Anti-Psychotic Meds.docx

ANTI PSYCHOTIC MEDS: Black Box Warning: Increased mortaility in elderly patients with dementia-related psychosis. - - If D2 centers are blocked in the mesolimbic dopamine system, including the reward mechanism or "pleasure center" of the brain is as well, leading to: - Apathy,...

ANTI PSYCHOTIC MEDS: Black Box Warning: Increased mortaility in elderly patients with dementia-related psychosis. - - If D2 centers are blocked in the mesolimbic dopamine system, including the reward mechanism or "pleasure center" of the brain is as well, leading to: - Apathy, Anhedonia, poor motivation/interest, Lack of joy from social interactions - apathy, lack of initiative, anhedonia, indifference, blunted affect, and reduced insight into disease Umbrella term for symptoms caused by chronic blocking of D2 receptors in the nigrostriatal pathway: - Dystonia - Akathisia - Parkinsonian Syndrome - Tardive Dyskinesia - - **Extrapyramidal Syndrome:\ Dystonia** - Acute dystonia\'s are involuntary contractions of major muscle groups: - Torticollis (stiffness or torsion of the neck) - Retrocollis (neck extension) - Oculogyric crisis (upward deviation of the eye) - Opisthotonos (backward arching of the head, neck, spine) - Possible laryngospasm - Risk factor include young age, male, use of cocaine, and history of dystonia. - Not dose related **Extrapyramidal Syndrome** **[Akathisia]** - Most common form of EPS, is dose related - Risk factors: Older age, female, negative symptoms. - Presents as motor restlessness, the urge to move, and the inability to sit still. **[Parkinsonian Syndrome]** - Symptoms include mask like face, resting tremor, cogwheel rigidity, shuffling gait, pill rolling, and bradykinesia. - **Extrapyramidal Syndrome:\ Tardive Dyskinesia (TD)** - Results if D2 receptors in the nigrostriatal pathway are chronically blocked. - A hyperkinetic movement disorder that may cause tongue and facial movements - 25% develop TD over a 5-year period. - May be reversed if the D2 blockade is removed early enough but is irreversible in some patients - May be masked by high doses of an antipsychotic - [Neuroleptic Malignant Syndrome] - A life-threatening emergency - Can occur at any time in treatment - NMS rarely beyond 1 month after initiation of a neuroleptic agent. - Not dose dependent, but higher doses are a risk factor - Differential Dx include: - Serotonin Syndrome - Anticholinergic delirium - Malignant hyperthermia [Symptoms:] - Mental Status Change - Muscular Rigidity - Hyperthermia, usually a high fever (usually the defining symptom) - Autonomic Instability [Treatment:] - Discontinuation of the antipsychotic - Treatment of Hyperthermia - IV Hydration - IV Dantrolene - IV Benzos - Hyperprolactinemia - Blocking of D2 receptors in the tuberoinfundibular pathway. - May cause: - Galactorrhea - Gynecomastia - Amenorrhea in women - Sexual dysfunction - Prolonged hyperprolactinemia may lead to osteoporosis, infertility, and hypogonadism in men. - **Hyperprolactinemia** - May also be caused by other medications or medical conditions - Serum prolactin concentration \> 20 ng/ml - Risperdal and Invega are most likely to increase prolactin levels Treat by changing to a Prolactin sparing medication such as Aripiprazole, Caripiprazine, or Quetiapine. Muscarinic Cholinergic SEs - Degrees of muscarinic cholinergic blockade differ by antipsychotic. - Typical agents often cause more EPS and have weak anticholinergic properties, while atypical agents often cause fewer EPS SE's and have stronger anticholinergic properties. - Dopamine and acetylcholine have a reciprocal relationship in the nigrostriatal pathway. - Anticholinergic agents remove dopamine inhibition when dopamine receptors are blocked, diminishing the excess choline. - - - Other side effects Blockade of Histamine H1 receptors - Weight gain and sedation Blockade of α1-adrenergic receptors - Orthostatic Hypotension - Drowsiness Metabolic SE - Weight gain - Dyslipidemia - Diabetes/Insulin resistance - Hypertension - - - - Long-Acting Injectables (LAI):\ Dosing schedules - Invega Sustenna -- 4 weeks - Invega Trinzia- 12 weeks - Abilify Maintena -- 4 weeks - Aristada -- 4, 6, or 8 weeks - Risperdal Consta- 2 weeks - Risperdal Perseris 4 weeks - Haldol Decanoate -- 4 weeks - Prolixin Decanoate- 2 weeks - Also called classical, conventional, or first-generation antipsychotics - Discovered by accident