Bipolar Disorder Pharmacology & Pharmacotherapy PDF

BIPOLAR DISORDER PHARMACOLOGY & PHARMACOTHERAPY Bipolar Disorder ❖ Mood disorder characterized by recurrent fluctuations in energy, mood, and behavior ❖ Characterized by at least one manic, hypomanic, or mixed episode during the course of illness...

BIPOLAR DISORDER PHARMACOLOGY & PHARMACOTHERAPY Bipolar Disorder ❖ Mood disorder characterized by recurrent fluctuations in energy, mood, and behavior ❖ Characterized by at least one manic, hypomanic, or mixed episode during the course of illness Bipolar Spectrum Bipolar Disorder Type I > - I manic/mixed episode Bipolar Disorder Type II > - hypomania Cyclothymic Disorder > - hypomania/dysthymia Bipolar Disorder NOS American Psychiatric Association., American Psychiatric Association. Task Force on DSM-5. Diagnostic and statistical manual of mental disorders : DSM-5. Washington, DC: American Psychiatric Association; 2013. Bipolar Subtypes ❖ Bipolar I Disorder ❖ Characterized by one or more manic or mixed episodes, usually accompanied by major depressive episode ❖ Bipolar II Disorder ❖ Characterized by one or more major depressive episodes accompanied by at least one hypomanic episode Manic Episode ❖ A distinct period of abnormally and persistently elevated, expansive, or irritable mood, lasting at least 1 week ❖ During the period of mood disturbance, 3 or more of the following are present: ❖ Inflated self-esteem or grandiosity ❖  need for sleep (rested after 3 hrs) ❖ More talkative than usual or pressured speech ❖ Flight of ideas/thought racing ❖ Distractibility ❖ Increase in goal-directed activity/psychomotor agitation ❖ Excessive involvement in pleasurable activities that have a high potential for painful consequences ❖ Sufficiently severe to cause marked impairment American Psychiatric Association., American Psychiatric Association. Task Force on DSM-5. Diagnostic and statistical manual of mental disorders : DSM-5. Washington, DC: American Psychiatric Association; 2013. Manic Episodes ❖ DIGFAST mnemonic for mania/hypomania ↳ Dboch D: Distractibility/Poorly Confused I: Insomnia G: Grandiosity/ self-esteem F: Flight of Ideas/Racing thoughts A: Activity ’ed in goal directed activity S: Speech pressured…more talkative T: Thoughtlessness: “risky behaviors” Diagnostic Criteria Stahl SM. Stahl's essential psychopharmacology : neuroscientific basis and practical applications. 3rd ed, Fully rev. and expanded. ed. Cambridge ; New York: Cambridge University Press; 2008. Illustration of Bipolar I Disorder Stahl SM. Stahl's essential psychopharmacology : neuroscientific basis and practical applications. 3rd ed, Fully rev. and expanded. ed. Cambridge ; New York: Cambridge University Press; 2008. Copyright2008. Bauer MS. Bipolar disorder. Ann Intern Med. 2022;175(7):ITC97-ITC112. Pathophysiology ❖ Neurochemical imbalance theories ❖ Excess in excitatory neurotransmission + decrease in inhibitory neurotransmission ❖ Excess catecholamine activity manifests as mania ❖ Deficiencies in GABA &  glutamate cause dysregulation of neurotransmitters ❖ Dysregulation in 2nd Messenger Systems ❖ Abnormal cAMP and phophoinositide 2nd messenger systems ❖ Hyperactive G proteins in bipolar patients Tondo et al., Acta Psychiatr Scand 2003;108:4-14 Patient presents with mania ❖ Access for secondary causes of mania ❖ Rule out organic causes ❖ Infectious ❖ Encephalitis ❖ HIV ❖ Influenza ❖ HSV/Viral ❖ Neurosyphillis ❖ Hyperthyroidism ❖ Tumors/Neoplasms ❖ Neurological manifestations ❖ Rule out iatrogenic causes Acute Treatment of Mania ❖ Initial treatment for a manic episode often includes a mood stabilizer and adjunctive anxiolytics with or without ↳ benzo a short-term antipsychotic buspirone , , BB antihistamine antipsych , , antidepressant , gabapentinolds ❖ APA Recommendations ❖ 1st Line Treatment ❖ Monotherapy with lithium, valproate, or an atypical antipsychotic for mania of moderate severity ❖ Combination therapy of [lithium or valproate] + an atypical antipsychotic for patients with severe mania or mania w/psychotic features ❖ Mixed episodes or Rapid Cycling ❖ Use valproate  CANMAT 2018 Guidelines severe Moderate ↳❖ First line combos for mania ❖ 1st line monotherapies ↳ for mania ❖ Quetiapine + Li/DVX ❖ Lithium ❖ Aripiprazole + Li/DVX ❖ Divalproex (Valproate) ❖ Risperidone + Li/DVX ❖ Quetiapine ❖ Asenapine + Li/DVX ❖ Asenapine ❖ 2nd line treatments ❖ Aripiprazole ❖ Olanzapine ❖ Paliperidone (> 6 mg) ❖ Mono or combo w/Li or DVX ❖ Risperidone ❖ Carbamazepine ❖ Cariprazine ❖ Ziprasidone Yatham LN, Kennedy SH, et al. Canadian Network for Mood andAnxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder. Bipolar Disorders. 2018;20:97–170. ❖ Haloperidol Young-Mania Rating Scale ❖ 11-item scale to assess severity of mania ❖ Often used in clinical trials ❖ Seven items-Scored 0 to 4 ❖ Four items-Scored 0 to 8 ❖ Irritability ❖ Speech ❖ Thought Content ❖ Disruptive/Aggressive Behavior ❖ Max Score ❖ 60 points ❖ >25 indicative of severe mania ❖ 19-24 indicative of moderate mania ❖ < 11 indicative of euthymia Do Nomovize Lithium ❖ Gold-standard treatment for classic mania ❖ Universally accepted ❖ Group IA alkaline metal ❖ Narrow therapeutic index ↑ becomes challenging ❖ Prominent use in late 1940s as a salt substitute ❖ Removed from US Market ❖ Treatment effects for mania noted in 1949 Lithium Indications ❖ Bipolar Disorder ❖ Maintenance Treatment ❖ Bipolar Disorder ❖ Manic Episode adding wh ❖ Other usage S antidepressant ❖ Depressive episodes associated with Bipolar Disorder ❖ Psychotic features associated with Bipolar Disorder ❖ One Black Boxed Warning > - Lithium toxicity ↳ dehydration can cause it Am J Psychiatry 2002; 159:1-50. Pharmacology of Lithium ❖ In all honesty it really is unknown ❖ Possible Mechanisms ❖ Inhibit presynaptic exocytoxic release of dopamine ❖ Inhibition of inositol monophosphatase ❖ Decrease in second messengers ❖ Decrease in cAMP ❖ Inhibition of glycogen synthase kinase-3β ❖ Modulation of gene expression ❖ Serotonergic involvement ❖ Increase presynaptic reuptake of NE ❖ Decrease 5HT reuptake and increase 5HT receptor sensitivity ❖ Accelerate metabolism of NE ❖ List goes on and on and on Brunton, Laurence. Goodman & Gilman’s: The Pharmacological Basis of Therapeutics. New York: McGraw-Hill, 2006. Pharmacology of Lithium Stahl SM. Stahl's essential psychopharmacology : neuroscientific basis and practical applications. 3rd ed, Fully rev. and expanded. ed. Cambridge ; New York: Cambridge University Press; 2008. Copyright 2008. Pharmacokinetics of lithium P.I ❖ Absorption ❖ Rapidly absorbed ❖ 60-90% for extended release ❖ 100% for immediate release & solution ❖ Peak concentrations ❖ 0.5-3 hours for immediate release ❖ 4-12 hours for extended release ❖ 0.25-1hour for solution ❖ Volume of Distribution ❖ 0.3-0.4 L/kg ❖ Concentrates in brain, kidney, thyroid, & bone Pharmacokinetics of Lithium P.II ❖ Metabolism ❖ Not metabolized ❖ Elimination ❖ 95% excreted unchanged ❖ 80% reabsorbed @ proximal tubule ❖ 24 hour t½ Lithium Adverse Effects ❖ Most common ❖ CNS Effects ❖ Weakness, drowsiness, fatigue, dizziness, ataxia, slurred speech, memory difficulties ↑ toxicity sign ❖ Tremor ❖ Management ❖ Gastrointestinal upset Lithium ❖ Nausea (up to 50%) > - first starting ❖ Vomiting ❖ Diarrhea > - dehydration = toxicity Nephrogenic effects of lithium ❖ Potential to induce NDI symptoms polydipsia polyuria ↑ ↑ ❖ Excess thirst and urination ❖ Management Endocrine effects of lithium ❖ Lithium-Induced-Hypothyroidism ❖ Suppresses thyroid function in 42% of patients ❖ 19% develop overt hypothyroidism ↑ TH 7 ❖ 23% develop subclinical hypothyroidism normal TY ❖ Mechanisms ❖ Inhibits thyroid ability to concentrate iodine and synthesize iodinated thyroglobulin ❖ Suppresses 2nd messenger system response of TSH activation ❖ Inhibits conversion of T4 to T3 Livingstone C, Rampes H. Lithium: a review of its metabolic adverse effects. J Psychopharmacol. May 2006;20(3):347-355. Other notable ADEs of lithium benigh ❖ Weight gain ❖ Leukocytosis - ❖ Up to 4-10 kg in 30% of patients ❖  1.5 x baseline neutrophil count ❖ Cardiac effects - brugada syndrome ↳ can worsen ❖ EKG changes ❖ Dermatological ↳ QT prolongation ❖ Acne ❖ Hypercalcemia 4 ❖ Hyperparathyroidism ❖ Psoriasis activation elevation in calcium Lithium Preparations Generic Name Trade Name Formulation mEq Lithium carbonate N/A 150 & 300 mg IR 4.06, 8.12 capsules capsules Lithium carbonate N/A 300 mg IR tablets 8.12 tablets Lithium carbonate Eskalith® 450 mg ER tablets 12.18 controlled-release tablets Lithium carbonate Lithobid® 300 mg ER tablets 8.12 slow-release tablets Lithium citrate syrup Cibalith-S® 560 mg liquid 8 mEq/5mL - Always order in mEq or mL to reduce medication errors Keep in mind…Lithium is not equivalent to lithium carbonate 300 mg lithium=1597 mg of lithium carbonate Both 300 mg of the carbonate and 5 mL of the citrate contain roughly 8 mEq Lithium Dosing Acute Mania Package Insert 1800 mg/day (in divided doses) Empiric Dosing 300 mg 2-3 times/day (adjust dose based on lithium levels) Dosage Range for Acute Episode Varies (Up to 2400 mg/day) Dosage Range for Maintenance Varies (Up to 1200 mg/day) Caution! 