MY MEDICATION MADE ME DO IT: SIDE EFFECTS ASSOCIATED WITH - - PowerPoint PPT Presentation

MY MEDICATION MADE ME DO IT: SIDE EFFECTS ASSOCIATED WITH ANTIPSYCHOTICS

Learning Objectives

• Explore the neurobiological bases of various side

effects (including cardiometabolic and movement disorders) associated with use of antipsychotics

• Provide a clinical update on management of side

effects commonly associated with antipsychotic use

Antipsychotic-Induced Movement Disorders

Extrapyramidal Symptoms (EPS)

Akathisia

• Patients often use terms such as "anxiety" or

"itching," although these do not really capture the essence of the condition

• Objective sign is disordered movement
• Mild to moderate
• Predominantly lower extremities, usually from hips to

ankles

• Shifting positions while standing or moving the feet

around while sitting

• Increasing severity
• Can involve the entire body
• Nearly incessant writhing and rocking, accompanied

by jumping around, running, and occasionally jumping out of a chair or a bed

Dopaminergic Hypoactivity Causes Akathisia—Or Does It?

Suggests direct DA link

• Occurrence in Parkinson’s disease
• Similar disorders—restless leg syndrome

(RLS) and periodic limb movement disorder (PLMD)—are treated with DA agonists

• Most APs are potent antagonists at the D2

receptor Suggests it’s more complicated than that

• No established direct link between

parkinsonism and akathisia

• Agents that cause least EPS can still

cause akathisia

• SSRIs can cause akathisia
• Indirect stimulation of 5HT2A inhibits DA

release

Hypothesized Mechanism of Akathisia: The Role of the Nucleus Accumbens

Cg1: cingulate gyrus, 1. OFC: orbitofrontal cortex. IL: infralimbic cortex. NAcbC: nucleus accumbens core. NAcbS: nucleus accumbens shell. VTA: ventral tegmental area. LC: locus coeruleus. Stahl SM et al. CNS Spectrums. 2011: www.neiglobal.com.

Akathisia: Incident Rates Across Indications in FDA Registration Trials

Agent Incident Rates of Akathisia Aripiprazole 10–13% monotherapy; 19–25% with lithium, divalproex, or antidepressants Asenapine 4–11% Brexpiprazole 4–14% (MDD, dosed 1–3 mg/day); 4–7% (SZ, dosed 1–4 mg/day ) Cariprazine 9–14% (SZ); 20% (3–6 mg/day) or 21% (9–12 mg/day) (BP-mania) Clozapine 3% Iloperidone 1–2% Lurasidone 6–22% (SZ); 4–11% (BP-depression) Olanzapine 3% Paliperidone 6–9% Quetiapine 1–4% Risperidone 5–9% Ziprasidone 8–10%

BP: bipolar depression. MDD: major depressive disorder. SZ: schizophrenia. Goldberg, Ernst. Managing the side effects of psychotropic medications. 2012.

Treatment Strategies for Akathisia

• Dosage reductions
• Change to lower-risk agents if feasible
• Withdrawal akathisia can occur; allow at least 6 weeks before judging effectiveness of

dose reduction/medication switch

• Benzodiazepines
• Centrally-acting beta blockers
• Propranolol 30–90 mg/day
• Betaxolol 10–20 mg/day
• Amantadine 100–200 mg bid
• Gabapentin 1200 mg/day
• Trazodone 100 mg/day
• Mirtazapine 15 mg/day
• Anticholinergics (e.g., benztropine): no clear value

Goldberg et al. Managing the side effects of psychotropic medications. 2012.

Drug-Induced Parkinson’s (DIP)

• DIP is the most common movement disorder induced by drugs that affect dopamine

receptors (e.g., DRBAs)

• Risk factors: age, female gender
• Genetic risk factors: genes associated with GABA receptor-signaling pathway are involved

in neuroleptic-induced TD in schizophrenic patients

Shin and Chung. J Clin Neurol. 2012;8:15-21.

Incidence and Prevalence of DIP (in Korea)

Han S et al. BMC Pub Health 2019;19(1328):1-9.

Which drugs are most commonly associated with high risk for DIP?

Clinical Characteristics of DIP

• Clinically categorized as bilateral and symmetric parkinsonism
• More prominent bradykinesia and rigidity
• However, approximately 30–50% patients with DIP show asymmetric parkinsonism and tremor

at rest

Treatment for DIP

Stop taking the

• ffending drug

Patient Type Treatment Patients who cannot stop taking antipsychotics for psychiatric reasons Switch to atypical antipsychotics with lower risk of EPS Patients who have been prescribed DA antagonists due to GI disturbances Stop taking offending drug immediately Anticholinergics Trihexyphenidyl Benztropine Amantadine Levodopa

Antipsychotic-Induced Metabolic Disorders

*4–6-week pooled data: Marder SR et al. Schizophr Res 2003;61(2-3):123-36;

† 6-week data: Allison DB et al. Am J Psychiatry 1999;156(11):1686-96; Jones et al. ACNP; 1999.

