antidepressants medication related problems

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2021 Annual Meeting & ExhibitionNovember 4-7, 2021 | San Diego, California

Antidepressants: Medication Related Problems

Presented by:

Demetra Antimisiaris, PharmD, BCGP, FASCP

Christopher P. Alderman, BPharm, PhD, FSHP, BCGP, BCPP

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Meet the Speakers

Demetra AntimisiarisAssociate Professor, University of LouisvilleSchools of Medicine and Public Health

Director, Frazier Polypharmacy ProgramConsultant Pharmacist

Chris AldermanAssociate Professor, University of South Australia - Clinical & Health Sciences

Editor in Chief - The Senior Care Pharmacist

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Disclosure

The speakers have no conflicts of interest relevant to the content of this presentation.

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Pharmacist Learning Objectives

• Investigate complex antidepressant metabolic drug interactions.• Explain the mechanism of sedative effects for two classes of

antidepressants.• Describe a toxidrome related to antidepressant use.• Relate antidepressant effects or toxicity to antidepressant

pharmacologic activity.

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Pharmacy Technician Learning Objectives

• List medical conditions that can co-occur with depression• Identify medications associated with serotonin toxicity• Explain how antidepressants may cause toxicity in older adults

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is Important

Cooper JW FM, Cook A, Burfield A. Psychotropic and psychoactive drugs and hospitalization rates in nursing facility residents. Pharmacy Practice. 2007;5(3):140-144.

Pharmacology

Efficacy

5HT: 5-hydroxytryptamine (Serotonin)

DA: Dopamine

NE: Norepinephrine

Acetylcholine, Histamine, alpha-1

Central Nervous System (distribution)

T1/2- half life

Elimination-Renal-CYP pathways

PharmacodynamicsPharmacokinetics

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is ImportantToxicologyPharmacodynamicsPharmacokinetics

Avoidable Harm

CYP interactions

Renal dose toxicity

Vd

AgitationTremorsMyoclonusMovementsNauseaDiarrheaBleedingSexual dysfunctionPsychiatric activationDrowsinessUrinary hesitancy

Weight gainMetabolic syndromeDrowsinessConstipationDry mouthBlurred visionSedationConfusionHypotensionDizzinessHypertensionMore…

Cooper JW FM, Cook A, Burfield A. Psychotropic and psychoactive drugs and hospitalization rates in nursing facility residents. Pharmacy Practice. 2007;5(3):140-144.

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Psychoactive Medication Burden

Higher psychoactive medication load: associated with increased risk of all-cause hospitalization in long term care residents.

Increases with advancing age: Australian study found peak at 85-89 years of age.

Co-occurring psychiatric conditions: may result in risky, high burden, poly-psychoactive, medication use.

Brett J, Pearson SA, Daniels B, Wylie CE, Buckley NA. A cross sectional study of psychotropic medicine use in Australia in 2018: A focus on polypharmacy. British J of Clin Pharm. 2020.Cooper JW FM, Cook A, Burfield A. Psychotropic and psychoactive drugs and hospitalization rates in nursing facility residents. Pharmacy Practice. 2007;5(3):140-144.

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2021 Annual Meeting & ExhibitionNovember 4-7, 2021 | San Diego, California Antimisiaris, D., McHolan, B., Moga, D., Mospan, C. Depression Series: "Medication Related Problems." Sr Care Pharm 2021; 36(2): 68-82.

Conditions Co-Occurring with Depression

Possibly also:

• Altered Appetite

• Confusion/Memory Impairment

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American Geriatrics Society“Choosing Wisely”

American Geriatrics Society Choosing Wisely; Ten Things Clinicians and Patients Should Question. AGS Website. 2015 https://www.choosingwisely.org/societies/american-geriatrics-society/Accessed January 2018.

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https://www.choosingwisely.org/societies/american-geriatrics-society/

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Overlapping Neuromodulation and Receptor Effects

ToxidromesDeliriumSerotonin SyndromeNeuroleptic Malignant SyndromeAkathisiaImpaired RespirationMedication Induced Movement Disorders

FallsMisdiagnosisPrescribing CascadeFunctional and Cognitive Impairment

Hilmer SN, Gnjidic D, Le Couteur DG. Thinking through the medication list - appropriate prescribing and deprescribing in robust and frail older patients. Aust Fam Physician. 2012;41(12):924-928.Rovner BW, David A, Lucas-Blaustein MJ, Conklin B, Filipp L, Tune L. Self-care capacity and anticholinergic drug levels in nursing home patients. The Am J of Psych. 1988;145(1):107-109.