50% of patients end up toxic when too aggressive Patients vary in dose required to reach desired blood concentration and response. Base dosage off therapeutic levels and clinical response. Lithium: Drug Monitoring ❖ Target Lithium Plasma Concentrations Li (mEq/L) Acute Phase Maintenance Phase Most Common 0.8-1.0 0.6-0.8 Occasional 1.0-1.2 0.8-1.0 ❖ Rarely shoot for higher levels during acute/maintenance phase ❖ Acute phase (inpatient): q 1-2 times weekly ❖ Maintenance phase (outpatient): q 3-6 months ❖ Css=5 days ❖ Check drug level 12 hours after the dose Lithium: Drug Monitoring > - weight gain Chem 10a CBC Metabolic tests Baseline 6-12 mos Baseline 6-12 Baseline 6-12 mos mos Kidney Functionb Thyroid Function Dermatologic Baseline 6-12 mos Baseline 3 mos, then Baseline 6-12 mos 6-12 mos a (Includes calcium, phosphorus, & Mg) ❖ EKG b (Includes urea/lytes, CrCl, 24 hr urine vol.) ❖ (+) for preexisting cardiac disease ❖ > 40 old ❖ Pregnancy test ❖ of child bearing age Lithium Toxicity Mild Toxicity (1.5-2.0 mEq/L) Lethargy, fatigue/drowsiness, muscular weakness Coarse hand tremor Nausea, vomiting, diarrhea** Moderate Toxicity (2.0-2.5 mEq/L) Confusion, ataxia, gait changes, speech changes Nystagmus, myoclonic twitches EKG Changes (flat/inverted T-waves) Severe Toxicity (>2.5 mEq/L) Grossly impaired consciousness, increased deep tendon reflexes Seizures, Syncope Renal insufficiency Coma/Death **Tends to occur earlier in toxicity/Often first sign Handler J. Lithium and antihypertensive medication: a potentially dangerous interaction. J Clin Hypertens (Greenwich). Dec 2009;11(12):738- 742. Risk Factors for Lithium Toxicity ❖ Advanced age ❖ Schizophrenia medication > - compliance ❖ Poor mental status at baseline ❖ Dehydration ❖ Malnutrition ❖ Rapid rise in lithium levels Lithium Toxicity Management ❖ Elevated level w/signs & symptoms ❖ Discontinue Li+ ❖ Discontinue drugs that  Li+ conc. ❖  absorption of other drugs if concurrent overdose ❖ Protect oral airway if unconscious ❖ Volume resuscitation via IV Fluids ❖ Gastric lavage, whole bowel irrigation with PEG to prevent continued absorption of lithium ❖ Final management…Hemodialysis Hemodialysis-Lithium Toxicity ❖ Hemodialysis indications: ❖ Hemodialysis required ❖ Lithium level of 3.5-4.0 mEq/L Goal: ❖ Hemodialysis maybe required: Lithium level < 1 mEq/L 6-8 hr post dialysis ❖ Lithium level of 2.0-3.5 mEq/L ❖ Marked symptoms of toxicity ❖ Neurological signs (seizures, stupor, coma) ❖ Hemodialysis not generally required: ❖ Lithium level of 1.5-2.0 mEq/L ❖ Fluid therapy and diuresis indicated ❖ Use dialysis if Li level is not < 1.0 mEq/L within 30 hours Lithium: Drug Interactions ❖ Influencing factors that increase lithium levels and place patients at risk for toxicity… ❖ Diuretics** ❖ Angiotensin ❖ Thiazides  levels Receptor Blockers** ❖ K+ Sparing & Loop ❖ Salt Restriction** Diuretics have minimal effects on levels ❖ Dehydration** ❖ NSAIDs** ❖ Elderly ❖ Aspirin is an ❖ Renal disease exception (low dose) ❖ ACE Inhibitors** ** Major Drug Interaction Lithium: Drug Interactions ❖ Influencing factors that decrease lithium levels and place patients at risk for relapse… ❖ Carbonic Anhydrase Inhibitors ❖ Acute Mania ❖ Acetazolamide primarily ❖ Pregnancy Methyl Xanthines ❖ Theophylline ❖ Caffeine ❖ Mannitol Patient Counseling for Lithium ❖ Administer with food to  GI ADEs ❖ Slower onset of action (1 week) compared to atypical antipsychotics ❖ Keep well hydrated to avoid toxicity ❖ Counsel on potential adverse effects ❖ Especially changes to occur renally Divalproex Sodium (Depakote®) ❖ Mechanism as a mood stabilizer ❖ Uncertain ❖ Blockade of voltage-sensitive Na+ channels ❖  GABA concentrations ❖ Stimulation via glutamic acid decarboxylase ❖ Regulate downstream signal transduction ❖ Inhibits glycogen synthetase kinase 3 (GSK3) ❖ Inhibits phosphokinase C ❖ Inhibiting signals hypothesized to  mania ❖ Activates neuroprotective factors Divalproex Sodium (Depakote®) Indication Recommended Dose Target Level Acute Mania 500-1000 mg/day 50-125 mgc/mL -Initial dose 15 mg/kg Trough levels Avg starting dose(750 Css=5 days mg/d) -May  by 250-500 mg every 1-3 days (Based on tolerability) Maximum Dose 60 mg/kg/day Onset of action=5 days Medication Trade Formulation Strength Valproic Acid Depakene® Syrup, Capsule 250 mg/mL, 250 mg Divalproex sodium Depakote® Delayed release tab 125, 250, 500 mg Sprinkles 125 mg Divalproex sodium Depakote ER® Extended release 250, 500 mg tab  Divalproex Sodium (Depakote®) ❖ Common adverse effects of divalproex/valproic acid derivatives ↳> NIV , constipation , diarrhea ❖ Black box warnings for divalproex? ↳ terratogenic , thrombocytopenia ❖ Drug-drug Interactions for divalproex? C : hepatic disease , hypersensitivity , Urea Cyclic disorder Pregnancy Divalproex Monitoring Baseline Steady-State Every 3 Every 6-12 If symptoms (Minimally 3 days months (for months arise of full treatment) first 6 months) Drug levels (trough) X X X CBC w/differential X X X X Liver Function Tests X X X X (LFTs) Amylase/Lipase X Electrolytes X X Prothrombin Time X X X Androgens X Ammonia levels X Pregnancy test in X X women of childbearing age Weight/BMI/Waist X X X size Dermatologic X X Carbamazepine (Equetro®) ❖ FDA approved in 2005 for the treatment of bipolar disorder ❖ Brand Name: Equetro® ❖ Mechanism in bipolar disorder ❖ Blockade of voltage-sensitive Na+ channels ❖ Blocks kindling > - rapid cycling : mania + depression ❖ Modulates or decreases presynaptic aspartate and glutamate release ↳ NMDA receptors Carbamazepine (Equetro®) ❖ Common adverse effects of carbamazepine? ↳> N/V , constipation , dry mouth , derm effects ❖ Black box warnings for carbamazepine? ↳ (Steven Johnson) hypersensitivity , teratogenic , osteoporosis Ubrupt Stop = seziures , hyponatremia ❖ Drug-Drug Interactions for carbamazepine? ↳ conceptives carbamazepine , alprazolam , oral Citalopram , simvastatin , Clozapine Carbamazepine Dosing ❖ Initial dose ❖ 200 mg BID ❖ Increase by 200 mg/day ❖ Dose adjust base on response ❖ Maintenance Dose ❖ Approximately 1000 mg/day ❖ Up to 1600 mg/day ❖ Individualized treatment ❖ Therapeutic monitoring ❖ Recommended by APA Carbamazepine Monitoring Baseline 2 weeks Monthly for 2nd Every 6-12 If symptoms & 3rd Month of months arise treatment Drug levels X X X (trough) CBC X X X X X LFTs X X X X Electrolytes X X X X Kidney function X X Urinalysis (UA) X X Pregnancy test in X X women of childbearing age Thyroid cascade X X Eye exam X Dermatologic X X Clinical Efficacy in Mania ❖ Lithium ❖ Versus Placebo ❖ (87/140, 70% response rate) ❖ 20-30% of patients non-responsive ❖ Versus Anticonvulsants ❖ No difference in response ❖ CBZ & VPA are generally more tolerable ❖ VPA trends to be more effective for patients with rapid cycling ↓ more preffered Clinical Efficacy in Mania ❖ Divalproex ❖ Equally effective as lithium ❖ More (+) response for mixed episodes + rapid cycling ❖ (+) response for lithium non-responders ❖ Carbamazepine > - Not good w/ Paxlovid : pt gets COVID ❖ Considered equally effective ❖ More commonly used in Europe vs. USA ❖ Considered 2nd line treatment Other “Mood Stabilizers/AEDs” ❖ Topiramate ❖ No difference than placebo ❖ Less effective than lithium ❖ Oxcarbazepine ❖ (+) open-label trials, small DB-RCTs ❖ (-) large study showed no differ. vs pcb ❖ Reserved for combination treatment in patients who have failed 2nd line tx. Schatzberg AF, Nemeroff CB. The American Psychiatric Publishing textbook of psychopharmacology. 