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DIFFICULT CASES: CRACKING THE CODE: MAKING THE “CASE”: CHALLENGING SCENARIOS IN MENTAL HEALTH SATURDAY/2:00-3:00PM ACPE UAN: 0107-9999-16-021-L01-P Activity Type: Application-Based 0.1 CEU/1 hr Learning Objectives for Pharmacists: Upon completion of this CPE activity participants should be able to: 1. Recognize symptoms typically seen in a patient presenting with serotonin syndrome 2. Identify psychotropic medications that potentially prolong the QT interval 3. Recommend drug therapy options for a patient with treatment resistant depression 4. Assess a patient for metabolic side effects of antipsychotics Speaker: Megan Leloux, PharmD, BCPP Megan Leloux is a clinical psychiatric pharmacist at the Mayo Clinic Hospital, St. Marys Campus in Rochester, MN. A proud Iowa native, Dr. Leloux graduated from the University of Iowa College of Pharmacy in 2008. She then went on to complete a PGY1 pharmacy practice residency at Avera McKennan Hospital and a PGY2 psychiatric pharmacy residency at the Avera Behavioral Health Center in Sioux Falls, SD. She became a board certified psychiatric pharmacist in 2012. In addition to psychiatry, Dr. Leloux also works with the neurology and family medicine teams at the hospital and will begin working in ambulatory care setting in 2016. Speaker Disclosure: Megan Leloux reports no actual or potential conflicts of interest in relation to this CPE activity. Off-label use of medications will be discussed during this presentation. FEBRUARY 13, 2016 | IOWA EVENTS CENTER | DES MOINES, IOWA Making the Case: Challenging Scenarios in Mental Health Megan Leloux, PharmD, BCPP Disclosure • Megan Leloux reports no actual or potential conflicts of interest associated with this presentation 1 Learning Objectives • Upon successful completion of this activity, pharmacists should be able to: 1. Recognize symptoms typically seen in a patient presenting with serotonin syndrome. 2. Identify psychotropic medications that potentially prolong the QT interval. 3. Recommend drug therapy options for a patient with treatment resistant depression. 4. Assess a patient for metabolic side effects of antipsychotics. Click to edit • Click to edit Master text styles • Second level • Third level • Fourth level • Fifth level 2 Click to edit • Click to edit Master text styles • Second level • Third level • Fourth level • Fifth level Patient Case • 66 YOF presenting to ED with acute mental status change, tachycardia, nausea, and febrile. • PMH: hypertension, asthma, depression, fibromyalgia, GERD, recurrent UTIs • Medications: • amlodipine 5 mg daily • hydrochlorothiazide 25 mg daily • fluticasone/salmeterol 100 mcg/50 mcg 1 inhalation BID • albuterol inhaler 2 puffs q4h prn shortness of breath • citalopram 40 mg daily • gabapentin 600 mg TID • tramadol 50 mg q6h prn pain • omeprazole 40 mg daily • nitrofurantoin 50 mg every night • Multiple labs pending to rule out infection, etc. • Could this be related to medications? 3 Serotonin Syndrome • Serotonin CNS actions: mood, sleep, pain, vomiting, thermoregulation, sexual behavior • Adverse drug reaction: Overstimulation of serotonin receptors • 5-HT2A and 5-HT1A receptors • Mild to severe/life-threatening symptoms • Dose related • Mortality: 2-12% • First described in 1950/1960s with monoamine oxidase inhibitors • Made famous by Libby Zion case in 1984 Cooper B, et al. AACN Adv Crit Care. 2013;24:15-20. Iqbal M, et al. Ann Clin Psychiatry. 2012;24:310-8. Buckley N, et al. BMJ. 2014;348:g1626. Nordstrom K, et al. J Emerg Med. 2016;50:89-91. Frank C. Can Fam Physician. 2008; 54:988–992. Signs and Symptoms of Serotonin Syndrome • Clinical diagnosis • Acute onset: Initiation, increased dose/overdose, combinations of serotonergic medications, drug interactions • Mild Moderate Severe Autonomic Excitation Neuromuscular Excitation Altered Mental Status Serotonin Syndrome Cooper B, et al. AACN Adv Crit Care. 2013;24:15-20. Buckley N, et al. BMJ. 2014;348:g1626. Nordstrom K, et al. J Emerg Med. 2016;50:89-91. 