Estimated weight change at 10 weeks on ”standard" dose

6 Weight change (kg) 5 4 3 2 1

• 1
• 2
• 3

13.2 Weight change (lb) 11.0 8.8 6.6 4.4 2.2

• 2.2
• 4.4
• 6.6

†

*

Mean Change in Weight During Antipsychotic Treatment

Which receptors hypothetically mediate cardiometabolic risk?

Stahl SM. Stahl’s essential psychopharmacology. 4th ed. CUP; 2013.

Increases food intake Interferes with satiety signals from the gut

Predictors of Antipsychotic-Induced Weight Gain

• Olanzapine: gain of >2 kg in first 2–3 weeks predicts later (26-week)

gain >10 kg1

• Younger age2
• Nonwhite2
• Low baseline BMI3
• Female4
• Pharmacogenetic predictors (5HT2C -759T allele5, MTHFR 677C/T “CC”

genotype6)

• 1. Degenhardt EK et al. J Clin Psychopharmacol 2011;31(3):337-40.
• 2. Lipkovich I et al. J Clin Psychopharmacol 2006;26(3):316-20.
• 3. Kinon BJ et al. J Clin Psychiatry 2001;62(2):92-100.
• 4. Gebhardt S et al. J Psychiatr Res 2009;43(6):620-6.
• 5. Templeman LA et al. Pharmacogenetics Genomics 2005;15(4):195-200.
• 6. Srisawat U. Int J Neuropsychopharmacol 2014;17(3):485-90.

Metabolic Monitoring Protocol for Patients on SGAs

Baseline 4 weeks 8 weeks 12 weeks Quarterly Annually Every 5 years Personal/family history X X Weight (BMI) X X X X X Waist circumference X X Blood pressure X X X Fasting plasma glucose X X X Fasting lipid profile X X X

ADA-APA. Consensus Development Conference. Diabetes Care 2004; 596–601.

Tolerability of Atypical Antipsychotics

SEDATION Aripiprazole Brexpiprazole Cariprazine Iloperidone Lurasidone Paliperidone Risperidone Ziprasidone Asenapine Olanzapine Clozapine Quetiapine WEIGHT GAIN Cariprazine Lurasidone Ziprasidone Aripiprazole Asenapine Brexpiprazole Iloperidone Paliperidone Risperidone Quetiapine Clozapine Olanzapine EPS Clozapine Iloperidone Quetiapine Aripiprazole Brexpiprazole Cariprazine Asenapine Lurasidone Olanzapine Ziprasidone Paliperidone Risperidone Best choice Worst choice

Patients on atypical antipsychotics should be regularly monitored for side effects, including BMI

Augmenting Options for Intolerable Weight Gain

• Diet
• Small, frequent meals
• Lean protein with every

meal/snack

• Veggies
• Exercise
• 60 minutes/day for weight loss
• 45–60 minutes most days for

weight stability

• Adjunct medications
• Amantadine
• Bupropion
• Lamotrigine
• Lorcaserin
• Metformin
• Naltrexone-bupropion
• Orlistat
• Phentermine-topiramate
• Topiramate
• Zonisamide
• GLP-1 Agonists
• Dulaglutide, liraglutide, semaglutide

Stahl SM. Stahl's Essential Psychopharmacology: Prescriber's Guide. 6th ed. 2018; Serretti A, Mandelli L. J Clin Psychiatry 2010;71(10):1259-72.

Olanzapine/Samidorphan

Correll CU et al. AJP in Advance. 2020; Epub ahead of print.

Summary

• Antipsychotics are associated with movement disorders as well as metabolic

effects including weight gain, altered glucose metabolism, and dyslipidemia

• Differentiating among various extrapyramidal symptoms (EPS) is important for

accurate diagnosis of movement disorders

• Agents associated with the least EPS risk can still cause akathisia
• Drug-induced parkinsonism (DIP) is the most common movement disorder

induced by DRBAs

• Awareness of effective treatment strategies available for akathisia and DIP

enhances appropriate treatment of movement disorders

• Education, monitoring (e.g., weight, glucose and lipids) and risk/benefit

assessment of specific treatments is required to reduce risk of cardiometabolic issues

Posttest Question 1

Joseph constantly shifts positions while standing and moves his feet while sitting. He also rocks bath and forth and occasionally jumps out of the chair. When asked to describe his symptoms he has tremendous difficulty and says he “feels anxious and has constant itching.” Joseph most likely has which movement disorder?

• 1. Tardive dyskinesia
• 2. Drug-induced parkinsonism (DIP)
• 3. Akathisia
• 4. None of the above

Posttest Question 2

Mary is a 73-year-old patient with prominent bradykinesia and rigidity, along with postural tremors. Her SPECT scan reveals that dopamine transporter (DAT) uptake was normal and symmetric in the bilateral striatum. She likely has which movement disorder?

• 1. Drug-induced parkinsonism (DIP)
• 2. Parkinson’s disease unmasked by DRBAs
• 3. Both 1 and 2
• 4. None of the above

Posttest Question 3

A patient who has been taking an atypical antipsychotic for 6 months has experienced a 22-pound weight gain since baseline. Which of the following pharmacologic properties most likely underlies this patient's metabolic changes?

• 1. Dopamine 2 antagonism
• 2. Serotonin 2A antagonism
• 3. Serotonin 2C antagonism
• 4. Alpha 1 adrenergic antagonism