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Pharmacologic Classes and Pharmacodynamics• Antidepressants span a wide variety of pharmacodynamic (PD) characteristics.

• Most antidepressants augment serotonin

PD effects, and toxicities, are broadly similar within a pharmacologic class

Fasipe O. Neuropharmacological classification of antidepressant agents based on their mechanisms of action. Archives of Med and Health Sciences. 2018;6(1).

Antidepressants that do not augment serotonin

Bupropion Dopamine (DA) and Norepinephrine(NE) reuptake inhibitor

Atomoxetine and Reboxetine Selective NE transport inhibitorsKetamine NMDA glutamate receptor antagonist (also,

memantine, amantadine, and dextromethorphan)

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Pharmacologic Classes and PharmacodynamicsSome antidepressants exhibit different receptor activity at different doses.

Fasipe O. Neuropharmacological classification of antidepressant agents based on their mechanisms of action. Archives of Med and Health Sciences. 2018;6(1).de Boer T. The effects of mirtazapine on central noradrenergic and serotonergic neurotransmission. Int Clin Psychopharmacol. 1995 Dec;10 Suppl 4:19-23. doi: 10.1097/00004850-199512004-00004. Erratum in: Int Clin Psychopharmacol 1996 Jun;11(2):153. PMID: 8930006.

Example: Mirtazapine, an “atypical antidepressant”

LOW DOSEStrong antihistamine effect

HIGH DOSEAlpha 2 antagonism at central presynaptic alpha 2 inhibitory auto receptors

Sedation without anticholinergic effects

Disinhibition of multiple neurotransmitters: NE, 5HT, DA, acetylcholine

Mirtazapine is useful for patients with SSRI induced erectile dysfunction and migraine headaches. Mirtazapine has anxiolytic (much like buspirone), sedative-hypnotic, antiemetic and appetite stimulatory effects.

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Pharmacologic Classification of Primarily Serotonergic Antidepressant Agents

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Pharmacologic Classification of Primarily Serotonergic Antidepressant Agents

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Pharmacologic Classification of Primarily Non-Serotonergic Antidepressant Agents

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Receptor Subtypes

Action in areas of the body: brain spinal cord, bone

and gut

Serotonin (5HT) Adverse Effects OverviewIncreased serotonin load can

cause (symptoms of serotonin syndrome):

TremorsAgitation

Disrupted SleepMyoclonus

Movement DisordersNausea/Vomiting

DiarrheaBleeding

Sexual Dysfunction

Acute stimulation of 5HT2A and 5HT2C in the brain may

cause acute mental agitation, anxiety or panic

attacks

Observed in early serotonergic antidepressant

dosing, before anxiolytic effects take effect

Stahl SM. Stahl’s Essential Psychopharmacology. Cambridge U P Cambridge, United Kingdom. 2013:530-567.

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Self Assessment Question 1Beth is 81-year-old, takes a daily aspirin and clopidogrel for a recent cardiovascular disease intervention, she is having difficulty sleeping. Her doctor wants to recommend a sleep aid.Which of the following could cause a pharmacodynamic and

pharmacokinetic toxicity?A. Melatonin

B. DiphenhydramineC. TemazepamD. Paroxetine

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Motor Movement Disorders (5HT adverse effects)

Drugs which stimulate 5HT2A & 5HT2C in the basal ganglia (i.e., SSRIs)

may lead to motor movement disorders

Serotonin has an inhibitory effect on DA neurotransmission*

An exception in SSRI class: fluoxetine (and several atypical antipsychotics)

5HT2C antagonist action leads to increased DA and NE release in

prefrontal cortex

-Akathisia

-Psychomotor Impediment

-Parkinsonism

-Dystonic Movements

Caution: combining serotonergic medications

tramadol, triptans, St. John’s Wort, antidepressants,

antipsychotics, even opioids

Caution: CYP interactions, and 5HT2A/2C agonism

( inhibition of DA), anti-DA effects of antipsychotics

Stahl SM. Stahl’s Essential Psychopharmacology. Cambridge U P Cambridge, United Kingdom. 2013:530-567.

