergic properties tend to cause more EPS and vice versa Dopamine and acetylcholine have a reciprocal relationship in the nigrostriatal pathway Therefore, you may see anticholinergics given along with conventional AP to decrease EPS, but it does nothing to mitigate risk of tardive dyskinesia

Question 33

Other actions of conventional AP Conventional AP also can block H1 receptors Side effects: weight gain, drowsiness Blockade of alpha-1 adrenergic receptors Side effects: orthostatic hypotension, drowsiness Key point: while conventional antipsychotics vary in their degree of blockade of various secondary receptors (and thus vary in degree of certain side effects), their efficacy in positive Sx via DA blockage is thought to be equivalent within the class.

Question 34

Extrapyramidal Symptoms (EPS) Acute Dystonia Sudden onset Fixed/Sustained painful contraction of the neck muscles (torticollis), tongue, eyes (oculogyric crisis) Can be life threatening if it affects airway Txt: Cogentin, Artane, Benadryl, Benzos- Ativan Lower dose if possible Hours to days

Question 35

Extrapyramidal Symptoms (EPS) Akathisia Internal and external restlessness Subjective anxiety, restlessness, inability to remain still Constant need to pace or walk Txt: Drug of choice= Beta blocker (Propranolol), Benzos (Klonopin, Ativan) Lower dose if possible Change to an atypical Days to months

Question 36

Extrapyramidal Symptoms (EPS) Pseudo-Parkinsonism Bradykinesia(shuffled gait), masklike face, cogwheel rigidity, pill-rolling tremor Txt: Cogentin, Artane, Benadryl, Symmetrel (Amantadine) Lower dose if possible Days to months

Question 37

Do not co-prescribe drugs in efforts to prevent EPS. Associated w/ high anticholinergic side effects Caution w/ Elderly patients. If necessary, anticholinergics should be prescribed at the lowest dose possible.

Question 38

Bruxism (involuntary teeth grinding) Occurs especially during sleep Can result in destruction of teeth structure, TMJ dysfunction, sleep disturbances. Management Reduce dose or switch Dental guards First line: Buspar 2nd line: Benzos (Clonazepam); Gabapentin

Question 39

Tremor More prominent in the hands ?? Fine vs. Coarse; resting vs. postural vs. intentional Common meds: Lithium, valproic acid, lamotrigine, SSRIs etc. Management Educate about caffeine intake – can worsen tremors Reduce or switch agent First-line: Propranolol, Inderal, Benztropine (Cogentin)

Question 40

Tardive Dyskinesia Tardive= D2 Blockade in the Nigrostriatal Pathway =late occurring Involuntary Choreoathetoid movements of face, mouth, lips (lip smacking) tongue (fly catcher tongue) and other body parts (facial grimacing, eye blinking, trunk, limbs etc. ) Occurs in patients who have used neuroleptics for months to years ( Sooner in older adults) Risk factors: older age, women, patients with affective disorders, FGA, duration of txt, higher dose, African American Affects about 20-30% of patients who on antipsychotics or months or years. Up to 50% of cases will remit (without further antipsychotic use) Mostly irreversible Management: Dose reduction; D/C med; switch to an atypical antipsychotic; Clonazepam, Amantidine, Tetrabenazine. 2017: First FDA approved treatment for TD (Valbenazine=Ingrezza); Deutetrabenazine (Austedo) AIMS (Abnormal Involuntary Movement Scale) testing initially then Q3-6 months Risk factors: High doses, long duration, old age, women, hx of EPS, substance abuse (heavy smoking), diabetes Patient Education: TD symptoms may initially worsen transiently as medication dosages are lowered. Consider switching to Clozaril (Lowest risk of TD)

Question 41

Neuroleptic Malignant Syndrome (NMS) Life-threatening idiopathic reaction to antipsychotic medications (more common w/ FGAs) Medical Emergency w/ 20% mortality rate if untreated Generally apparent 2 weeks of treatment initiation F= Fever A= Autonomic Instability (Tachycardia, HTN, Diaphoresis) L= Leukocytosis T= Tremor E= Elevated CPK R= Rigidity (lead pipe) E= Excessive sweating (diaphoresis) D= Delirium (mental status changes) Risk factors: High doses, high potency, LAIs Risk factors: Young males early in treatment with high potency antipsychotics Management D/C medication Supportive care (hydration, IV benzos- for relaxation; cooling blankets) Administer sodium dantrolene, bromocriptine, amantadine ECT can be effective

Question 43

General Information of Atypical (2nd Generation Antipsychotics) Accounts for 80% of total antipsychotics prescribed. MOA: Blocks both dopamine and serotonin receptors Less likely to cause EPS, TD or NMS May be more effective than typical antipsychotics in treating negative symptoms of schizophrenia Used to treat acute mania, bipolar disorder and as adjunctive in unipolar depression Also used in treating borderline personality disorder, PTSD and certain childhood psychiatric disorders (e.g., tic disorders)