4th ed. Washington, D.C.: American Psychiatric Pub.; 2009. Other “Mood Stabilizers/AEDs” ❖ Gabapentin ❖ Not effective ❖ Levetiracetam ❖ Open label adjunct show some improvement ❖ Use caution? “KepRage” Schatzberg AF, Nemeroff CB. The American Psychiatric Publishing textbook of psychopharmacology. 4th ed. Washington, D.C.: American Psychiatric Pub.; 2009.  close -> Schizophrena was higher Atypical Antipsychotics > - More moderate dosage ❖ Primary mechanism of action ❖ Blockade of dopamine (D2) and serotonin (5HT2A) receptors ❖ Reduces glutamate hyperactivity ❖ Blocks DA hyperactivity ❖ 1st line treatment for manic episodes ❖ Faster onset of action compared to other mood stabilizers ❖ (+) for psychotic features of mania ❖ Long term use is still questioned ❖ All antipsychotics are antimanic! ↳ can pick any Atypical Antipsychotics ❖ Common adverse effects of atypical antipsychotics? ↳ Metabolic side effects ↳ Eps ❖ How do you differentiate treatments? ↳ evidence quetiapine : best ❖ Which are preferred treatments and which are reserved? ↳ ↳ clozapine quetiapine ❖ Role of clozapine in mania? ↳ for treatment resistance L 3rd line Atypical Antipsychotic Dosing Medication Treatment of Acute Mania Average Starting Dose Average Target Dose (mg/day) Low High Aripiprazole 15 15 45 Asenapine 20 10 20 Quetiapine 150 300 800 Risperidone 2 2 6 Ziprasidone 80 80 160-200 Olanzapine 15 10 20-30 Cariprazine 1.5 3 6 Mood Stabilizers & Pregnancy ❖ Lithium ❖ Carbamazepine ❖ Category D ❖ Category D ❖ Avoid in 1st Trimester ❖ Avoid during pregnancy/1st trimester ❖ Epstein anomaly (4-12% risk) ❖ Risk of neural tube defects ❖ Valproic Acid ❖ Category D ❖ Avoid during pregnancy ❖ Risk of neural tube defects ❖ Fetal valproate syndrome Adjunctive Agents ❖ Typical antipsychotics ❖ Largely replaced by the atypical antipsychotics ❖ Risk of TD  in patients w/mood disorders tardive disconisia ❖ Effective for agitation if no AAP on board atypical antipsychotic ❖ Benzodiazepines ❖ May be as needed throughout course of disease ❖ Substance abuse considerations ❖ Beta Blockers > - propanolol ❖ Utilized for treatment of tremor associated with lithium or divalproex sodium ↓ From lithium Bipolar Depression ❖ Bipolar depression is often misdiagnosed or not diagnosed at all ❖ More patients are in depressed state vs manic state ❖ Research less extensive in BPD ❖ Must r/o unipolar depression if 1st visit Unipolar vs. Bipolar Depression ❖ Critical Information ❖ Discriminating Signs BP disorder only ❖ Patient history ❖ Racing thoughts, irritability, or both ❖ Family history ❖ Depression marked by ❖ Course of illness hypersomnolence, anergia, and hyperphagia Jerr ❖ Response to previous treatments ❖ Earlier age of onset ❖ Lifestyle ❖ Sudden or paradoxical responses to traditional antidepressants Jar ❖ Overall less time spent well Muzina DJ, Colangelo E, Manning JS, Calabrese JR. Differentiating bipolar disorder from depression in primary care. Cleve Clin J Med. Feb 2007;74(2):89, 92, 95-89 passim. Muzina DJ, Kemp DE, McIntyre RS. Differentiating bipolar disorders from major depressive disorders: treatment implications. Ann Clin Psychiatry. 2007;19(4):305-312. CANMAT Guidelines 2018 > - for BP depression ❖ 1st LineAgents ❖ 2nd LineAgents ❖ Quetiapine ❖ Divalproex ❖ Lurasidone ❖ Adjunctive bupropion or ❖ Mono or combo w/Li + DVX SSRIs > - combo whistline ❖ Lithium ❖ Cariprazine ❖ Lamotrigine ❖ Olanzapine/Fluoxetine ❖ ECT Yatham LN, Kennedy SH, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder. Bipolar Disorders.2018;20:97–170. Atypical Antipsychotics ❖ FDA approved treatments for Bipolar Depression > - Not mania ❖ Quetiapine (Seroquel®) J less ❖ Lurasidone (Latuda®) > - Not for manla ❖ Cariprazine (Vraylar®) dosage ❖ Olanzapine/Fluoxetine [OFC] ❖ (Symbyax®) ❖ Efficacy is not a class effect Lurasidone (Latuda®) ❖ FDA Approved in October 2010 ❖ Launched in February 2011 ❖ FDAApprovals ❖ October 28th, 2010-Schizophrenia ❖ June 28th, 2013-Bipolar Depression Indication Starting Dose Recommended Dose Schizophrenia 40 mg per day 40 mg to 160 mg per day Bipolar Depression 20 mg per day 20 mg to 120 mg per day u ❖ Dosage Forms: low dose ❖ Tablets: 20 mg, 40 mg, 60 mg, 80 mg and 120 mg ❖ Lurasidone is administered once daily & should be taken with food Picture Source: J Clin Psychiatry Lurasidone (Latuda®) ❖ Pharmacology ❖ 5-HT2A≥D2>5-HT7/5-HT1A>α2 ❖ Very weak α1 & 5-HT2C affinity appetite - Weight gain - stimulation ❖ No affinity for M1 & H1 ❖ Pharmacokinetics ❖  absorption ❖ Highly protein bound ❖ Metabolism via CYP 3A4 ❖ T½ : 18 hours ❖ Two active metabolites ❖ (ID-14283 & ID-14326) Cariprazine (Vraylar®) ❖ FDA Approved in September 2015 ❖ FDAApprovals ❖ Schizophrenia ❖ Bipolar Mania/Bipolar Depression Indication Starting Dose Recommended Dose Schizophrenia 1.5 mg/day 1.5 mg/day to 6 mg/day Bipolar Mania 1.5 mg/day 3 mg/day to 6 mg/day Bipolar Depression 1.5 mg/day 3 mg/day to 6 mg/day ❖ Dosage Forms: ❖ Capsules: 1.5 mg, 3 mg, 4.5 mg, and 6 mg Cariprazine (Vraylar®) ❖ Pharmacology ❖ D3, D2, 5-HT1A partial agonist ❖ D3>D2>5-HT1A≈α1>5-HT2A>H1 ❖ Pharmacokinetics ❖ Highly protein bound ❖ Metabolized by CYP 3A4 ❖ Two major active metabolites ❖ Desmethyl cariprazine (DCAR) ❖ Didesmethyl cariprazine (DDCAR) ❖ Long t½ for parent drug: 2-4 days ❖ 1-3 weeks for DDCAR Lithium in Bipolar Depression ❖ Majority of studies conducted for acute manic episodes vs. depressed episodes ❖ Lithium more effective vs placebo in 8 out 9 cross over studies ❖ Small studies (Patient range up to 40 patients) ❖ Suicide protective ❖ 7-to-8 fold difference of completed suicides vs. patients treated with lithium Zornberg GL, Pope HG, Jr. Treatment of depression in bipolar disorder: new directions for research. J Clin Psychopharmacol. Dec 1993;13(6):397-408. Tondo L, Jamison KR, Baldessarini RJ. Effect of lithium maintenance on suicidal behavior in major mood disorders. Ann N Y Acad Sci. Dec 29 1997;836:339-351. Lamotrigine (Lamictal®) ❖ FDA approved for maintenance tx in BPAD ❖ Not effective in acute treatment of mania ❖ 1st line treatment for acute bipolar depression ❖ Not FDA approved Lamotrigine (Lamictal®) ❖ Why is lamotrigine considered a 1st line treatment for acute bipolar depression? ❖ No primary endpoints statistically separated from placebo Pooled Response Rate for Lamotrigine in Acute Bipolar Depression Clinical Trials (5 Trials) Percent Responders Placebo (n=530) 38% Lamotrigine (n=541) (%) 47% §§ NNT=12 §§ p < 0.01 vs placebo 0% 20% 40% 60% Geddes JR, Calabrese JR, Goodwin GM. Lamotrigine for treatment of bipolar depression: independent meta-analysis and meta-regression of individual patient data from five randomised trials. Br J Psychiatry. Jan 2009;194(1):4-9. Ketter TA, et al. Treatments for bipolar disorder: can number needed to treat/harm help inform clinical decisions? Acta Psychiatr Scand. Mar 2011;123(3):175-189. Lamotrigine Maintenance Tx ❖ Pooled-analysis of two placebo-controlled 18 month trials of lamotrigine and lithium in maintenance for BPAD I Numbers Needed to Treat in Bipolar Maintenance Any Mania Depression Episode Prevention Prevention Lamotrigine 9 23 15 Lithium 7 8 49 Goodwin GM, Bowden CL, Calabrese JR, et al. A pooled analysis of 2 placebo-controlled 18-month trials of lamotrigine and lithium maintenance in bipolar I disorder. J Clin Psychiatry. Mar 2004;65(3):432-441. Lamotrigine (Lamictal®) ❖ Common adverse effects