*Serotonin AGONISM at 5HT2C inhibits DA and NE release

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Sleep Disturbance, Sexual Dysfunction, GI disturbance, Nausea and Vomiting (5HT adverse effects)

Disrupted Sleep

• Stimulation of 5HT2A in brainstem sleep centers

• Induction of rapid muscle movement (myoclonus)

• Disrupted Sleep

Sexual Dysfunction

• Stimulation of 5HT2A/2C in spinal cord

• Inhibition of reflexes of orgasm and ejaculation

Nausea & Vomiting

• Activation of 5HT3 in the hypothalamus or brain stem: nausea/vomiting

• Stimulation of 5HT3/4 in gastrointestinal track: bowel irritability, cramps and diarrhea

Stahl SM. Stahl’s Essential Psychopharmacology. Cambridge U P Cambridge, United Kingdom. 2013:530-567.Fasipe OJ. Neuropharmacological classification of antidepressant agents based on their mechanisms of action. Arch Med Health Sci. 2018(6):80-94.

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Increased Risk of Bleeding (5HT adverse effects)Platelets are dependent on plasma uptake of serotonin for platelet aggregation.Drug that inhibit serotonin reuptake, inhibit the serotonin transporter protein, which transports serotonin into platelets.SSRIs, SNRIs, and NE effects may

impact 5HT levels, thus, transporter activity.

Studies conflict about statistically

significant increase in bleeding risk for people receiving serotonergic and

anticoagulant drugs

concomitantly.

Bleeding risk is individual and involves:

• Anticoagulant Medication Burden

• Frailty

• History of Bleeding

• Falls and Trauma HistoryVan Haelst IM, Egberts TC, Doodeman HJ, et al. Use of serotonergic antidepressants and bleeding risk in orthopedic patients. Anesthesiology. 2010;112(3):631-636.Verdel BM, Souverein PC, Meenks SD, Heerdink ER, Leufkens HG, Egberts TC. Use of serotonergic drugs and the risk of bleeding. Clin Pharmacol Ther. 2011;89(1):89-96.de Abajo FJ. Effects of selective serotonin reuptake inhibitors on platelet function: mechanisms, clinical outcomes and implications for use in elderly patients. Drugs & Aging. 2011;28(5):345-367.Bell JS, Taipale HT, Soini H, Pitkala KH. Concomitant use of SSRIs, NSAIDs/aspirin and gastroprotective drugs among residents of long-term care facilities: a medical record review.Antimisiaris, D., et al. (2021). Depression Series: "Medication Related Problems." Sr Care Pharm 36(2): 68-82.

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Non-5HT Receptor Adverse Effects

Fasipe OJ. Neuropharmacological classification of antidepressant agents based on their mechanisms of action. Arch Med Health Sci. 2018(6):80-94.Neff D, Guise A, Guralnick ML, et al. Duloxetine for the treatment of post-prostatectomy stress urinary incontinence. Can Urol Assoc J. 2013;7(5-6):E260-262.By the American Geriatrics Society Beers Criteria Update Expert P. American Geriatrics Society 2015 Updated Beers Criteria for Potentially Inappropriate Medication Use in Older Adults. J of the Am Geri Soc. 2015;63(11):2227-2246.

Norepinephrine Effects

SNRIs, TCAs, bupropion (To some degree, fluoxetine)Stimulating, activationWakefulnessIncreased blood pressureUrinary hesitancyWeight loss

Bupropion (NE and Dopamine)

Same as NE Effects (table to the left)(Plus, DA effects listed below)Positive ionotropic effectsCold feeling, vasoconstrictionNausea/vomitingVivid dreams, hallucinationsAgitation

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Fasipe OJ. Neuropharmacological classification of antidepressant agents based on their mechanisms of action. Arch Med Health Sci. 2018(6):80-94.Neff D, Guise A, Guralnick ML, et al. Duloxetine for the treatment of post-prostatectomy stress urinary incontinence. Can Urol Assoc J. 2013;7(5-6):E260-262.By the American Geriatrics Society Beers Criteria Update Expert P. American Geriatrics Society 2015 Updated Beers Criteria for Potentially Inappropriate Medication Use in Older Adults. J of the Am Geri Soc. 2015;63(11):2227-2246.

Antihistamine & AntimuscarinicEffects

Antihistamine Weight gainMetabolic syndromeDrowsiness

Antimuscarinic ConstipationUrinary retentionDry mouthBlurred visionSedation/confusionImpaired cognition

Alpha 2 BlockadeAlpha 1 Blockade

Alpha 2 Blockade

Increases 5HT and NE transmission, to some extent also DA and acetylcholine

Alpha 1 Blockade (TCAs, some atypical antipsychotics)

HypotensionDizzinessDrowsiness

Non-5HT Receptor Adverse Effects

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Self Assessment Question 2

Bob has high blood pressure. Despite taking medications for blood pressure, he struggles to keep his blood pressure under control. Which of the following antidepressants, if prescribed to Bob, would require added blood pressure monitoring?