4 Diagnostic Tools Sternbach Criteria • Oldest • Misdiagnose anticholinergic toxicity as SS Radomski Criteria • Divides patients into mild and severe categories Hunter Serotonin Toxicity Criteria • Newest • Most accurate: 84% sensitivity, 97% specificity Cooper B, et al. AACN Adv Crit Care. 2013;24:15-20. Buckley N, et al. BMJ. 2014;348:g1626. Different from Neuroleptic Malignant Syndrome • Neuroleptic Malignant Syndrome • Result of dopamine inhibition • Slow onset • Days, up to 2 weeks after starting or increasing dose of dopamine antagonist • Extrapyramidal features and rigidity • NOT clonus Buckley N, et al. BMJ. 2014;348:g1626. 5 Implicated Medications • Overstimulation of 5-HT2A receptors • Less problematic? • Serotonin receptor antagonists • Selectivity for other serotonin receptor subtypes • Antipsychotics, buspirone, antimigraine drugs, antiemetics Cooper B, et al. AACN Adv Crit Care. 2013;24:15-20. Buckley N, et al. BMJ. 2014;348:g1626. Drugs and Serotonin Syndrome Serotonin Reuptake Inhibition •SSRIs, SNRIs, TCAs, trazodone •Amphetamines, cocaine •Tramadol, meperidine, methadone, fentanyl •Dextromethorphan •St. John’s wort •Sibutramine Receptor Agonists •Triptans •Buspirone •Lithium (indirectly) Serotonin Syndrome Serotonin Releasing Agents •Amphetamines, cocaine, MDMA •Levodopa (indirectly) Serotonin Metabolism Inhibition •MAOIs •Linezolid Cooper B, et al. AACN Adv Crit Care. 2013;24:15-20. Buckley N, et al. BMJ. 2014;348:g1626. Nordstrom K, et al. J Emerg Med. 2016;50:89-91. 6 Management of Serotonin Syndrome • Stop serotonergic medications • Supportive care • Fluid resuscitation • Cooling measures • Agitation: benzodiazepines • Also help with hyperthermia caused by muscle rigidity • Antidote • Cyproheptadine: antihistamine with 5-HT2A antagonistic activity • Case studies suggest effectiveness but no evidence from RCT • Cautiously consider chlorpromazine or olanzapine • Severe: paralysis and ventilation Cooper B, et al. AACN Adv Crit Care. 2013;24:15-20. Buckley N, et al. BMJ. 2014;348:g1626. Nordstrom K, et al. J Emerg Med. 2016;50:89-91. Prevention • Patient education • Reduce exposure when able • Is it ok to combine? • MAOIs: AWAYS avoid combinations; washout period • SSRIs + Triptans, TCAs, CBZ: sparse evidence to support avoiding combination • SSRIs + tramadol: caution with higher doses, elderly, CYP2D6 inhibitors • Modulation of serotonin Cooper B, et al. AACN Adv Crit Care. 2013;24:15-20. Buckley N, et al. BMJ. 2014;348:g1626. Park S, et al. J Pharm Pract. 2014;27:71-8. 7 Patient Case • 66 YOF presenting to ED with acute mental status change, tachycardia, nausea, and febrile. • PMH: hypertension, asthma, depression, fibromyalgia, GERD, recurrent UTIs • Medications: • amlodipine 5 mg daily • hydrochlorothiazide 25 mg daily • fluticasone/salmeterol 100 mcg/50 mcg 1 inhalation BID • albuterol inhaler 2 puffs q4h prn shortness of breath • citalopram 40 mg daily • gabapentin 600 mg TID • tramadol 50 mg q6h prn pain • omeprazole 40 mg daily • nitrofurantoin 50 mg every night • Per patient’s spouse, tramadol was recently prescribed • Could this be related to medications? • Yes! Patient Case • Patient’s mental status worsens and becomes too obtunded to protect her airway. • Intubated/sedated in medical ICU. • More labs, testing ordered including an ECG. • ECG reveals a QTc of 505 ms. • Could this be related to medications? 8 QT Interval Vieweg W, et al. Drugs Aging. 2009;26:997-1012. QT Interval • Measurement from the beginning of the QRS complex to the end of the T wave • Onset of ventricular depolarization repolarization • Depolarization: rapid influx of sodium • Repolarization: efflux of potassium (IKr and IKs) • Inverse relationship with heart rate • “Corrected” QT (QTc) reported • Bazett’s formula: flawed Beach S, et al. Psychosomatics. 