of lamotrigine? ↳ Rash (Steven Johnson) ❖ Drug-Drug Interactions for lamotrigine? ↳ ? Okay.... Lamotrigine & Aseptic Meningitis Picture provided via: http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm222269.htm [Accessed 10/5/2011] Lamotrigine Dosing for BPAD Lamotrigine Patients taking Patients taking Patients taking Dosing valproic acid non-EIAED* EIAED* phenobarb products Carbazapine Weeks 1 & 2 12.5 mg/day 25 mg/day 50 mg/day Weeks 3 & 4 25 mg/day 50 mg/day 100 mg/day Week 5 50 mg/day 100 mg/day 200 mg/day Week 6 100 mg/day 200 mg/day 300 mg/day Week 7/FDA 100 mg/day 200 mg/day 400 mg/day Target Dose Antidepressants in BPD ❖ Use in bipolar disorder is controversial ❖ No clinical studies have ever shown an advantage over placebo in the presence of a mood stabilizer ❖ Induction of mania tends to be higher among antidepressants with noradrenergic activity ❖ Maintenance treatment suggest a possible role in patients with BPAD II disorder and in patients with a robust acute response initially Antidepressants in BPAD Induction of Mania with Antidepressants 11.20% 12% 10% Percentage 8% 4.20% 6% 3.70% 4% 2% 0% Placebo SSRIs TCAs Peet M. Induction of mania with selective serotonin re-uptake inhibitors and tricyclic antidepressants. Br J Psychiatry. Apr 1994;164(4):549- 550.  STEP-BD ❖ No advantage/disadvantage of adding antidepressant to mood stabilizer Effectiveness of Adjunctive Antidepressant Tx. in BPAD Mood Stabilizer + Placebo (n=187) 27.30% Mood Stabilzer + Antidepressant 23.50% (n=179) 0% 5% 10% 15% 20% 25% 30% % of Patients with Durable Recovery Sachs GS, Nierenberg AA, Calabrese JR, et al. Effectiveness of adjunctive antidepressant treatment for bipolar depression. N Engl J Med. Apr 26 2007;356(17):1711-1722. Miscellaneous & Off-label Treatments ❖ Modafinil ❖ Carbamazepine ❖ Pramipexole ❖ Omega-3-Fatty Acids ❖ Inositol ❖ Thyroid Supplementation ❖ Stimulants ❖ N-acetyl cysteine ❖ Adjunctive riluzole ❖ Adjunctive topiramate Maintenance therapy ❖ Guidelines suggest that medications used to achieve remission from the most recent mood episode should be continued into the maintenance phase. Final Thoughts ❖ Remember to consider the following when recommending pharmacotherapy ❖ Phase of Illness ❖ Prior response and tolerability ❖ Medical complications ❖ Adverse effects of medications ❖ Drug-Drug Interactions ANXIETY DISORDERS PHARMACOLOGY & PHARMACOTHERAPY Objectives ❖ Differentiate diagnostic requirements of various anxiety disorders including generalized anxiety disorder, panic disorder, and social anxiety disorder ❖ Compare and contrast antidepressants & benzodiazepines available for the treatment of various anxiety disorders ❖ Assess and evaluate the appropriateness of pharmacological therapy for a patient with an anxiety disorder What is Anxiety? ❖ Anxiety is… ❖ The unpleasant emotion commonly caused by ❖ Perception of danger ❖ Threatens the individual ❖ What is the difference between fear & anxiety? ❖ Is anxiety normal? ❖ Healthy or Fatal… Clinical Forms of Anxiety ❖ Specific Phobias ❖ Social Phobia (Social Anxiety Disorder) ❖ Panic Disorder ❖ Post-Traumatic Stress Disorder ❖ Obsessive-Compulsive Disorder ❖ Generalized Anxiety Disorder  Pathophysiology of Anxiety Disorders “Fear Factory” Stahl, SM. Stahl’s Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. Cambridge University Press. 3rd Edition. 2008. All Rights Reserved NEI Global. Prevalence of Anxiety & Related Disorders Disorder Prevalence Anxiety Disorders Specific Phobia 3%-13% Social Anxiety Disorder/Social Phobia 5%-10% Panic Disorder (PD) 1%-4% Agoraphobia 2%-6% Generalized Anxiety Disorder (GAD) 3%-8% Trauma-and Stressor-Related Disorders Posttraumatic Stress Disorder (PTSD) 8% Obsessive-Compulsive and Related Disorders Obsessive Compulsive Disorder (OCD) 2%-3% Body Dysmorphic Disorder 2% Hoarding Disorder 2%-5% Trichotillomania 0.6%-3.4% Differential Diagnosis ❖ Cardiovascular ❖ Gastrointestinal ❖ Arrhythmias ❖ Irritable bowel syndrome ❖ Hypertension ❖ Ulcerative colitis ❖ Mitral Valve Prolapse ❖ Peptic ulcer ❖ MI/Angina ❖ Respiratory ❖ Hyperadrenergic state ❖ COPD/Hyperventilation ❖ Endocrine ❖ Asthma ❖ Hyperthyroidism ❖ Pulmonary Embolism ❖ Hypothyroidism ❖ Neurological/Misc. ❖ Cushing’s/Adrenal ❖ Epilepsy malignancy ❖ Migraine ❖ Hypoglycemia ❖ Pain Comorbid Conditions Tourette’s Disorder (OCD) Substance Abuse Hypochondriasis Anxiety Anxiety Major Depressive Personality MajorDisorder Depression Personality Disorder D/Os Psychosis (OCD)  Drug-Induced Anxiety ❖ CNS Stimulants ❖ Miscellaneous ❖ β2 agonists ❖ Anticholinergic toxicity ❖ Amphetamines ❖ Cycloserine ❖ Cocaine ❖ Dapsone ❖ Methylphenidate ❖ Caffeine ❖ Withdrawal effects ❖ Ephedrine ❖ Alcohol ❖ Weight loss agents ❖ Anxiolytics ❖ Decongestants ❖ Benzodiazepines ❖ Antidepressants ❖ Opioids Simple anxiety…or phobia ❖ Marked/Persistent fear in excess cued by the presence or anticipation of a specific object/situation ❖ Exposure=immediate anxiety ❖ Person recognizes fear is in excess ❖ The situation is avoided or endured w/distress ❖ The avoidance or distress in the feared situation interferes with the person’s life… Specific Phobias Common Phobias?? Specific Phobias ❖ Treatment ❖ Non-pharmacological methods ❖ Cognitive-Behavioral Therapy ❖ Exposure Therapy ❖ Medications ❖ Not-indicated ❖ Benzodiazepines can interfere w/CBT ❖ Do not use concurrently together Social Anxiety Disorder (SAD) ❖ Marked/Persistent fear of one or more social or performance situations ❖ Individual fears that he/she will act in a particular way causing humiliation or embarrassment ❖ Exposure to the feared social situation provokes anxiety ❖ The person recognizes the fear is excessive ❖ The avoidance or distress in the feared situation interferes with the person’s life…  Social Anxiety Disorder (SAD) Scale Description Interpretation Liebowitz Social 24-item scale, 13 Each item is rated for fear and avoidance Anxiety Scale items for behavior on a Likert scale of 0-3 (0=never, (LSAS) performance 3=severe or usually) anxiety and 11 for social situations Scoring Moderate: 55-65 Clinician rated Marked: 65-80 Severe: 80-95 Used for diagnosis Very Severe: >95 and assesses treatment response Response=score of 50 Remission=score - phenelzine  Treatment Algorithm for SAD FDA Approved Txs Generalized SAD -Paroxetine -Paroxetine CR -Sertraline SSRI or SNRI for 12 Infrequently -Venlafaxine XR Used for SAD ALL SSRIs are effective weeks Response: Continue No response: Switch to Partial Response: for 12 months another SSRI or SNRI Consider augmenting with buspirone or Inadequate Repsonse: clonazepam Switch to mirtazapine or phenelzine Source: Dipiro β-Blockers for “Performance Anxiety” ❖  perception anxiety…not an actual treatment ❖ Blunts autonomic overflow from NE ❖  rate ❖ Blushing ❖ Tremor ❖ Blood pressure changes ❖ Propranolol 10-80 mg PO 1 hr prior to event ❖ Atenolol 25-100 mg PO 1 hr prior to event β-Blockers for “Performance Anxiety” Contraindications Relative Contraindications Common Side Effects ❖ Cardiogenic Shock ❖ Underlying respiratory illness ❖ Fatigue ❖ Sinus bradycardia; ❖ Diabetes ❖ Bradycardia greater than 1st degree mellitus/hyperglycemia ❖ Hypotension heart block ❖ Depression ❖ Depression ❖ Cardiac failure ❖ Peripheral Vascular Disease ❖ Dizziness ❖ Bronchial asthma ❖ Cardiac insufficiency ❖ Vivid dreams ❖ Known hypersensitivity ❖ Reynaud’s Disease ❖ Impotence ❖ Insomnia * start low go slow A FDA approved Antidepressants for Social Anxiety Parameter Fluvoxamine Paroxetine Paroxetine Venlafaxine Sertraline Controlled Release Controlled Release Extended Release Initial Dose 100 mg/d 20 mg/d 25 mg/d 37.5 mg/d 25-50 mg/d Titration 50 mg/wk 10 mg/wk 12.5 mg/d 37.5-75 50 mg/wk mg/wk Dose 150-300 mg/d 10-60 mg 25-75 mg/d 75-225 mg/d 50-200 mg Range Max Dose 300 mg/d 60 mg 75 mg/d 225 mg/d 200 mg Metabolism 1A2 2D6 2D6 2D6 2D6, 2C9 PK Intrxns Strong 1A2 Strong Strong 2D6 Weak 2D6 Weak-to- Inhibitor & 2D6 Inhibitor Inhibitor moderate 2C19 Inhibitor Inhibitor 2D6 Inhibition Sources: Dipiro 7th edition, Kaplan & Sadocks Comprehensive Textbook of Psychiatry, Hemeryck et al. Curr Drug Metab 2002. Summary of Social Anxiety Disorder ❖ More spotlight due to marketing techniques of pharmaceutical companies ❖ Important to distinguish from performance anxiety, stage fright, and shyness ❖ PRN β-Blocker can be used for certain situations ❖ SSRIs/Venlafaxine XR are 1st line treatments ❖ Rule out concurrent substance abuse before recommending treatment Generalized Anxiety Disorder (GAD) ❖ Excessive anxiety and worry, occurring more days than not for at least 6 months, about a number of events or activities (2 or more) ❖ The person finds it difficult to control worries ❖ Associated with 3 or more of the following: ❖ Restlessness ❖ Fatigue Other Findings w/GAD: ❖ Concentration difficulties Trembling, twitching, feeling shaky ❖ Irritability Autonomic hyperactivity ❖ Muscle tension Vigilance ❖ Sleep disturbance ❖ The anxiety causes significant impairment or distress  Rating Scales for GAD Scale Description Interpretation Hamilton 14-item scale Each item is scored on a scale of 0 (not present) Anxiety Scale assesses severity to 4 (severe) (GAD) of anxiety symptoms Scoring Mild: 0-17 Mild to moderate: 18-24 Clinician-rated Moderate to severe: 25-30 Used for Remission: 70% reduction in symptoms or score interpreting 1 month ❖ Consider converting short t½ med to long t½ med ❖ Total daily dose decrements should not be more frequent than once every 7 days ❖  dose by 20%-25% a week ❖ Patient dependent…may require slower titration if on medication longer Buspirone (Buspar®) ❖ 5-HT1A partial agonist ❖ Post-synaptic and pre-synaptic ❖ Metabolite=α2 Antagonism ❖ No BZD-GABA complex activity ❖ No anticonvulsant properties ❖ Only anxiolytic effects ❖ Possible antidepressant effects (minor) ❖ Anxiolytic effects at 10-60 mg/day ❖ 5 mg TID… by 5 mg every 2-3 days Buspirone (Buspar®) ❖ Delayed onset of action ❖ Pharmacokinetic parameters do all the time ❖ Bioavailability- variable. > - take with food once Vise versa ❖ Short t½=2.5 hours ❖ 3A4 substrate ❖ High first pass metabolism ❖ Active metabolite=1-pyrimidinylpiperazine ❖ (1-PP) ❖ Non-linear pharmacokinetics  Buspirone (Buspar®) Buspirone vs Oxazepam for GAD 25 23 Hamilton Anxiety Rating Scale 21 19 17 Buspirone 15-30 mg (n=87) 15 13 Oxazepam 30-60 mg (n=99) 11 9 7 Baseline Week 1 Week 2 Week 4 Week 6 Strand M, et al. A double-blind, controlled trial in primary care patients with generalized anxiety: A comparison between buspirone and oxazepam. J Clin Psychiatry; 51:[9, Suppl]:40-45. Buspirone (Buspar®) ❖ ADEs with buspirone ❖ Other considerations ❖ Dizziness ❖ Buspirone vs BZDs ❖ Insomnia ❖ Immediate effects vs delayed effects ❖ Nervousness (akathisia?) ❖ Use in other anxiety ❖ Headache disorders? ❖ GI upset  Anxiolytic Drug Interactions w/Antidepressants Drug-Drug Alprazolam Clonazepam Diazepam Lorazepam Buspirone Inhibition (3A4) (3A4) (2C19, 3A4) (Gluc.) (3A4) Interactions Fluoxetine (2C, 2D6, 3A4) ✓ ✓ ✓ ✓ Fluvoxamine (1A2, 2C, 3A4) ✓ ✓ ✓ ✓ Paroxetine (2D6) Duloxetine (2D6) Bupropion (2D6) Nefazadone (3A4) ✓ ✓ ✓ ✓ A 62-year-old patient with diabetes, depression, hyperlipidemia, and peptic ulcer disease presents with symptoms of anxiety including trembling, irritability, and palpitations. The patient’s medication regimen includes metformin, bupropion, rosuvastatin, and famotidine. Which medication is most likely to contribute to symptoms of anxiety? Antidepressants in GAD ❖ All SSRIs are effective in the treatment of GAD ❖ FDA Approved SSRIs include: ❖ Paroxetine ❖ Escitalopram ❖ SNRIs are effective for treatment of GAD ❖ Duloxetine (FDAApproved) ❖ Venlafaxine XR (FDAApproved) ❖ TCAs effective (imipramine best studied; not approved) ❖ Efficacy ❖ Response rate= approx 66% ❖ Remission rate= approx 30%  SSRI Pharmacokinetics Parameter Prozac® Zoloft® Paxil® Celexa® Lexapro® Luvox® Tmax (hrs) 6-8 4.5-8.5 5 2-4 5 2-8 t½ 4-6 days 26 hrs 21 hrs 33 hrs 30 hrs 17 hrs Active Nor-Flx Des-Ser None De-Cit None None Metabolite t½ of 4-16 days 62-104 hrs - 3 hrs - - metabolite Protein 95% 98% 95% 80% 56% 77% Binding Metabolism 2D6, 2C9 2D6, 2C9 2D6 2C19, 3A4 2C19, 3A4 1A2 F-Bioavail. 95% 36% - ≥ 80% 80% 53%  SNRIs for Treatment of GAD Duloxetine in GAD Ham-A Total Score HAM-A Anxious Mood HAM-A Tension 0 -2 -4 Total Reduction -6 -8 -10 -12 -14 Duloxetine 60-120 mg Venlafaxine XR 75-225 mg Placebo Source: Hartford J, et al. Duloxetine as an SNRI treatment for generalized anxiety disorder: results from a placebo and active-controlled trial. International Clinical Psychopharmacology 2007, 22:167-174. SSRI & SNRI Adverse Effects (Review) Common Adverse Effects of SSRIs Nausea Diarrhea Indigestion Insomnia/Sleep Disturbances Impotence/Erectile dysfunction Anorgasmia Fatigue Emotional blunting Increased Sweating Changes in appetite Headache Dizziness Other Adverse Effects of SSRIs Discontinuation Syndrome Bleeding Risks (Bruising, GI Bleeds) Hyponatremia (SIADH) Weight Gain Extrapyramidal Effects (Rare) Emergence of Suicidal Thinking  Pregabalin (Lyrica®) ❖ Chemistry O CH2NH2 00 * 0 · ❖ Water-soluble amino acid o · ❖ Designed to be a structural mimetic to gamma-aminobutyric CH2CO2H acid (GABA) GABApentin ❖ No direct action at GABA receptors OH PreGABAlin O GABA NH2 Brunton, Laurence. Goodman & Gilman’s: The Pharmacological Basis of Therapeutics. New York: McGraw-Hill, 2010. Safety and Tolerability ❖ Safety and Tolerability ❖ CNS Depressant Effects ❖ Somnolence ❖ Sedation ❖ Weight gain ❖ Peripheral edema ❖ Discontinuation Syndrome ❖ Schedule V-Controlled Substance ❖ What’s the risk? > - abuse potential ❖ Is there a concern in GAD? Clin Drug Investig 2009;29:203-13. Expert Opin. Drug Saf 2012;11(3):487-502 Rev Prescrire February 2012;32(340):116-118 Dosing ❖ Lack of standard dosing in the United States…however… ❖ United Kingdom Dosing Standards ❖ The dose range is150 to 600 mg per day given as two or three divided doses. ❖ Starting dose of 150 mg/day. ❖ May be increased by150 mg per week based on response ❖ Maximum dose: 600 mg/day ❖ Discontinue dose over a minimum of one week per dosing criteria Place in therapy for Pregabalin? ❖ Not considered a 1st line treatment ❖ SSRIs and SNRIs are still preferred ❖ Option for patients who have failed standard therapies or who cannot tolerate adverse effects of standard treatments ❖ Consideration for patients who have comorbid disorders or for those that SSRI/SNRI maybe difficult to use ❖ Partial seizures ❖ Diabetic neuropathy ❖ Bipolar disorder ❖ Intolerabilities Other Therapies in GAD ❖ Tricyclic Antidepressants ❖ Effective for treatment of GAD ❖ Adverse effects limit utilization; reserved for patients who have failed SSRIs ❖ Imipramine is the best studied in clinical trials ❖ Hydroxyzine ❖ Antihistamine with (+) response for GAD ❖ Occasionally used PRN ❖ Not effective for comborbid disorders ❖ Mirtazapine ❖ Positive open-label trials have shown efficacy in GAD ± MDD  Quetiapine XR in GAD ❖ 8 week DB-RCT of Quetiapine XR in GAD 70% 62.7% 60% 52.7% 53.7% 50% 46.2% Percentage 37.3% 40% 31.5% 28.4% Response Rate (%) 30% 27.4% Remission Rate (%) 20% 10% 0% Placebo Quetiapine XR Quetiapine XR Escitalopram (n=212) 150 mg/d 300 mg/d 10 mg/d (n=212) (n=201) (n=203) Int Clin Psychopharacol 2011;27:40-54. Therapeutic Expectations for GAD ❖ Similar expectations among all treatments ❖ Non-pharmacological mechanisms including CBT, coping skills, relaxation, and stress management should be apart of treatment plan ❖ Faster reductions seen with benzodiazepines…but should only be used for short-term treatment low close of benzo or stop ↑ ideal  Panic Disorder ❖ Recurrent unexpected panic attacks ❖ A discrete period of intense fear or discomfort, in which four or more of the following symptoms developed abruptly and reached a peak within 10 minutes Nausea or abdominal distress Palpitations,   rate Feeling dizzy/lightheaded Sweating Derealization/depersonalization Trembling/shaking Fear of losing control or going crazy Shortness of Breath Fear of dying Feeling of choking Paresthesias Chest pain or discomfort Chills or hot flashes SC is a 20-year-old man reporting excessive anxiety when meeting new people or when he is in large crowds since middle school. While giving a speech for his college public speaking class, he fears being humiliated and worries when he will have to do it again. After 1 month, he dropped the class and avoids any future classes that involve oral presentations. His physician would like to start venlafaxine XR. What starting dose would you recommend and why?  