A. CitalopramB. VenlafaxineC. Paroxetine D. Trazodone

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Drug Interactions: a major considerationSeveral antidepressants have phase I (CYP P450) drug interactions that may be clinically significant.

• Most have some degree of CYP inhibitory effects

• Often multiple pathways

Antidepressants with strong CYP 2D6 inhibitory actionFluoxetine > Paroxetine > Duloxetine >BupropionFollowed by: Sertraline = Citalopram = Escitalopram

For older people and people living with polypharmacy:

SertralineCitalopram

Escitalopram

Are safer choices regarding CYP P450 interactions.

Low Y, Setia S, Lima G. Drug-drug interactions involving antidepressants: focus on desvenlafaxine. Neuropsychiatr Dis Treat. 2018;14:567-580.Markowitz JS, Donovan JL, DeVane CL, et al. Effect of St John’s wort on drug metabolism by induction of cytochrome P450 3A4 enzyme. JAMA.

2003;290(11):1500-1504.

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2021 Annual Meeting & ExhibitionNovember 4-7, 2021 | San Diego, California Antimisiaris, D., McHolan, B., Moga, D., Mospan, C. Depression Series: "Medication Related Problems." Sr Care Pharm 2021; 36(2):

68-82.

Medication Inhibitory effect on CYP isoenzymes

Fluoxetine, norfluoxetine

(active metabolite)

CYP2D6**, CYP2C9*, CYP3A4*, CYP2C19*,

CYP1A2

Fluvoxamine CYP1A2**, CYP2C19**, CYP2C9*, CYP3A4*,

CYP2D6

Paroxetine CYP2D6**, CYP1A2, CYP2C9, CYP2C19,

CYP3A4

Sertraline CYP2D6*, CYP1A2, CYP2C9, CYP2C19, CYP3A4

Duloxetine CYP2D6* only pathway inhibited

Bupropion CYP2D6* only pathway inhibited

Potent CYP inhibition indicated by **, moderate by *, and weak by no symbol

CYP Inhibition of Select Antidepressant Agents

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Case:65 years of age

• Tim is the chief information officer at his company. Stressful job, shingles outbreak last year (carbamazepine for trigeminal neuralgia), atrial fibrillation (metoprolol), tore rotator cuff 3 months ago with surgical repair. • With all the recent health problems and stress, he was

started on fluoxetine 10mg daily a month before his rotator cuff surgery. He was prescribed tramadol post surgery for pain.• Leading up to surgery, he felt dizzy, he thought dizziness was

due to pain.• Post surgery, tramadol didn’t relieve his pain, so he was

prescribed acetaminophen with codeine, which was mildly effective. • Three weeks post surgery, Tim is brought to ED confused,

dizzy, agitated, with tremors. Blood pressure was 104/78, heart rate was 58.


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What is the root cause of Tim’s current state of confusion, dizziness, agitation, tremors, low blood pressure and heart rate?

A. FluoxetineB. CarbamazepineC. Acetaminophen with Codeine D. Tramadol

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Antimisiaris, D., McHolan, B., Moga, D., Mospan, C. Depression Series: "Medication Related Problems." Sr Care Pharm 2021; 36(2): 68-82.

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Antidepressant Discontinuation Syndrome20% of persons taking

antidepressants for at least 6 weeks experience

antidepressant discontinuation syndrome with abrupt

withdrawal of antidepressant • Can occur with tapering• SSRIs, SNRIs, and NE effects

may impact 5HT levels, thus transporter activity

Switching and stopping antidepressants - Australian Prescriber (nps.org.au)

Symptoms of ADS: flu-like symptoms,

nausea, abdominal pain,

balance disturbance,

akathisia, tremor, agitation, anxiety,

insomnia, hypervigilance,

sensory disturbance

Common with short acting antidepressants Less common with long-acting venlafaxine

ER; or those with active metabolites like fluoxetine,

bupropion, duloxetine, trazodone, venlafaxine

Although uncomfortable, not usually medically dangerous in

contrast to benzo or alcohol withdrawal

Warner CH, Bobo W, Warner C, Reid S, Rachal J. Antidepressant discontinuation syndrome. Am Fam Physician. 2006;74(3):449-456.Judge R, Parry MG, Quail D, Jacobson JG. Discontinuation symptoms: comparison of brief interruption in fluoxetine and paroxetinetreatment. Int Clin Psychopharmacol. 2002;17(5):217-225.