2013;54:1-13. Rautaharju P, et al. Circulation. 2009 ;119:e241-50. 9 Prolonged QTc • Congenital vs. acquired • KCNH2 • Definition: QTc ≥450 ms in males and ≥460 ms in females • AHA/ACC/HRS • QTc above the 99th percentile should be considered abnormal • >470 ms for males, >480 ms for females • Why do we care? Drew B, et al. Circulation. 2010;121:1047. Torsades de Pointes (TdP) • Polymorphic ventricular tachycardia (VT) that occurs in the setting of acquired or congenital QT interval prolongation • “Twisting of the points” • Asymptomatic, spontaneous resolution syncope sudden death • Prolonged QT = predictor for TdP • QTc ≥ 500 ms • Interval change of ≥ 60 ms • Relative risk increases significantly Beach S, et al. Psychosomatics. 2013;54:1-13. 10 Risk Factors for Prolonged QT Advanced Age Female > Male Circadian Variation Cardiovascular Disease Congenital LQTS Electrolyte Abnormalities • “Silent” mutations • Hypokalemia • Hypomagnesemia • Hypocalcemia Medications Beach S, et al. Psychosomatics. 2013;54:1-13. Vieweg W, et al. Drugs Aging. 2009;26:997-1012. Medications and Prolonged QT • Block the IKr current mediated by KCNH2 • Classes include antiarrhythmics, antimicrobials, psychotropics, others • Thorough QT studies • Mean increases in QTc < 5 ms 5-20 ms >20 ms • Not all QT prolonging drugs have same risk of TdP • Amiodarone • Drug interactions and multiple prolonging agents Beach S, et al. Psychosomatics. 2013;54:1-13. http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm073153.pdf. Accessed December 10, 2015. Darpo B. Br J Pharmacol. 2010;159:49–57. Funk K, et al. Annals of Pharmacotherapy. 2013;41:1330-1341. 11 Medications and Prolonged QT • https://crediblemeds.org • QTDrugs Lists Known Risk of TdP Possible Risk of TdP Conditional Risk of TdP Drugs to Avoid in Congenital Long QT https://crediblemeds.org. Accessed December 12, 2015. Focus on Antidepressants Tricyclic Antidepressants • Block sodium channels • Also block IKr and calcium channels • Problematic in patients with underlying cardiac disease • Review of TCAs and QTc prolongation • Amitriptyline most commonly reported Beach S, et al. Psychosomatics. 2013;54:1-13. Vieweg W, et al. Psychosomatics. 2004;45:371-7. Vieweg W, et al. Drugs Aging. 2009;26:997-1012. 12 Focus on Antidepressants Selective Serotonin Reuptake Inhibitors • Safer than TCAs • Block IKr • Case reports of QTc prolongation/TdP with SSRIs • 2011 FDA study on citalopram • 8 week, randomized, multi-center, double-blind, placebo-controlled, crossover study of 119 participants Citalopram Dose Increase in QTc (ms) 90% CI (ms) 20 mg/day 8.5 (6.2, 10.8) 40 mg/day* 12.6* (10.9, 14.3)* 60 mg/day 18.5 (16.0, 21.0) Moxifloxacin 400 mg 13.4 (10.9, 15.9) *estimate based on serum concentrations Beach S, et al. Psychosomatics. 2013;54:1-13. US Food and Drug Administration. FDA Drug Safety Communication: Abnormal heart rhythms associated with high doses of Celexa (citalopram hydrobromide). Available at http://www.fda.gov/Drugs/DrugSafety/ucm269086.htm. Accessed December 11, 2015. Focus on Antidepressants • Updated citalopram dosing recommendations: • Doses above 40 mg not recommended • Doses above 20 mg not recommended in patients • >60 years of age • Hepatic impairment • Poor CYP2C19 metabolizers or concomitant potent CYP2C19 inhibitors • Not recommended in congenital LQTS • Discontinue if QTc >500 ms • Controversial: • Conflicting data • Mean QTc increase may not be clinically significant FDA Drug Safety Communication: Revised recommendations for Celexa (citalopram hydrobromide) related to a potential risk of abnormal heart rhythms with high doses. Available at: http://www.fda.gov/Drugs/DrugSafety/ucm297391.htm. Accessed December 11, 2015. Funk K, et al. Annals of Pharmacotherapy. 2013;41:1330-1341. 