Panic Disorder Treatment Short-term BZD (2-4 Yes weeks) + Is treatment urgent SSRI/Venlafaxine for patient to function and no history of substance abuse No SSRI or Venlafaxine Adequate Response: Continue 12-14 months If treatment failure switch to another SSRI or Venlafaxine If treatment failure switch to another SSRI, SNRI, or Imipramine If treatment failure add BZD or atypical antipsychotic to antidepressant Post-Traumatic Stress Disorder (PTSD) ❖ A condition marked by the development of symptoms after exposure to traumatic life events ❖ Reacts with fear and helplessness ❖ Reliving the event ❖ Avoids reminiscing ❖ Common precipitating events include: ❖ War ❖ Torture ❖ Natural disasters/catastrophes ❖ Assault/Rape PTSD-Diagnosis ❖ Person exposed to a traumatic event that the person experienced, witnessed, or confronted with an event or events that involved actual or threatened death or serious injury, or a threat to the physical integrity of self or others ❖ The person’s response involved intense fear, helplessness, or horror ❖ The traumatic event is persistently re-experienced ❖ Persistent avoidance of stimuli associated with the trauma and numbing of general responsiveness (not present before the trauma) ❖ Persistent symptoms of increased arousal ❖ Symptoms last for at least a month Treatment Strategies for PTSD ❖ Psychotherapy ❖ Behavior therapy, hypnosis, individualized treatments ❖ Pharmacotherapy ❖ 1st line treatment is SSRI or SNRI ❖ Improvement in all 3 sx clusters and QOL measures, treatments safe ❖ Two approved antidepressants ❖ Sertraline (Zoloft®) > - older pt preffered ❖ Paroxetine (Paxil®) > - missed one close > withdrawal - ❖ Other effective 1st line agents ❖ Fluoxetine and Venlafaxine Nightmares associated with PTSD ❖ Common venue for re-experiencing traumatic event ❖ No approved treatment ❖ Blockade of α1-adrenonergic receptors may be efficacious ❖ Common treatments I blocker alpha ❖ Prazosin - 36mg - ❖ Reduction in nightmare severity consistently reported in open-label trials ❖ More effective for combat-related PTSD ❖ Can be used in addition to antidepressant ❖ Occasionally second generation antipsychotics are used adjunctively for treating hyperarousal and nightmares that have not been adequately addressed with 1st line treatments ❖ Not routinely used but in some cases patients are treated with quetiapine, olanzapine, or risperidone in addition to an SSRI ❖ Evidence is limited Other treatments and targets for PTSD Target Symptoms Medication Options Anger Adjunctive antimanic agents; anticonvulsants (?) Intrusive thoughts Atypical antipsychotics Hypervigilance Atypical antipsychotics; α2 agonists Therapeutic Expectations for PTSD ❖ Good response = 75% reduction in symptoms ❖ If patient is responsive to pharmacotherapy continue treatment for up to 12 months ❖ Can use various rating scales ❖ If not effective w/1st line treatment consider other antidepressant ❖ Targeting symptoms with different pharmacological options might be necessary (numbing, nightmares) ❖ Monitor for adverse effects and any sign of relapse ❖ Avoid benzodiazepines if possible ↳ makes It worse ! Obsessive Compulsive Disorder ❖ Obsessive Compulsive Disorder (OCD) is an anxiety disorder that is represented by a diverse group of symptoms that include both or either of the following: ❖ Obsessions ❖ Recurrent intrusive thought, feeling or idea ❖ Mental event ❖ Compulsions ❖ Conscious, standardized, recurrent behavior ❖ Patients acknowledges the irrationality of their obsessions and behavior Clinical Presentation ❖ Majority of patients experience both obsessions & compulsions ❖ Strong desire to resist among majority of patients although little resistance is applied Common Obsessions Common Compulsions ❖ Need for exactness ❖ Hoarding/Collecting ❖ Safety/prevention of harm ❖ Checking ❖ Contamination ❖ Cleaning ❖ Aggression ❖ Counting ❖ Sex ❖ Repeating ❖ Doubt ❖ Arranging/Organizing ❖ Religious ❖ Praying/Repenting  Pathophysiology of OCD ❖ High genetic concordance rate Increased Activation of CSTC Loop ❖ Cortico-striatal- Compulsions thalamic-cortical loop Worry (“worry loop”) involved & Anxiety with pathogenesis Obsessions Multiple Neurotransmitters Modulate this circuit Stahl SM. Stahl's essential psychopharmacology : neuroscientific basis and practical applications. 3rd ed, Fully rev. and expanded. ed. Cambridge ; New York: Cambridge University Press; 2008.  Pharmacotherapy of OCD Trazadone * * Worsen OCD First Line Treatment ↓ SSRI, FDA Maximal Dosage, 12 weeks active metabolite Change SSRI or clomipramine FDA Maximal Dosage, 12 weeks (2-3 agents including clomipramine) Utilize maximal dose studied Augment with 2nd Generation Optimize plasma levels (TCA) Antipsychotic (AAP) Combine Intravenous SSRI or Trial an SNRI Change AAP clomipramine + SSRI Clomipramine or MAOI agent Novel Treatments Deep Brain Stimulation, Neurosurgery, or γ knife surgery Derived from : Stein DJ, Hollander E, Rothbaum BO. Textbook of anxiety disorders. 2nd ed. Washington, DC: American Psychiatric Pub.; 2010. & Abudy A, Juven-Wetzler A, Zohar J. CNS Drugs 2011;25:585-96.  Clomipramine (Anafranil®) ❖ Clomipramine Collaborative Study DB-RCT Trials evaluating Clomipramine in OCD 28 26 Placebo (n=120) 24 Clomipramine (n=118)  Placebo (n=129) 22 ‡  Clomipramine (n=134) 20    p - Not for alcohol disorder Wrap-up for Anxiety Treatments ❖ Recognition of anxiety disorder determines which treatments are appropriate ❖ SSRIs are 1st line treatments in the majority of anxiety disorders ❖ Consider pharmacokinetic properties when selecting ❖ Lower dosages maybe indicated due to activating properties ❖ Benzodiazepines should be reserved for patients requiring immediate relief of anxiety in GAD and Panic Disorder ❖ Generally not beneficial in treatment of OCD, PTSD, or simple phobias ❖ Shortest duration of use is recommended CD is a 34-year-old man experiencing frequent flashbacks and nightmares of a very traumatic event that occurred a few years ago. He feels constantly “on edge” and easily startled. His primary care provider diagnosed CD with posttraumatic stress disorder (PTSD). CD’s primary care provider prescribed Lexapro 10 mg daily. CD is now admitted in the hospital for methicillin- resistant Staphylococcus aureus (MRSA) cellulitis on his right lower leg. Which antibiotic should be avoided? SC is a 20-year-old man reporting excessive anxiety when meeting new people or when he is in large crowds since middle school. While giving a speech for his college public speaking class, he fears being humiliated and worries when he will have to do it again. After 1 month, he dropped the class and avoids any future classes that involve oral presentations. Which of the following antidepressants is the most appropriate initial treatment for this young man with newly diagnosed social anxiety disorder? SB is a 55-year-old woman who reports excessive worrying, poor concentration, back and neck pain, and difficulty sleeping through the night. She constantly worries about losing her job as a data analyst despite the fact that she recently received a promotion. These symptoms have progressively worsened in the past 7 months and have negatively affected her relationships with friends. Previous medication trials include sertraline, fluoxetine, and venlafaxine extended release (ER). She has a history of atrial fibrillation, hypertension, alcohol use disorder, suicidal ideation, and medication nonadherence due to her busy