in the 1950s when Thorazine, a drug with antihistamine properties, was observed to be therapeutic in psychotic patients. - Found to decreased motor movements and behavioral indifference. - Therapeutic affect due to the blockade of D2 receptors in the mesolimbic dopamine pathway. - Mainly targets positive symptoms of psychosis - Unfortunately, Typical antipsychotics block D2 receptors in all areas of the brain, leading to a multitude of side effects. - **Thorazine (chlorpromazine)** - **Serentil (mesoridazine)** - **Mellaril (thioridazine)** **Mid-potency** - **Loxitane (loxapine)** - **Prolixin (fluphenazine)** - **Haldol (haloperidol)** - **Trilafon (perphenazine)** - **Orap (pimozide)** - **Navane (thiothixene)** - **Stelazine (trifluoperazine)** Not available in U.S: - Cyamemazine, flupenthixol, pipothiazine, sulpiride, zuclopenthixol - Haldol (haloperidol) [Dosage] - 1-40mg; max daily 100mg [Formulations] - PO tablet, liquid, IM, IV, & deaconate [Indications] - FDA: psychosis, Tourette's, schizophrenia - Children: severe physical aggression & short-term for hyperactivity - Off label: bipolar d/o, behavioral disturbances in dementias, delirium - Approve age 3 & over [Side effects:] - Dizziness, sedation, dry mouth, constipation, urinary retention, blurry vision, decreased sweating, hypo/hypertension, tachycardia, - Neuroleptic malignant syndrome - Akathisia, Parkinsonism, Tardive dyskinesia/ tardive dystonia - Agranulocytosis, leukopenia [Contraindications] - CNS depression & Parkinson's disease Thorazine(chlorpromazine) [Dosage] - 10-800mg daily; typical 200-800mg [Formulations] - PO tablet, liquid, IM, IV, & deaconate [Indications] - FDA: schizophrenia, severe agitation, psychosis, nausea/ vomiting, acute intermittent porphyria, tetanus, intractable hiccups. - Children: severe physical aggression & hyperactivity associated with ODD/ conduct disorder or ADHD - Off label: bipolar d/o, restlessness before surgery - Approve age 1 & over [Side effects:] - Hypotension, tachycardia, syncope, weight gain, sexual dysfunction, priapism - Neuroleptic malignant syndrome - Akathisia, Parkinsonism, Tardive dyskinesia/ tardive dystonia - Agranulocytosis [Contraindications] - CNS depression, with metrizamide, Reye's Syndrome, sulfite hypersensitivity, - - Compared to Typical antipsychotics - Equal positive symptom reduction - Lower EPS - Lower Hyperprolactinemia - More common metabolic SEs - Classified as serotonin dopamine antagonists - Block Dopamine 2 receptors - Block 5HT2a receptors - Enhancement of dopamine release in certain areas of the brain, reducing motor side effects and possibly improving cognitive symptoms. - - - 5HT2a Receptors - Located on cortical pyramidal neurons - Excitatory and can enhance downstream glutamate release which inhibits dopamine release - 5HT2a stimulation of cortical pyramidal neurons by serotonin hypothetically blocks downstream dopamine release in the striatum. - **So theoretically blocking 5HT2a receptors will prevent the release of glutamate, preventing the inhibition of dopamine** - \*See Stahl 142-152 for in depth learning - Aripiprazole (Abilify) - Asenapine (Saphris) - Brexpiprazole (Rexulti) - Cariprazine (Vraylar) - Clozapine (Clozaril) - Illoperidone (Fanapt) - Pimavanserin (Nuplazid) - Lurasidone (Latuda) - Olanzapine (Zyprexa) - Paliperidone (Invega) - Quetiapine (Seroquel) - Risperidone (Risperdal) - Ziprasidone (Geodon) - Lumateperone (Caplyta) - SGA Minimum Effective Doses - - - - - - - Metabolic Risk **[High]** - Clozapine (Clozaril), Olanzapine (Zyprexa) **[Moderate]** - Risperidone (Risperdal), Paliperidone (Invega), Quetiapine (Seroquel), Iloperidone (Fanapt) **[Low]** - Ziprasidone (Geodon), Lurasidone (Latuda), Aripiprazole, Asenapine (Abilify), Cariprazine (Vraylar) Labs & Monitoring - Prior to Initiation - Weight/BMI/Waist circumference - EKG - CMP - CBC with diff. - Fasting Lipid Panel - Blood pressure Monitoring - BMI quarterly - Blood pressure, Lipids, and Glucose within 3 months, and then every 6 months. - Prolactin as needed - CBC with diff as needed - Abnormal Involuntary Movement Scale periodically - Clozaril (clozapine) - First antipsychotic to be recognized as atypical - Gold standard for efficacy in schizophrenia - Only antipsychotic to demonstrate increased efficacy compared to other antipsychotics. - Only antipsychotic to be FDA approved for reducing the risk of suicide in schizophrenia