13 Focus on Antidepressants Other SSRIs • Escitalopram does not have same FDA warning • Fluoxetine: studies do not show statistically significant increases in QTc; case reports showing rare risk • Sertraline: usually in combination with other QTc prolonging meds • Paroxetine: least amount of data suggesting risk FDA Drug Safety Communication: Revised recommendations for Celexa (citalopram hydrobromide) related to a potential risk of abnormal heart rhythms with high doses. Available at: http://www.fda.gov/Drugs/DrugSafety/ucm297391.htm. Accessed December 11, 2015. Funk K, et al. Annals of Pharmacotherapy. 2013;41:1330-1341. Focus on Antidepressants QTc Prolongation and Overdose Low Risk? • Venlafaxine╪ • Duloxetine • Bupropion* • New Drugs • Desvenlafaxine, Levomilnacipran, Vilazodone, Vortioxetine • Mirtazapine • Trazodone Case reports of QTc prolongation at therapeutic doses *Not listed in CredibleMeds ╪ Beach S, et al. Psychosomatics. 2013;54:1-13. https://crediblemeds.org. Accessed December 12, 2015. Hasnain M et al. CNS Drugs. 2014;28:887-920. Product Information. FETZIMA (levomilnacipran). Forest Laboratories, Inc. 2014. Product Information. VIIBRYD (vilazodone). Forest Laboratories, Inc. 2015. Product Information. BRINTELLIX (vortioxetine). Takeda Pharmaceuticals America, Inc. 2014. 14 Focus on Antipsychotics • Mechanism: block IKr • Typical/First Generation • Low potency > High potency • Dose dependent • Thioridazine • Highest risk among antipsychotics • Product labeling: baseline ECG, potassium • Contraindicated in patients with QTc > 450 ms, h/o arrhythmias; hypokalemia • Inhibitors of CYP2D6, poor metabolizers • Mesoridazine: removed from market Beach S, et al. Psychosomatics. 2013;54:1-13. US Food and Drug Administration: Mellaril (thioridazine HCL) Dear Healthcare Professional Letter Jul 2000. Available at http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm174994.htm. Accessed December 13, 2015. Focus on Antipsychotics • Haloperidol • Previous studies had shown relatively mild QTc prolonging effects of PO and IM haloperidol • 2007 FDA Alert • Post-marketing analysis found 229 cases of prolonged QTc interval with 73 reports of TdP in which 11 cases were fatal • IV vs. PO • Eight of 11 fatal cases involved IV haloperidol • Cardiac monitoring recommended Beach S, et al. Psychosomatics. 2013;54:1-13. US Food and Drug Administration: Information for Healthcare Professionals: Haloperidol (marketed as Haldol, Haldol Decanoate and Haldol Lactate) Available at: http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessio nals/ucm085203.htm. Accessed December 13, 2015. 15 Focus on Antipsychotics Harrigan et al 2004 Antipsychotic Pfizer 054 Study Mean QTc increase (ms) Antipsychotic Mean QTc Increase (ms) Haloperidol 7.1 Haloperidol 4.7 Ziprasidone 15.9 Ziprasidone 20.6 •Quetiapine 5.7 Quetiapine 14.5 •Olanzapine Pfizer 054 1.7 Olanzapine 6.4 Risperidone 3.9/3.6 Risperidone 10.0 Thioridazine 30.1 Thioridazine 35.8 Beach S, et al. Psychosomatics. 2013;54:1-13. Harrigan E, et al. J Clin Psychopharmacol. 2004;24:62-9. FDA. Briefing Document of Zeldox Capsules (Ziprasidone). New York: Pfizer Inc, July 18 2000; 116. Focus on Antipsychotics Association with QTc Prolongation *Possible TdP Risk Risk ╪Conditional Association with TdP Ziprasidone╪ +++ + Iloperidone* ++ - Paliperidone* ++ - Risperidone* + + Asenapine* + - Lurasidone + - Quetiapine╪ + + Caution with CYP2D6, CYP3A4 inhibitors Recently added to list Caution in patients with CV risk Olanzapine* + + Clozapine* + + Increased risk of sudden cardiac death Aripiprazole* + + Non-fatal TdP after low dose Brexpiprazole - - Cariprazine - Beach S, et al. Psychosomatics. 2013;54:1-13. Nelson S, et al. Ann Pharmacother. 2013;47:e11. Epub 2013 Jan 29. Product Information. FANAPT (iloperidone) . Novartis Pharmaceuticals. 2014. Product Information. INVEGA (paliperidone). Janssen Pharmaceuticals. 2007. Product Information. SAPHRIS (asenapine). Actavis Inc. 2015. Product Information. LATUDA (lurasidone). Sunovion Pharmaceuticals. 2013 Product Information. REXULTI (brexpiprazole). Otsuka Pharmaceutical Co. 2015. Product information. VRAYLAR (cariprazine). Actavis Inc. 2015. 