work schedule. Her current medications include warfarin 2.5 mg PO daily, metoprolol succinate 25 mg PO daily, and lisinopril 10 mg PO daily. The psychiatrist is seeking a recommendation. Which medication has an FDA indication for generalized anxiety disorder and would be a reasonable option for SB? SC is a 20-year-old man reporting excessive anxiety when meeting new people or when he is in large crowds since middle school. While giving a speech for his college public speaking class, he fears being humiliated and worries when he will have to do it again. After 1 month, he dropped the class and avoids any future classes that involve oral presentations. While going over the different treatment options with the patient, the patient indicated concerns with venlafaxine and side effects. The most significant dose- related adverse effect of venlafaxine is: A mother comes to pick up a new prescription for fluoxetine for her 10-year- old son who has been diagnosed with major depression and obsessive-compulsive disorder. Her son has never received any antidepressant. Along with medication counseling, what is the pharmacist required to provide? CD is a 34-year-old man experiencing frequent flashbacks and nightmares of a very traumatic event that occurred a few years ago. He feels constantly “on edge” and easily startled. His primary care provider diagnosed CD with posttraumatic stress disorder (PTSD). Which medication should be avoided in CD? A patient brings in a new prescription for alprazolam today and asks if it will interact with any of his medications. He is currently taking lacosamide and carbamazepine for seizures, citalopram for depression, acetaminophen with codeine for low back pain, and warfarin for a recent deep vein thrombosis (DVT). Which of the following is most likely to have a clinically significant pharmacokinetic drug–drug interaction with the new prescription? Questions Eating Disorders Jacqueline Cleary, PharmD, BCACP Associate Professor of Pharmacy Practice OB210F About Me! Primary care integrated with behavioral health, addiction, psychiatry, and social services 8 primary care offices Pediatrics to adults Affiliated with Saratoga Hospital (and AMC) PGY2 Ambulatory Care Residency How to reach me? Canvas discussion board Email works best OB210F by appointment or via zoom Virtual and recorded review session week of 11/11 Schedule going forward… Today: eating disorders 11/11-11/13-> headache – Quiz due on 10/30 at 2pm disorders – Quiz due 11/18 at 2pm 10/28-11/1-> pain pharmacology 11/15 EXAM 3 – Quiz due on 11/4 at 2pm *through pain management 11/4-11/8-> pain management 11/18-> substance use – Quiz due on 11/11 at 2pm disorders (PGY2 Resident) – Quiz due 11/20 at 2pm Learning Objectives Identify sings and symptoms of anorexia nervosa (AN) and bulimia nervosa (BN) Recognize nonpharmacological treatment options for eating disorders Differentiate between pharmacologic options for eating disorder Lets lay some groundwork… What are eating disorders? Diagnosis Anorexia Nervosa- DSM V – Restriction of energy intake relative to requirements leading to significantly low body weight – Fear of weight gain or behaviors to avoid weight gain – Body image disturbance, denial of seriousness of illness, undue influence of body weight/shape on self-evaluation Two types of AN Binge eating/purging Restricting Avoidant/Restrictive Food Intake Disorder DSM V – Eating or feeding disturbance – One of the following: Significant weight loss Significant nutritional deficient Dependence on supplements or enteral feeding Marked interference with functioning – Not due to lack of food, culturally sanction practice, eating disorder, medical condition or other mental disorder Psychological Symptoms Body image disturbance Psychological Fear/anxiety symptoms Cognitive rigidity > - can't change mind Obsessionally Social anxiety AN Altered reward Physical condition- Behaviors Altered threat Malnutrition Habit Behaviors Restricting/Fasting Psychological Exercising symptoms Binge eating Vomiting Laxative abuse Taking diet pills or appetite AN suppressants Physical Behaviors Avoid “risk” foods or entire condition- Malnutrition food groups Calorie counting Physical Symptoms Psychological symptoms AN Physical condition- Behaviors Malnutrition Bulimia Nervosa DSM V – Recurrent binge eating – Recurrent compensatory behaviors to prevent weight gain – On average once a week for three months – Self evaluation unduly influence by body shape and weight – Does not occur exclusively during episodes of anorexia nervosa Psychological Symptoms Body image disturbance Psychological symptoms Fear/anxiety Preoccupations Stress induced bingeing More shame BN Better insight Physical condition- Malnutrition Behaviors Behaviors Restricting/Fasting Binge eating Psychological symptoms Exercising Vomiting Laxative abuse Taking diet pills or appetite suppressants BN Avoid “risk” foods or entire food Physical condition- Behaviors groups Malnutrition Calorie counting Physical Symptoms Weight cycles Psychological Complications of binge symptoms eating and purging-> electrolyte abnormalities Loss of dental enamel GERD BN Abrasions on knuckles Physical condition- Behaviors (Russell’s sign) Malnutrition Puffy cheeks Epidemiology Majority in ’s (90% of cases) 1% anorexia nervosa ( ) 1-4% bulimia nervosa ( ) Vocational risks, socioeconomics class, and sexual orientation can play a role No large differences between race and ethnicity for BN but for AN more common in Caucasians Udo and Grilo, 2018, Marques et al, 2011 Epidemiology Increased eating disorder pathology over time in US college students from 2013-2020 especially in individuals with higher BMI, those who identified as male, bisexual, gay, lesbian, or queer Higher rates of eating disorder in gay and bisexual men than heterosexual men Romano et al 2022, Feldman et al, 2007  Complications of Restricting AN Organ System Effected Consequences General Effects Muscle atrophy, loss of body fat, osteoporosis CNS Brain atrophy, decrease cortical mass, seizures, abnormal EEG Cardiovascular Bradycardia, hypotension with marked orthostasis, peripheral edema, decrease cardia diameter, narrowing of ventricular walls Renal Prerenal azotemia Metabolic Vitamin and mineral deficiencies Endocrine Decreased LH, FSH, estrogen/testosterone, thyroxin, T3 and increased prolactin  Complications of BN and Purging AN Organ System Effected Consequences Metabolic Hypokalemia alkalosis or acidosis, hypochloremia, dehydration, loss of vitamins and minerals Renal Prerenal azotemia, acute and chronic renal failure Cardiovascular Arrhythmias, cardiac toxicity Dental Surface enamel loss, dental caries Gastrointestinal Swollen parotid glands, increase serum amylase, gastric distention, IBS Musculoskeletal Cramps tetany  buproprion Etiology Roles of serotonin, norepinephrine, and dopamine are involved in controlling eating behaviors – Increase in 5-HT -> satiety and reduces food consumption – 5-HT receptor antagonists increases appetite QUIZ YOURSELF WHAT DURG DOES THIS? – Increase in DA leads to motor activity and weight loss QUIS YOURSELF WHAT DRUG DOES THIS? – Dysfunction of B3 adrenergic activity and leptin feedback – Reduced B endorphins in anorexia and bulimia – Genetic and physical/emotional abuse Assessment SCOFF (2 indicates clinically significant AN or BN) EDE-Q Medical workup: weight history, comorbidities, vitals (orthostatics), labs, EKG, DEXA Patient Case Example 22 year old female who is 5’6” with a weight of 104lbs (BMI 16.8), high weight of 115lbs (BMI 18.6) and low weight of 80 lbs. (BMI 12.9). What is this patients BMI goal? A. >10 B. >15 C. >18 D. >20- this could also be a goal too depending on the progression of your patient BMI (Body Mass Index) < 20: underweight BMI headache disorders  Quiz due 11/18 at 2pm Part I Pain Pathophysiology and Classification Objectives Understand how pain is processed through the CNS Define abnormal painful conditions (ie: hyperalgesia and allodynia) Describe the difference between acute and chronic pain Classify pain syndromes (ie: nociceptive, neuropathic, inflammatory) “An unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage” Drakulich A. Practical Pain Management. 