Question 44

Atypical antipsychotics/2nd generation Pines(Olanzapine, quetiapine, asenapine, clozapine)= ↑risk of weight gain, metabolic syndrome, diabetes Dones (risperidone, lurasidone, ziprasidone, iloperidone)= ↑risk of movement disorders, cardiac conduction problems ↓ S/E: Metabolic syndrome = Obtain baseline and monitor BMI,weight, fasting glucose, waist circumference, BP, HbA1c and fasting lipids Features: obesity, elevated triglycerides, low HDL levels, BP greater than 135/85 Weight gain, HLD, Hyperglycemia, elevated LFTs, QTC prolongation,

Question 45

Quetiapine (Seroquel) **Strongest H1 antagonism*** Comes in XR Rare cataract formation Weight gain, Sedation and orthostatic hypotension

Question 46

Olanzapine (Zyprexa)/ Zydis (Disintegrating from) Causes significant weight gain, sedation and dyslipidemia (strong H1 antagonism) Acute agitation IM acts within 15min Monitor for dose-related hyperprolactinemia PO/IM/LAI formulation Relprevv (Injection)= Monitor 3 hours post injection d/t risk of delirium & sedation syndrome (Post injection syndrome)

Question 47

Risperidone (Risperdal) LAI- Consta (Watch for lump at injection site= may persist for several weeks) Doses > 6mg = increase EPS risk Greatest prolactin elevation among atypical Often used also in children (behavioral, autism spectrum d/o) and older adults (major neurocog with behavioral disturbances), aggression, irritability

Question 48

Ziprasidone (Geodon) Injectable form QTC prolongation Take with food to ↑absorption (300 calorie meal) PO/IM formulation Weight neutral

Question 49

Paliperidone (Invega) LAI(Sustenna- Monthly) (Trinza- every 3 months) Metabolite of Risperdal Do not use if hx of qtc prolongation, recent myocardial infarction, heart failure

Question 50

Aripiprazole (Abilify) Partial D2 agonist Can be activating (Akathisia) and less sedating PO/IM, LAI formulation (Maintenna) Weight neutral Watch for orthostatic hypotension Adjunctive tx of depression, bipolar

Question 51

Brexpiprazole (Rexulti) Similar to aripiprazole Slightly lower risk of akathisia

Question 52

Lumateperone (Calypta) Relatively new Approved for schizophrenia

Question 53

Lauroxil (Aristada) 441mg, 662 mg, 882 mg IM Q month

Question 54

Iloperidone (Fanapt) Similar class s/e, metabolic, motor, prolactin increase, dose-dependent weight gain, orthostatic hypotension

Question 55

Asenapine(Saphris) Sublingual administration (cannot eat or drink x 10 min after taking), fairly rapid onset of action (utility as PRN inpatient vs IM) Still very expensive, not commonly used

Question 56

Lurasidone (Latuda) Take w/ food (350 calories) for absorption Approved for bipolar depression Low risk for metabolic syndrome

Question 57

Criprazine (Vraylar) Also approved for the acute treatment of mania, mixed episodes of bipolar 1 d/o Long half life Associated w/ EPS (Akatisia, parkinsonism-like features)

Question 58

Clozaril: Perform WBC/ANC weekly for first 6 months of treatment and can decrease frequency there-after

Question 59

Clozapine(Clozaril) Fazaclo (ODT)- Denigrating form Agranulocytosis in 1% of patients Neutropenia in about 3% Off label use Treatment resistant bipolar disorder Dementia Parkinson's related psychosis or agitation Common adverse effects HTN Hypotension Tachycardia Dislipidemia Weight gain Constipation Sialorrhea Drowsiness/sedation Used to treat refractory schizophrenia(i.e., treatment resistant) Only antipsychotic shown to decrease SI risk Less likely to cause TD Weight gain is most prominent More anticholinergic s/e- tachycardia, constipation etc. Hypersalivation (sialorrhea) occurs in 30-80% Agranulocytosis( highest first 3 months of treatment)= Monitor WBC and Absolute neutrophil count (ANC) D/C med if ANC is <1.5 (1500) ANC General Management of Sialorrhea Chew sugarless gum Place towel over pillow especially if nocturnal sialorrhea is a problem Med: Glycopyrrolate (Robinul) -fewer Anticholinergic side effects) Benztropine, Artane etc. Note: Associated with myocarditis and cardiomyopathy typically in early stages of treatment (e.g., SOB, chest pain and swelling in LE)