16 Focus on Antipsychotics • Ray et al 2009 • Both typical and atypical antipsychotics were associated with a 2fold increase risk in sudden cardiac death vs. nonusers • Dose-related increase risk • Wu et al 2015 • Antipsychotic use associated with 1.5-fold increase in ventricular arrhythmia and/or sudden cardiac death • Significantly higher among those with short-term use (< 7 days) Ray W, et al. N Engl J Med. 2009;360:225-35. Wu C, et al. J Am Heart Assoc. 2015;4(2):e001568. Prevention of Prolonged QT Identify high risk patients • Obtain accurate medical/family history • Evaluate baseline ECG, electrolytes Substitute alternative medications in high risk patients Medications • • • • Monitor for drug interactions Adjust doses for renal/hepatic impairment Minimize combinations of QT prolonging medications STOP Correct electrolyte imbalances Monitor • ECG at drug peak or at steady state • Electrolytes Patient education Nielsen J, et al. CNS Drugs. 2011;25:473-90. Calderone V, et al. J Pharm Pharmacol. 2005;57:151-61. Zemrak W, et al. Am J Health Syst Pharm. 2008;65:1029-38. 17 Patient Case • Patient’s mental status worsens and becomes too obtunded to protect her airway. • Intubated/sedated in medical ICU. • More labs, testing ordered including an ECG. • ECG reveals a QTc of 505 ms. • Citalopram • omeprazole • Given levofloxacin, ondansetron • K = 2.5 (diuretic use, nausea) • Could this be related to medications? • Yes! Patient Case • Patient stabilized in ICU; extubated, QT has normalized. • Admits to overdosing on citalopram and tramadol “to end it all.” • Agrees to transfer to inpatient psychiatric unit for ongoing care. • Per patient, failed two other antidepressants and citalopram has been discontinued while in the ICU. • What treatment options are available for this patient? 18 Treatment Resistant Depression • Definition • Inadequate benefit to one or two different medication trials • STAR*D • Only about 35% will achieve remission on initial treatment • 30% with Step 2; <15% for Steps 3 and 4 • Treatment refractory depression • “Pseudo-resistant” • Verify adherence • Adequate dose and duration • Diagnosis; comorbidities Rush A, et al. CNS Drugs. 2009;23:627-647. STAR*D Step 1 Step 2 Switch Bupropion SR Sertraline Venlafaxine XR Step 3 Switch Mirtazapine Nortriptyline Step 4 Switch Tranylcypromine Citalopram Augment Citalopram + Bupropion SR Citalopram + Buspirone Augment Step 2 med + T3 Step 2 med + Lithium Switch Venlafaxine XR + Mirtazapine Rush A, et al. CNS Drugs. 2009;23:627-647. 19 Practice Guidelines • American Psychiatric Association (2010) • Texas Medication Algorithm Project (2000) • British Association for Psychopharmacology Guidelines (2015) • Canadian Network of Mood and Anxiety Treatments (2009) • Clinical Practice Recommendations for Depression (2009) • Institute for Clinical Systems Improvement (2013) Connolly K, et al. Drugs. 2011;71:43-64. Treatment Options • Same medication class • Different mechanism of action Switch • • • • Augmentation • Combination Lithium T3 Buspirone Stimulants Atypical antipsychotics • Two treatment arms in STAR*D • Citalopram + bupropion • Venlafaxine ER + mirtazapine Rush A, et al. CNS Drugs. 2009;23:627-647. Connolly K, et al. Drugs. 2011;71:43-64. 20 Treatment Options: Focus on Atypical Antipsychotics • Mechanism of action: 5-HT2A antagonism • Increase in dopamine in mesocortical pathway • Improve depressive and negative symptoms (schizophrenia) • 5-HT1A partial agonist; serotonin/norepinephrine reuptake inhibition • Pros: • Most studied augmentation treatment option • Several well-designed trials showing efficacy • Cons: • Industry supported trials • Relatively short duration • No head-to-head comparisons Connolly K, et al. Drugs. 2011;71:43-64. Wright B, et al. Pharmacotherapy. 