Resource

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https://www.nps.org.au/australian-prescriber/articles/switching-and-stopping-antidepressants

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Falls and Fractures• Orthostatic hypotension and

anticholinergic effects are the core features of

antidepressants’ link to falls

• Excessive serotonergic effects can contribute

The 2019 Beers Criteria recommends avoidance of

prescribing SSRIs, SNRIs and TCA in older people with a history of

fractures or falls

Per AGS Beers Criteria: amitriptyline, doxepin*, nortriptyline, paroxetine are not recommended

due to their highly anticholinergic and

orthostatic properties

*If doxepin is required: avoid doses < 6mg

because of anticholinergic effects

The combination of antidepressants with

two or more CNS active agents

increases the risk of falls and should be

avoided

Mol A, Bui Hoang PTS, Sharmin S, et al. Orthostatic hypotension and falls in older adults: A systematic review and meta-analysis. J of the Am Med Directors Assoc. 2019;20(5):589-597 e585.By the American Geriatrics Society Beers Criteria Update Expert P. American Geriatrics Society 2019 Updated AGS Beers Criteria(R) for Potentially Inappropriate Medication Use in Older Adults. Journal of the American Geriatrics Society. 2019;67(4):674-694.

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Risk of QT ProlongationMonitor for QT prolongation when using multiple psychoactive medications, & (multiple or any) QT prolonging drugs

Non-medication risk factors: age, hypokalemia, hypocalcemia, cardiac ischemia, cardiomyopathies, hypothyroidism, hypoglycemia, genetics

Comparison Table F-S. Drug Facts and Comparisons. Drug Facts and Comparisons eAnswers. Wolters Kluwer Health, Inc. Riverwoods, IL. http://onlinefactsandcomparisonscom. 2020; Accessed Multiple Dates in 2020.Armstrong SEM, Brown HK, Shorey C, et al. No Association Between Trazodone and Corrected-QT Prolongation in Older Adults. J Clin Psychopharmacol. 2019;39(5):528-530.

Several studies have concluded that citalopram does appear to prolong QT differently than most other SSRIs

FDA max dose citalopram for older people: 20mg daily

The propensity of citalopram and escitalopram to prolong QT is subject to much debate

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Risk of QT Prolongation

Drugs Associated with High Risk of QT Prolongation & Torsades de PointesAntidepressants SSRIs, TCAs, lithium, moclobemideAntihistamines Loratadine, diphenhydramineAntimicrobials Ciprofloxacin, moxifloxacin, erythromycin, clarithromycin,

fluconazole, voriconazole, pentamidineAntipsychotics MultipleCardiac Drugs Amiodarone, sotalol, disopyramideOther Drugs Cisapride, ondansetron, dolasetron, methadone, arsenic,

chloroquine

Isbister, G. Risk assessment of drug-induced QT prolongation. Aust Prescr 2015; 38:20-24. https://www.nps.org.au/australian-prescriber/articles/risk-assessment-of-drug-induced-qt-prolongation accessed Dec 2020.

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Selective Serotonin Reuptake Inhibitors as a Class

• Extensive drug-drug interactions

• Little to no effect on seizure threshold

• Renal dose adjustments are not usually necessary

• Side effects: bleeding, tremor, headache, nausea, vomiting, diarrhea, hyponatremia, dry mouth (some), sexual dysfunction

• Wide inter pharmacological class variation

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https://www.nps.org.au/australian-prescriber/articles/risk-assessment-of-drug-induced-qt-prolongation%20accessed%20Dec%202020

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SSRI Characteristics Clinical notesCitalopram SSRI, less selectivity than escitalopram,

weak antihistamine properties, can interact with alpha 1 adrenergic receptors, M1 muscarinic receptors and the norepinephrine transporter (Racemic mixture of R and S enantiomer)

Weak inhibitor of CYP P450 2D6; consists of 2 enantiomers, R and S, maximum dose in older adults is 20mg due to QT prolongation risk

Escitalopram S enantiomer of racemic citalopram, no antihistamine properties

The most selective of SSRI class. No CYP P450 2D6 inhibitory property, risk of QT prolongation still exists

Fluoxetine SSRI, NRI, 5-HT2C antagonist action (increases DA and NE levels)

NE effect at higher doses only, CYP P450 2D6 and 3A4 inhibition, multiple drug interactions, exceptionally long half-life (72 hours), active metabolite


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SSRI Characteristics Clinical notes

Sertraline Serotonin reuptake inhibition (SSRI), dopamine reuptake inhibition. The clinical significance of is unknown but may improve energy, concentration, and motivation. Sigma 1 receptor activity may help anxiety and psychotic depression.