and schizoaffective disorder. - Not a first line treatment choice, usually reserved for treatment resistant schizophrenia, due to unfavorable side effect profile - May be very sedating - Associated with excessive salivation, myocarditis. - Increased Risk of Seizures - Associated with greatest degree of weight gain and cardiometabolic risk - - - Clozaril (clozapine) - Associated with the life-threatening complication agranulocytosis and neutropenia in 0.5 -- 2.0 % of patients. - May result in infection and death - Other SE's may include tachycardia, constipation, and myocarditis. - Myocarditis is rare and only occurs in the first 6 weeks - Will need baseline and weekly Troponin and C-reactive protein levels for first 6 weeks - Clozaril (clozapine) - Must be part of a national registry to prescribe Clozaril, the Risk Evaluation Mitigation Strategy Program. - Recommended ANC monitoring for the General Population and Benign Ethnic Neutropenia patients can be found in your Stahl book (YOU NEED TO KNOW THIS). - General population ≥ 1,500 μL - Benign ethnic neutropenia: ≥ 1,000 μL - Obtain CBC with diff every week for the first 6 months, then every 2 weeks for the next 6 months, and then every month after the patient has been on Clozaril for 1 year. Clozaril (clozapine) [Dosing] - start at 25 mg PO QHS, and then increase by 25-50 mg per day until the desired dose is reached. - Usually use split dosing - Average therapeutic range is 300-450 mg - Will require a plasma level of 350 ng/ml for a response - Levels greater than 700 ng/ml are usually not well tolerated. - Zyprexa (olanzapine) - FDA approved for treatment of schizophrenia and mania in ages 13 and over - Dosage of 10-20 mg - Comes in ODT, IM and LAI formulations - Documented efficacy in treatment of Bipolar depression when combined with Prozac (Symbyax ages 10 and older) - Associated with sedation, metabolic SEs, significant weight gain, and sialorrhea - Lybalvi (olanzapine/samidorphan) approved June 2021 - Wide dosing range of 50 -800 mg, IR and XR formulations - IR formulation has a 6-8 hour half life Dosage - Insomnia (50-200 mg) - Depression (300-400 mg range) - Psychosis (600-800 mg) - Often under dosed - Sedation and weight gain are common; Associated with glaucoma - Low risk of EPS, essentially no prolactin elevation - May be preferred antipsychotic for Parkinson's and Lewy body dementia. - FDA approved - schizophrenia in ages 13 and up - mania in ages 10 and up - Bipolar Depression - adjunctive treatment of depression - Saphris (Asenapine) - FDA approved for treatment of mania in ages 10 and up, schizophrenia & bipolar maintenance. - Dosing range of 10-20 mg - Comes in a transdermal and SL formulation - Patients may not eat or drink 10 minutes after administration of SL formulation. - Bioavailibility decreases to 28 % if these instructions are not followed & decreased to 2% if swallowed - Start children at 5 mg SL BID to decrease risk of dystonia - Risperdal (Risperidone) FDA approved: - schizophrenia ages 13 and up, mania ages 10 and up, Irritability r/t Autism ages 5 and up, & bipolar maintenance [Dosage] - 2-8 mg for psychosis or mania; 0.5 -2 mg for agitation in children - Comes in tablet, liquid, ODT, and LAI formulations (Consta and Perseris) - More typical at high doses, may be more likely to cause EPS - Weight gain and sedation are common - Common elevation of prolactin even at low doses. - - - - - [Invega (paliperidone)] - Dosing 6-12 mg; Sustained released, once a day dosing. - FDA approved for management of schizophrenia ages 12 and older. - The active metabolite of Risperdal - Is not hepatically metabolized, eliminated via urinary excretion - Possibly better tolerated, with less sedation, EPS, and orthostasis. - Comes in LAI form Invega Sustenna - Dosing range of 80-160 mg in BMD, up to 200 mg in schizophrenia. - Comes in IM formulation - May give 10-20 mg at a time, with a max of 40 mg in a 24 hour period - Must take with food, as food can double bioavailability and increase absorption of this medication. - Around 500 kcal or a small meal - Weight gain is not associated with this medication - Half-life of 7 hours - Geodon (ziprasidone) - DRESS (Drug Reaction with Eosinophilia) FDA warning issued in 2014 - Rare but serious skin condition - Rash that may spread to other parts of the body, causing fever, swollen lymph nodes, swollen face, inflammation of organs, , an