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 it’s more complicated than that Suggests direct DA link • No established direct link between • Occurrence in Parkinson’s disease parkinsonism and akathisia • Similar disorders—restless leg syndrome (RLS) and periodic limb movement • Agents that cause least EPS can still cause akathisia disorder (PLMD)—are treated with DA agonists • SSRIs can cause akathisia • Most APs are potent antagonists at the D2 • Indirect stimulation of 5HT2A inhibits DA receptor 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 Patient Type Treatment Patients who cannot stop taking Switch to atypical antipsychotics with lower antipsychotics for psychiatric reasons risk of EPS Patients who have been prescribed DA Stop taking offending drug immediately antagonists due to GI disturbances Stop taking the offending drug Anticholinergics Trihexyphenidyl Benztropine Amantadine Levodopa

Antipsychotic-Induced Metabolic Disorders

Mean Change in Weight During Antipsychotic Treatment Estimated weight change at 10 weeks on ”standard" dose 6 13.2 5 11.0 Weight change (kg) Weight change (lb) 4 8.8 † 3 6.6 2 4.4 * 1 2.2 0 0 -2.2 -1 -4.4 -2 -6.6 -3 *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.

Which receptors hypothetically mediate cardiometabolic risk? Interferes with satiety signals from the gut Increases food intake Stahl SM. Stahl’s essential psychopharmacology. 4 th ed. CUP; 2013.

Predictors of Antipsychotic-Induced Weight Gain • Olanzapine: gain of >2 kg in first 2–3 weeks predicts later (26-week) gain >10 kg 1 • Younger age 2 • Nonwhite 2 • Low baseline BMI 3 • Female 4 • Pharmacogenetic predictors (5HT2C -759T allele 5 , MTHFR 677C/T “CC” genotype 6 ) 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 Every 5 Baseline 4 weeks 8 weeks 12 weeks Quarterly Annually years Personal/family X X history Weight (BMI) X X X X X Waist X X circumference Blood pressure X X X Fasting plasma X X X glucose Fasting lipid profile X X X ADA-APA. Consensus Development Conference. Diabetes Care 2004; 596–601.

Tolerability of Atypical Antipsychotics SEDATION WEIGHT GAIN EPS Best choice Aripiprazole Cariprazine Clozapine Brexpiprazole Lurasidone Iloperidone Cariprazine Ziprasidone Quetiapine Iloperidone Aripiprazole Aripiprazole Lurasidone Asenapine Brexpiprazole Paliperidone Brexpiprazole Cariprazine Risperidone Iloperidone Asenapine Ziprasidone Paliperidone Lurasidone Asenapine Risperidone Olanzapine Olanzapine Quetiapine Ziprasidone Clozapine Clozapine Paliperidone Worst choice Quetiapine Olanzapine Risperidone Patients on atypical antipsychotics should be regularly monitored for side effects, including BMI

Augmenting Options for Intolerable Weight Gain • Diet • Adjunct medications • Small, frequent meals • Amantadine • Lean protein with every • Bupropion meal/snack • Lamotrigine • Veggies • Lorcaserin • Exercise • Metformin • 60 minutes/day for weight loss • Naltrexone-bupropion • 45–60 minutes most days for • Orlistat weight stability • 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