2020. BEFORE WE DIVE IN REMEMBER… Pain motivates recuperation Pain drives escape and avoidance learning Pain is SUBJECTIVE Pain is adaptive Influence by expectation and emotions Inability to communicate does NOT rule out possibility of pain ASSESSMENT Pain intensity rating scales Scale of 1-10 Verbal descriptor scale Wong-Baker Facial Grimace Scale Activity Tolerance Scale NON VERBAL PAIN ASSESSMENT Vocal complaints Facial Grimaces/winces Bracing Restlessness Rubbing Other examples of pain assessments? What do you think? ↳ vital signs  PAIN PROCESSING 1.Transduction 2.Transmission 3.Perception 4.Modulation Available at https://nursekey.com/20-drugs-used-for-pain-management/. Accessed on July 28, 2021. Herndon C.M., & Ray J.B., & M. Kominek C (2020). Pain management. Pharmacotherapy: A Pathophysiologic Approach TRANSDUCTION Free ends of nociceptors are exposed to noxious stimuli -> release of excitatory compounds Exposures include: mechanical (pressure, swelling, incision), thermal (burn, scald), or chemical (toxic substance, infection, ischemia) Excitatory compounds include: serotonin, bradykinin, histamine, substance P, prostaglandins (sound familiar!?) Information comes from the periphery  TRANSMISSION Information travels from the periphery to the spinal cord and up to the brain Action potential generated from transduction transmitted through A and C fibers and terminates in the dorsal horn (CNS) Excitatory neurons are released from the terminal ending in the dorsal horn to propagate a signal from the spinal cord to the brain through the ascending pathways Excitatory neurons include: glutamate, neurokinins, substance P Impulse processed at the thalamus I excitatory GABA = Inhib Herndon C.M., & Ray J.B., & M. Kominek C (2020). Pain management. Pharmacotherapy: A Pathophysiologic Approach  * know this AFFERENT SENSORY FIBERS A- fibers C fibers Smaller Larger Unmyelinated Myelinated Slower Faster Produces “second pain” Produces the “first pain” feeling Dull, ache, burning, diffuse Sharp, sting, localized, Reaches the brain regions responsible for Activated by mechanical or thermal pain emotional responses Activated by various stimuli; mechanical, thermal, or chemical  ASCENDING PAIN PATHWAY THALAMUS IL: intralaminar nuclear group VP: ventral posterior nucleus http://www.sigmaaldrich.com/life-science/cell-biology/learning-center/pathway-slides- and/ascending-pain-pathway.html  PERCEPTION Conscious awareness of pain through activation of multiple higher brain structures, including the cortex Reticular system:  Responsible for the autonomic and motor response to pain (i.e. quickly removing a hand when it touches a hot stove) Somatosensory cortex:  Interprets pain information such as intensity, type, location, and relates pain sensations to past experiences Limbic system  Emotional and behavioral response to pain Herndon C.M., & Ray J.B., & M. Kominek C (2020). Pain management. Pharmacotherapy: A Pathophysiologic Approach Gatchel R, et.al. Pain and the Brain. Practical Pain Management. 8(5). Available at: https://www.practicalpainmanagement.com/resources/pain-brain. MODULATION The descending pain pathway utilizing inhibitory signals to block pain signals from being processed in the spinal cord Inhibitory neurotransmitters include: endogenous opioids, serotonin, norepinephrine, GABA (remember these!) * These result in analgesia  NEUROTRANSMITTER REVIEW Endogenous Serotonin Norepinephrine GABA opioids (5-HT) (NE) Bind to opioid Bind to 5HT Bind to alpha Binds to receptors and 5HT3 2 adrenergic GABAA and (brain and receptors receptors GABAB spinal chord) (medulla) (brainstem) receptors Herndon C.M., & Ray J.B., & M. Kominek C (2020). Pain management. Pharmacotherapy: A Pathophysiologic Approach MODULATION  Click for additional resources on nociception  http://www.jci.org/articles/view/4 2843  http://www.nature.com/nrrheum/j ournal/v5/n1/fig_tab/ncprheum09 72_F1.html#figure-title  MODULATION: REFERRED PAIN When irritation of dysfunction of one organ produces pain that is felt at in another area Convergence-projection theory: somatic and visceral pain fibers converge on the same neuron Examples of referred pain:  Cardiac pain to the inner aspect of the left arm  Pain in the tip of the shoulder caused by irritation of the central portion of the diaphragm  Pain in the testicle due to distension of the ureter Somatosensory neurotransmission: touch, pain, & temperature. Barrett K.E., & Barman S.M., & Brooks H.L., & Yuan J.J.(Eds.), (2019). Ganong's Review of Medical Physiology, 26e. McGraw Hill. https://accesspharmacy.mhmedical.com/content.aspx?bookid=2525&sectionid=204291198 Questions so far? What do you think? TYPES OF PAIN * Nociceptive - main type * Neuropathic Inflammatory NOCICEPTIVE PAIN Pain that arises from actual or threatened damage to non-neural tissue and is due to the activation of nociceptors Stimulated from (1) somatic or (2) visceral structures NOCICEPTIVE PAIN - limb -organs Somatic Visceral From bone, joint, muscle, skin or Visceral organs: i.e. GI tract and connective tissue pancreas Throbbing, achy May be related to a tumor, causing achy, localized pain Localized May be related to an obstruction, causing wide-spread cramping  NEUROPATHIC PAIN Pain caused by a lesion or disease of the somatosensory nervous system Patients may describe the pain as burning, electric, searing, tingling, and migrating or traveling  Phantom pain-> peripheral nerve injury  Burning pain -> central nerve injury Some causes of neuropathic pain include:  Amputation (phantom limb pain), herpes zoster, AIDS (peripheral neuropathy), diabetic neuropathy, fibromyalgia, and cancers that affect the spinal cord, among others http://www.iasp-pain.org/AM/Template.cfm?Section=Pain_Definitions&Template=/CM/HTMLDisplay.cfm&ContentID=1728#Neuropathicpain DEFINITIONS same er pain pain pains > pain Hyperalgesia - > -  Increased pain from a stimulus that normally provokes pain Allodynia  Pain due to a stimulus that does not normally provoke pain Peripheral Sensitization  An increase response to stimuli following a change in number and location of ion channels  Lowers the depolarization threshold  Co-Leaders of Case Development Pain Sensitization 10 Hyperalgesia. 8. Normal pain response Pain intensity 6 Injury 4 2. Allodynia 0 Stimulus intensity Figure: Am Fam Physician 2001;63:1979-84,1985-6 Can you experience hyperalgesia from opioid therapy? What do you think? INFLAMMATORY PAIN A localized protective reaction of tissue to irritation, injury, or infection, characterized by pain, redness, swelling, and sometimes loss of function Activates the nociceptive pathway Examples of inflammatory pain include:  Appendicitis, rheumatoid arthritis and inflammatory bowel disease FURTHER PAIN CLASSIFICATION Acute  Generally, does not last >3 months  Usually due to an identifiable cause such as surgery, illness, or injury and resolves when the underlying cause resolves Chronic > 90 days  Persists despite the fact that the injury has healed  Pain signals persist beyond three to six months and can last for years Cancer  Associated with malignancy  Can include both acute and chronic pain NEUROPLASTICITY Structural Remodeling Sensitization CNS Surgical Neuroplasticity Peripheral Peripheral injury and Nociceptive Nociceptive inflammation Fibers Sustained Fibers currents Hyperactivity Transient Sustained Activation Activation ACUTE CHRONIC SUBACUTE PAIN PAIN PAIN 130 days 31-89 days >90 1. Woolf CJ. Ann Intern Med. 2004;140:441-51. days 2. Petersen-Felix S and Curatolo M. Swiss Med Weekly. 2002;132:273-8. 3. Woolf CJ. Nature.1983;306:686-8. 4. Woolf CJ et al. Nature. 1992;355:75-8.  REVIEW OF PAIN TYPES Noxious A. Nociceptive Pain peripheral Brain stimuli B. Inflammatory Pain Inflammation Brain C. Neuropathic Pain Peripheral nerve damage M