Diarrhea side effect is approximately double that of other SSRIs.

Paroxetine SSRI, anticholinergic (M or muscarinic antagonism), weak norepinephrine reuptake inhibition (NRI)inhibition of nitric oxide synthetase which may contribute to sexual dysfunction.

Highly anticholinergic properties, potent inhibitor of CYP P450 1D6, short half-life (high risk of discontinuation symptoms). Beers Criteria potentially inappropriate medication.


Fluvoxamine SSRI, Sigma 1 receptor activity may help anxiety and psychotic depression. Inhibitor of CYP P450 1A2 and 3A4; multiple drug interactions, short half-life, nausea/sedation.

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Antidepressant Characteristics and Clinical NotesNortriptyline(TCA)

Best tolerated tricyclic antidepressant Serum levels can be checked, metabolite of amitriptyline. TCAs engage multiple receptors leading to multiple risks including syncope, falls/fractures, and are highly anticholinergic

Amitriptyline (TCA)

Most anticholinergic TCA, and most widely used for comorbid pain

Doxepin(TCA)

Low doses used for insomnia, avoid doses > 6mg in older adults, due to anticholinergic properties

Venlafaxine(SNRI)

High risk of hypertension (dose dependent) and nausea. NE effects at higher doses compared to lower dosesSerotonin Norepinephrine Reuptake Inhibitor (SNRI)

Desvenlafaxine (SNRI)

Active metabolite of venlafaxine, renal dose adjustment, short half-life

Duloxetine(SNRI)

Indicated for chronic neuropathic pain in addition to depression*Used off label for stress incontinence. (SNRIs- NE effects activate urethral alpha receptors, can be an issue for patients with urinary flow problems due to BPH)


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Antidepressant Characteristics and clinical notesMirtazapine(NASSA)

Side effects of weight gain and sedation due to antihistaminic effect.At low doses histamine effect predominant.

Bupropion(NDRI)

Take in the morning, can be activating. May elevate blood pressure and lower seizure threshold.

Trazodone(SARI)

Lower doses used for insomnia. Can cause orthostasis. At lower doses, antagonism of alpha 1, histamine and 5HT2a predominate, at higher doses, serotonin reuptake inhibition occurs.

Vortioxetine(5HT1 agonists/ blockade)

Has been studied in people 55-88 years of age (average 62). Side effects include headache, gastrointestinal disturbance, dizziness, constipation, bleeding, hyponatremia. Relatively new to market, novel mechanism.


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Toxidromes: Serotonin SyndromePresents with:

• Mental status changes• Neuromuscular

abnormalities• Autonomic instability• Can be accompanied

by rhabdomyolysis, acute renal failure, coma and respiratory failure

Risk factors:Increased 5HT synthesis and release, decreased break down and reuptake, altered receptor sensitivity.

Acquired MAO deficiency and 5HT metabolism can occur due to liver, cardiovascular, pulmonary disease, chronic tobacco use.

Remove offending

drugs

Monitor sodium levels

Heitmiller DR. Serotonin syndrome: a concise review of a toxic state. R I Med J (2013). 2014;97(6):33-35.Ener RA, Meglathery SB, Van Decker WA, Gallagher RM. Serotonin syndrome and other serotonergic disorders. Pain Med. 2003;4(1):63-74.Brown CH. Drug Induced Serotonin Syndrome. US Pharmacist. 2010. https://www.uspharmacist.com/article/druginduced-serotonin-syndrome Accessed Dec. 2020 35(11):HS- 16-21.