Question 60

Clozaril Note: Associated with myocarditis and cardiomyopathy typically in early stages of treatment (e.g., SOB, chest pain and swelling in LE)

Question 61

Clozapine Risk Evaluation and Mitigation Strategy (REMS) A centralized point of access for providers and pharmacists to certify before dispensing Clozapine. Severe neutropenia is and ANC less than 500/mcL Must be enrolled in the Clozapine risk eval & management strategy program (Clozaril REMS program) Prescribers are required to submit patient’s ANC levels to the Clozapine REMS program for every prescription of Clozapine. Once started ANC weekly x first 6 months Then Q2 weeks x 6 months Then Q4 weeks thereafter May check blood levels ≥ 350g/ml

Question 62

Atypical common side/adverse effects Typically described as food craving and binging Weight gain: ≥7% increase in weight from baseline Common with Clozapine, Olanzapine, Quetiapine Least with Aripiprazole, haloperidol, ziprasidone and lurasidone Monitoring: Weight, BMI, waist circumference per guidelines Management: Switch to weight neutral medication May add to regimen: Topiramate, Metformin, Orlistat, Aripiprazole.

Question 63

Atypical common side/adverse effects Metabolic Syndrome H1 receptor antagonism is associated with sedation and weight gain Weight gain – Metformin can be used to reduce or prevent Hyperlipidemia Hyperglycemia Monitor Baseline and ongoing; Weight Waist circumference BP HbA1c Fasting lipids NOTE: For patients established on antipsychotic medications, yearly labs should be considered.

Question 64

Note: Antipsychotics are metabolized primarily in the liver. Many metabolites are active and peak plasma concentrations is usually reached 2-3 hours after an oral dose.

Question 65

Atypical common side/adverse effects Elevated Prolactin Levels D2 blockade in the Tuberoinfundibular pathway= Hyper-prolactin Men= Gynecomastia, erectile dysfunction, low libido, galactorrhea Women = galactorrhea and absence of menses, low libido, galactorrhea Management Reduce or discontinue med Switch to a different medication If the above techniques are not feasible, add Aripiprazole to the regimen

Question 66

Smoking and antipsychotic medications An estimated 60-90% of schizophrenia patients smoke cigarettes for anxiolytic effects, enhanced attention and pro-cognitive effects Note: Smoking induces CYP1A2 enzymes and lowers the levels of certain antipsychotic medications Smoking cessation options should be routinely offered to patients.

Question 67

Medication Non-compliance Estimated 50+% of patients are non-compliant with medications Consider Long-acting injectables (LAIs) May need to initiate an oral form of the medication to demonstrate tolerance before starting a LAI. Oral form should be continued until the LAI has been established NOTE: Haldol and Prolixin dec use sesame oil – watch for allergic reactions in patients sensitive to sesame.

Question 68

Long Acting Injectables (LAIs) Fluphenazine Decanoate (dosed every 2 weeks) Haldol Decanoate (dosed monthly) Abilify Maintena (dosed monthly) Abilify Aristada (dosed monthly, every 6 weeks or every 2 months) Olanzepine Relprevv (dosed every 2 weeks or monthly- note post-injection delirium/sedation syndrome Invega Sustenna – dosed monthly Invega Trinza – dosed every 3 months Risperdal Consta – dosed every 2 weeks Risperdal (Perseris) dosed monthly; no oral overall required; SubQ injection

Question 69

Black-box warning for ALL antipsychotics Increased risk of death when used in the elderly and those with dementia related psychosis. Antipsychotics can be used for txt of agitation or psychosis in patients with dementia when symptoms are severe, dangerous and cause significant distress to the patient Increased risk of falls and non-vertebral fractures in patients 65+ No antipsychotic medication is approved in patients with dementia.

Question 70

Withdrawal Dyskinesia Occurs when stopping or reducing an antipsychotic medication Symptoms look like TD ( lip puckering, tongue movements etc) Though transient it can persist Management Watch and wait – see if symptoms go away May introduce a small dose of the antipsychotic med to quiet the movements

Question 71

Risk Mitigation Strategies Educate all patients, caregivers and/or surrogate decision makers on the effects, possible risks and benefits and recommended monitoring. Document…..document…..document Obtain appropriate parameters and labs as part of good practice AIMS testing EKG Weight, waist circumference Vitals (BP) Labs (HA1C, BMP, CBC, prolactin levels, fasting blood glucose, Lipid profile)

Question 72

Suicidality in children, adolescents and young adults Some antipsychotics are approved or used for the txt of depressive episodes in bipolar disorder or adjunctive txt for unipolar depression Monitor for risk of suicidal thinking and behavior for children, adolescents and young adults (< 24 years) for the first 3 months of treatment.