2013;33:344-59. Treatment Options: Focus on Atypical Antipsychotics FDA- Approved for Adjunctive Therapy for Major Depressive Disorder Olanzapine (in combination with fluoxetine) Quetiapine XR • Efficacy only established with fluoxetine monotherapy nonresponders • Significant increases in weight, lipids, glucose • Only the 300 mg treatment arm achieved statistical significance vs. placebo; not 150 mg treatment arm • Increases in weight, lipids, glucose Aripiprazole • First single agent FDA approved for augmentation • Consistently demonstrated benefit vs. placebo • Akathisia most common adverse effect Brexpiprazole • Newest medication approved • Difference over placebo comparable to aripiprazole and quetiapine. • Weight gain and akathisia most common adverse effects Connolly K, et al. Drugs. 2011;71:43-64. Wright B, et al. Pharmacotherapy. 2013;33:344-59. Thase M, et al. J Clin Psychiatry. 2015;76:1224-31. Thase M, et al. J Clin Psychiatry. 2015;76:1232-40. 21 Treatment Options: Focus on Atypical Antipsychotics • Nelson et al meta-analysis • 16 trials, 3480 patients • Trials included olanzapine, risperidone, quetiapine, aripiprazole • Adjunctive AA more effective than placebo • For response: • OR= 1.69 (95% CI= 1.46-1.95), p<0.00001 • NNT = 9 • For remission: • OR= 2.00 (95% CI= 1.69–2.37), p<0.00001 • NNT = 9 • No significant differences between agents • Discontinuation rates due to adverse effects • OR= 3.91 (95% CI= 2.68–5.72), p<0.00001 • NNH = 17 Nelson J, et al. Am J Psychiatry. 2009;166:980-91. Treatment Options • Non-pharmacologic • Cognitive therapy • Transcranial Magnetic Stimulation • Electroconvulsive Therapy • Investigational • Ketamine • Glutamatergic system: NMDA receptor antagonist • Rapid reduction in depressive symptoms • Transient • Adverse effects • Psychotomimetic and dissociative effects • CIII: Abuse potential Epstein I, et al. Psychiatry Res. 2014;220:S15-33. Newport D, et al. Am J Psychiatry. 2015;172:950-66. 22 Choosing Therapy Evidence-based Medicine • Strongest evidence: • Switch antidepressants • Augmentation with atypical antipsychotic (aripiprazole/quetiapine) • Lithium, T3, stimulant augmentation and antidepressant combinations need more study • Buspirone probably not effective Individualized medicine • • • • • • • Side effect profile Potential drug interactions Comorbid conditions Patient perceptions/beliefs Dosing regimen Monitoring requirements Cost Connolly K, et al. Drugs. 2011;71:43-64. Patient Case • Patient stabilized in ICU; extubated, QT has normalized. • Admits to overdosing on citalopram and tramadol “to end it all.” • Agrees to transfer to inpatient psychiatric unit for ongoing care. • Per patient, failed two other antidepressants and citalopram has been discontinued while in the ICU. • What treatment options are available for this patient? • Elected to start duloxetine and aripiprazole. 23 Patient Case • Six weeks after dismissal, patient meets with ambulatory care pharmacist for an initial comprehensive medication review. • Current medications: • duloxetine 30 mg daily • aripiprazole 5 mg daily • amlodipine 5 mg daily • hydrochlorothiazide 25 mg daily • fluticasone/salmeterol 100 mcg/50 mcg 1 inhalation BID • albuterol inhaler 2 puffs q4h prn shortness of breath • gabapentin 600 mg TID • omeprazole 40 mg daily • nitrofurantoin 50 mg every night • What monitoring would you recommend? Antipsychotics and Metabolic Side Effects • Atypical vs. Typical Antipsychotics • Low potency • Mechanism of action: • Energy storage vs. expenditure • Appetite stimulation • Blocking H1 and 5-HT2C • Alter glucose metabolism • Insulin resistance • Decreasing insulin secretion • Blocking M3 in pancreatic beta cells Baptista T, et al. CNS Drugs. 2008;22:477-95. Pramyothin P, et al. Curr Opin Endocrinol Diabetes Obes. 2010;17:460-6. 