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Medications Associated with Serotonin Toxicity• Opioids• Tramadol• Antimicrobials (including

antiretrovirals)• SSRIs, SNRIs, NDRIs, MAOIs, TCAs,

trazodone, mirtazapine, lithium• Triptans• Anxiolytics• Antihistamines• Dextromethorphan• Lithium

• Antitussives• Anti-emetics• Antiepileptic agents• Muscle Relaxants• Stimulants• Methylene Blue• Herbal products (St. John's Wort)• Amphetamines and derivatives• Substances of abuse (lysergic acid

diethylamide, opioids)

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Toxidromes: Anticholinergic Poisoning

Anticholinergic medications

may precipitate delirium, a life-threatening condition

Cumulative effects of multiple medications

Tricyclic AntidepressantsAntihistamines

Sleep aidsAntiemeticsLoperamide

Some Antipsychotic AgentsBladder MedicationsParoxetine and TCAs

There are over 600 unique pharmacological and herbal

compounds with anticholinergic effects

Early signs: tachycardia,

hypertension, flushing, dry mouth/skin

Later signs: psychosis, agitation,

hallucinations, seizures, altered

consciousness, coma

Corallo CE WA, Wu A. . Anticholinergic syndrome following an unintentional overdose of scopalamine. Ther Clin RiskManag. 2009;5:719-723.Gerretsen P, Pollock BG. Drugs with anticholinergic properties: a current perspective on use and safety. Expert Opin Drug Saf. 2011;10(5):751-765.

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Toxidromes: Hyponatremia

Filippatos TD, Makri A, Elisaf MS, Liamis G. Hyponatremia in the elderly: challenges and solutions. Clin Interv Aging. 2017;12:1957-1965.Chiu CY, Sarwal A, Azhar Munir R, Widjaja M, Khalid A, Khanna R. Syndrome of Inappropriate Antidiuretic Hormone(SIADH) Induced by Long-Term Use of Citalopram and Short- Term Use of Naproxen. Am J Case Rep. 2020;21:e926561.

• Age• Diuretic use• Dietary sodium intake• Congestive heart failure• SIADH• Renal disease• Vomiting/diarrhea• Hypothyroidism• Adrenal insufficiency• Opioid use• Some anticonvulsant use• Antipsychotic, ACE inhibitor, NSAID use• Oxytocin use

Highest Risk SSRIs, SNRIs, and mirtazapine

Lower Risk bupropion, trazodone and TCAs

Kidney’s response to ADH is increased with

nonsteroidal anti-inflammatory agents

Diuretics, SSRIs, and NSAIDs: most common

meds implicated in hyponatremia

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Toxidromes: Seizure Threshold Alteration

Most antidepressants lower the seizure

threshold.

The most concerning are TCAs and bupropion

Increased Risk• Higher antidepressant

doses• Additive medications• Advanced age• Anderlying neurological

pathology

Medications that lower seizure threshold may

impact a person's ability to continue

driving.

Pisani F, Oteri G, Costa C, Di Raimondo G, Di Perri R. Effects of psychotropic drugs on seizure threshold. Drug safety : an international journal of medical toxicology and drug experience. 2002;25(2):91-110.Wu CS, Liu HY, Tsai HJ, Liu SK. Seizure Risk Associated With Antidepressant Treatment Among Patients With Depressive Disorders: A Population-Based Case-Crossover Study. J Clin Psychiatry. 2017;78(9):e1226-e1232.

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Clinical Pearls• Familiarity with pharmacologic features can help anticipate adverse events,

and assist discussions with physicians

• The use of two or more antidepressants may be risky in older persons due to drug interactions and the pharmacodynamic complexity of antidepressant agents

• Older people have heightened baseline risk of QT prolongation, bleeds, altered seizure threshold, extrapyramidal syndrome, drug interactions

• Vulnerability to toxidromes: older persons live with polypharmacy, altered pharmacokinetics & pharmacodynamics, and low physiologic reserve

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Antidepressant use and risk of ADE in older people: population-based cohort study• 60,746 patients diagnosed with new episode of depression

• Ages 65-100, followed from 1996 to 2008

• 89% received at least one prescription for antidepressants

• Outcomes: all cause mortality, suicide, myocardial infarction, stroke, transient ischemic attack (TIA), falls, fractures, upper GI bleeding, epilepsy, traffic accidents, hyponatremia and adverse drug reactions

Results

SSRIs Associated with the highest adjusted hazard ratios for falls (1.55, 95% CI 1.58-1.73) andhyponatremia (1.52, 1.33 to 1.75) versus when no antidepressant used

Other antidepressants group

Highest adjusted hazard ratios for all cause mortality (1.66, 1.56-1.77), attempted suicide (5.16, 3.90-6.83), stroke/TIA (1.37, 1.22-1.55), fracture (1.64, 1.46-1.84), and epilepsy/seizures (2.24, 1.60-3.15)

Coupland, C., Dhiman, P., Morriss, R., et al. Antidepressant use and risk of adverse outcomes in older people: population-based cohort study. BMJ 2011;343:d4551