increase in white blood cells, and death. - Symptoms often develop 11-30 days after initiation of treatment. - QTc prolongation so contraindicated in patients with a hx of QTc prolongation - Not dose dependent but also might be? - QTc prolongation of the IM formulation is the same as or less than IM Haldol. - Often underdosed d/t fear of QTc prolongation. - Fanapt (iloperidone) - Dosing range of 12-24 mg in divided doses - Low level of EPS - Potent α1 antagonism - Well known for orthostatic hypotension and sedation - Dosing of 40-80 mg, but may go up to 160 mg FDA approved - bipolar depression, ages 10 and up & schizophrenia ages 13 and up. - Moderate affinity for 5HT7 receptors, which may benefit mood, cognitive impairment, and sleep - Lacks potent actions at D1, M1, and H1 receptors, which may be why it has less propensity for weight gain, sedation, and cognitive impairment - Neutral for lipids, glucose, and weight gain - Latuda (lurasidone) - Must be taken with a small meal, at least 350 kcal - Absorption is decreased by 50% on an empty stomach - Low level EPS - Akathisia can occur - Low issues with hyperprolactinemia - No known issues with QTc prolongation, one of the few antipsychotics without a warning. [Dosage range] - 5- 15 mg for ASD - 15-30 mg for Schizophrenia/mania - 2-10 mg for depression Formulation - Comes in Tablet, ODT, Oral solution and 2 LAI formulations (Maintena and Aristada) - Half life of 75 hours - Low level of EPS (except Akathisia), dyslipidemia, elevation of triglycerides, or insulin resistance, & weight gain FDA approved - Schizophrenia (13 & up), mania (10 & up), adjunctive treatment of depression, irritability with Autism (6 & up), Tourette's (6 &up), acute agitation in BMD and SZ - - - - - - - - - Abilify (aripiprazole) - D2 dopamine receptor partial agonist - Theoretically reduces dopamine output when dopamine concentrations are high, improving positive symptoms - Theoretically increases dopamine output when dopamine concentrations are low, improving cognition and negative symptoms. - Has 5HT1a partial agonist actions, may contribute to antidepressant actions - Lacks D1, anticholinergic, and antihistamine properties - May not deliver sufficient antipsychotic efficacy in difficult to treat patients. - No issues with hyperprolactinemia, and may even reverse hyperprolactinemia - Reports of issues with impulse control including compulsive gambling, shopping, binge eating, and sexual activity. - - Dopamine Partial Agonist & partial agonism at 5HT1a and D2 receptors with Antagonist activity at 5HT2a receptors - FDA indication for schizophrenia & adjunctive therapy for depression Dosing range: - 0.5 -- 2 mg for depression & 2-4 mg for schizophrenia - Half life of 91 hours - No issues with Hyperprolactinemia or QTc; Low levels of weight gain& EPS - Akathisia is the most likely, but less than Abilify - Same impulse control warning that Abilify carries. - In testing for an indication for managing agitation related to dementia. - May be of benefit for cognitive impairment in schizophrenia - Dopamine partial agonist - FDA approved for bipolar depression, schizophrenia, and mania. - Partial agonist for D2, 5HT1a, and 5HT2a - Will bind to D3 receptors over D2 receptors at low doses, but the clinical significance of this is unknown - High affinity for D3, D2, 5HT2b, and 5HT1a receptors - Dosing of 1.5-6 mg for schizophrenia - Dosing of 3-6 mg for bipolar - [2--3-day half-life] - - - - - Caplyta (lumeteperone) - FDA approved for schizophrenia, launched Q1 2020 - Dosed at 42 mg once a day with food - Most common side effects are sedation and dry mouth - Serotonin-dopamine antagonist - Blocks serotonin 2a receptors, post synaptic D2 receptors - Affinity for serotonin reuptake pump - Interactions at a myriad of other neurotransmitter receptors may contribute to efficacy - Moderate binding affinity for D1 and D4 receptors - - - - Nuplazid (pimavanserin) - A serotonin 2a/2c agonist/inverse agonist; inverse agonist and antagonist activity at 5HT2a receptors, and to a lesser extent 5HT2c receptors - FDA approved for hallucinations and delusions r/t Parkinson's - Dosing of 34 mg per day (comes in a 34 mg capsule and 10 mg tablet) - Warning for QTc prolongation - Common SEs are Peripheral edema, nausea, and confusion. - Should not worsen motor symptoms of Parkinson's - Previously under investigation for increased death rates. - - -