24 Antipsychotics and Metabolic Side Effects • Patients with severe mental illness vs. general population • Higher mortality rate • Shortened life expectancy • Cardiovascular disease among leading cause of death • Unhealthy lifestyle • Canadian Community Health Survey • Participants with self-reported mental health disorder where twice as likely to have experienced CVD or stroke compared to no mental health history • Psychotropic use was 2 and 3 times more likely to have CVD and stroke, respectively, compared to non-use Baptista T, et al. CNS Drugs. 2008;22:477-95. Pramyothin P, et al. Curr Opin Endocrinol Diabetes Obes. 2010;17:460-6. Goldie C, et al. Can J Cardiol. 2014;30: S120. Abstract #129. Presented at: Canadian Cardiovascular Congress; Vancouver, British Columbia. Comparing Atypical Antipsychotics Increasing Weight, Lipids, Glucose Risperidone Paliperidone Clozapine Olanzapine Quetiapine Asenapine Iloperidone Aripiprazole Brexpiprazole Cariprazine Ziprasidone Lurasidone Rummel-Kluge C, et al. Schizophr Res 2010;123:225-233. Product Information. FANAPT (iloperidone) . Novartis Pharmaceuticals. 2014. Product Information. LATUDA (lurasidone). Sunovion Pharmaceuticals. 2013. Product Information. INVEGA (paliperidone). Janssen Pharmaceuticals. 2007. Product Information. REXULTI (brexpiprazole). Otsuka Pharmaceutical Co. 2015. Product Information. SAPHRIS (asenapine). Actavis Inc. 2015. Product information. VRAYLAR (cariprazine). Actavis Inc. 2015. 25 American Diabetes Association and American Psychiatric Association Monitoring Guidelines Baseline 4 weeks 8 weeks 12 weeks Quarterly Annually Personal/ family history X Weight (BMI) X Waist circumference X Blood pressure X X X Fasting glucose X X X Fasting lipids X X Every 5 years X X X X X X X • Updates and alternatives to consider • Hemoglobin A1C • Annual screening for lipids • Point-of-care testing not validated for diagnosis • Non-fasting? Diabetes Care. 2004;27:596-601. Vanderlip E, et al. Psychiatr Serv. 2014;65:573-6. Management • Behavioral management • Exercise program • Dietary planning • Consider switching to another antipsychotic • Discontinuation trial • Same management principles apply • Follow guidelines for hypertension, diabetes, hyperlipidemia • Primary provider vs. psychiatrist • Opportunity for pharmacists? Stroup T, et al. Am J Psychiatry. 2011;168:947-56. Baptista T, et al. CNS Drugs. 2008;22:477-95. 26 Pharmacologic Interventions • Medications for antipsychotic-related weight gain • Topiramate, zonisamide, metformin, amantadine, appetite suppressants • AHRQ 2013 systematic review: • Improved weight control: • Behavioral interventions, metformin, topiramate, zonisamide, and adjunctive or switching to aripiprazole • Switching may be associated with higher rates of treatment failure • Nizatidine did not improve any outcome • Insufficient evidence for all other interventions; effects on glucose and lipid control • Clinical trial for lorcaserin (5-HT2C agonist) Baptista T, et al. CNS Drugs. 2008;22:477-95. Gierisch J, et al. Rockville (MD): Agency for Healthcare Research and Quality (US); 2013. Patient Case • Six weeks after dismissal, meets with ambulatory care pharmacist for an initial medication review. • Current medications: • duloxetine 30 mg daily • aripiprazole 5 mg daily • amlodipine 5 mg daily • hydrochlorothiazide 25 mg daily • fluticasone/salmeterol 100 mcg/50 mcg 1 inhalation BID • albuterol inhaler 2 puffs q4h prn shortness of breath • gabapentin 600 mg TID • omeprazole 40 mg daily • nitrofurantoin 50 mg every night • What monitoring would you recommend? • Glucose, lipids, weight, blood pressure, waist circumference 27 Take-home Points 1. Recognize symptoms typically seen in a patient presenting with serotonin syndrome. • Be aware of timeframe; hold medications 2. Identify psychotropic medications that potentially prolong the QT interval. • https://crediblemeds.org 3. Recommend drug therapy options for a patient with treatment resistant depression. • Individualized medicine 4. Assess a patient for metabolic side effects of antipsychotics. • Role for pharmacist QUESTIONS? Thank you! Go Hawks! 28