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Bleeding Risks with AntidepressantsA nonsystematic review of meta-analyses• Serotonin reuptake inhibitors (SRIs) increased risk of bleeding by 1.16-2.36-fold• The risk is synergistic between SRIs and nonsteroidal anti-inflammatory agents (OR 3.17-10.9)• Acid reducing medications may mitigate risk of GI bleeds in chronic NSAIDs and SRI users (OR 0.98-1.1)• Compared with aspirin alone, use of SRIs with aspirin is associated with increased risk of bleeding

(HR=1.42, 95% CI- 1.08-1.87)• Dual antiplatelet therapy alone vs. with SRI, increased risk of bleeding (HR-1.57, 95% CI-1.07-2.32)

Insights

SSRIs Increase gastric acidity, as well as inhibition of platelet aggregation

High SRI binding affinity vs low SRI binding affinity

Duloxetine, fluoxetine, paroxetine, clomipramine, and sertraline > amitriptyline, citalopram, escitalopram, imipramine and venlafaxine > bupropion, mirtazapine, doxepin, maprotiline, nortriptyline, trazodone, amoxapine and nefazodone

Longitudinal exposure

SRIs can increase gastric acidity almost immediately, it may take a week to deplete platelets of serotonin.

Bixby, A., VandenBerg, A., Bostwick, J. et al. Clinical Management of Bleeding Risk with Antidepressants. Annals of Pharmacotherapy. 2019, Vol. 53(2) 186-194.

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American Family Physician Review in Older Adults 2020• SSRIs cause ADEs at a similar frequency to placebo and have lower discontinuation

rates than tricyclic antidepressants up to 12 weeks of treatment*• One large cohort study found that SSRIs were associated with an increased risk of

falls, fractures and all cause mortality compared with no antidepressant over longer treatment period (median 364 days).

• Serotonin-norepinephrine reuptake inhibitors cause more ADEs and greater discontinuation of therapy during up to 12 weeks of treatment compared to placebo*

• Duloxetine increases the risk of falls over 12-24 weeks of treatment compared to placebo*

• Head-to-head comparisons reviewed found little significant difference between different classes of antidepressants

• *Strength of recommendation = B• Inconsistent or limited quality evidence

Salisbury-Afshar, E. Adverse Events of Pharmacologic Treatments of Major Depression in Older Adults. American Family Physician, 2020-02-01, Vol 1010, Issue 3, pages 179-181.

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Clinical monitoringAdverse Effect Monitoring Tools Observations or Studies

Movement Disorders AIMS Scale-Abnormal Involuntary Movement Scalehttps://www.dhhs.nh.gov/dcyf/adoption/documents/abnormal-involuntary-movement-scale-exam.pdf

Movement disorders can look like restlessness, “akathisia”, or restless legs, repetitive movement, or even agitation.Early serotonin toxicity can clinically look like restlessness, agitation and movement issues.

Serotonin Toxicity Hunter’s Criteria for the Diagnosis of Serotonin Toxicityhttps://www.aafp.org/afp/2010/0501/p1139.html

In the presence of serotonergic agent, yes to either of the following:Spontaneous clonus, inducible clonus with agitation or diaphoresis, ocular clonus with agitation or diaphoresis, tremor and hyperreflexia, hypertonia, temperature above 100.4°F and ocular or inducible clonus.

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https://www.dhhs.nh.gov/dcyf/adoption/documents/abnormal-involuntary-movement-scale-exam.pdf

https://www.aafp.org/afp/2010/0501/p1139.html

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Clinical monitoringAdverse Effect Monitoring Tools Observations or Studies

Hyponatremia Basic metabolic panel

Confusion, Cognitive Impairment

QT prolongation 12 lead electrocardiogram

Syncope, loss of consciousness

Bleeding Signs and symptoms of bleeding

Especially in patients vulnerable to bleeding and on multiple medications that can cause bleeding

Seizures Signs and symptoms of seizure

Awareness, alertness, confusion, speech, senses, muscle tone, movements, repetitive movements, incontinence, diaphoresis, altered breathing

Remember to monitor efficacy. Avoid ADEs by avoiding the use of ineffective medications

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Thank You;

Thoughts?

[email protected]

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https://www.choosingwisely.org/societies/american-geriatrics-society/

https://www.uspharmacist.com/article/druginduced-

https://www.nps.org.au/australian-prescriber/articles/risk-assessment-of-drug-induced-qt-prolongation%20accessed%20Dec%202020

Documents

antidepressants medication related problems