Download Making the "Case": Challenging Scenarios in Mental Health

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.
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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.
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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
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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!
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