CNS prescription drugs and their ability to impair, y. Antidepressants. Indications for the existence of behavioral toxicity of antidepressants

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1 CNS prescription drugs and their ability to impair, y FACTA 1 JG Ramaekers, Dept Neuropsychology & Psychopharmacology Maastricht University, The Netherlands (j.ramaekers@maastrichtuniversity.nl) TCAs RIMAs Antidepressants imipramine, amitriptyline, desipramine, doxepin moclobemide SSRIs fluoxetine, paroxetine, sertraline,.. (es)citalopram, fluvoxamine SNRIs SARIs NaSSA venlafaxine, milnacipran trazodone, nefazodone mirtazapine vortioxetine Indications for the existence of behavioral toxicity of antidepressants Epidemiological surveys Basic pharmacology Experimental studies 1

2 Crash risk? Epidemiological data Antidepressants Authors Cases vs Controls Odds Ratio TCAs Leveille et al (199) Ray et al (199) Rapoport (11) (NS) SSRIs Barbone et al (199) Ravera et al (1) Rapoport (11) (NS). 1.1 TCA+SSRIs TCAs+MAO-A Meuleners et al (11) Ravera (1) 1 (elderly) drivers with chronic condition! (NS) NS = not significant Synaptic Effects of Antidepressants Reuptake inhibition Receptor blockade TCA NE 5HT DA H1 α1 AcM D 5HT Imipramine X X X X X X X Amitriptyline X X X X X X X SSRIs Fluoxetine X Paroxetine X X X Sertraline X X Fluvoxamine X X (es) Citalopram X Synaptic Effects of Antidepressants Reuptake inhibitors M A O Receptor agonist Receptor blockade SNRIs NE 5HT DA A 5HT1 H1 α1 α 5HT 5HT3 5HT7 Venlafaxine X X Milnacipran X X RIMAs Moclobemide X SARIs Nefazodone X X X X Trazodone X X X X NaSSA Mirtazapine X X X X Vortioxetine X X X X

3 Driver impairment? Experimental data Models Antidepressants Results Psychomotor tests Cognition Actual driving All individual ADs Impairment after sedative ADs Schematic representation of the Road Tracking Test Left lane right lane +5V -5V Calculation and meaning of the weaving index 3

4 Δ SD Lateral Position (cm) Mean SDLP as a function of BAC SDLP change scores at legal BAC limits for driving under the influence in EC and US General design healthy subjects (N = 1 ) cross-over, double-blind, placebo controlled driving test at Tmax on Day 1 (acute effect) driving test after 1 or weeks of treatment (subchronic effect) therapeutic doses ( 1 or dose regimens) active control to demonstrate sensitivity TCAs and mianserin - DOX DOX AMI AMI IMI MIA MIA MIA - 5mg td 5 mg td 5 mg td 5+5mg 5 mg bd mg td mg td / mg td Day 1 Day 7/ Day 15 Equivalent effect of BAC (mg/ml) 1...5

5 Δ SD Lateral Position (cm) RIMAs, SSRIs, SARIs and SNRIs Equivalent effect of BAC (mg/ml) MOC FLU PAR PAR NEF NEF VENL VENL VOR ESC mg bd mg hs mg qam mg qam mg bd mg bd 37,5/75mg bd 37,5mg bd mg hs / mg hs Regular antidepressants Fluoxetine Sertraline Paroxetine Bupropion Venlafaxine (Es)Citalopram Trazodone Driving impairment after novel antidepressants could it ever occur? dose-effect studies acute vs subchronic effects pharmacokinetic interactions Poor vs Extensive metabolizers 5

6 SD Lateral Position (cm) Antidepressant effects at P5 isozymes CYP1A CYPC19 CYPD CYPE1 CYP3A3/ Substrates clozapine citalopram paroxetine ethanol sertraline propanolol moclobemide fluoxetine fluoxetine theophylline diazepam venlafaxine venlafaxine caffeine (N-demethyl) bupropion alprazolam mirtazapine omeprazole ß-blockers triazolam TCAs midazolam haloperidol diazepam mirtazapine terfenadine carbamazepine mirtazapine Inhibitors fluvoxamine moclobemide (nor)fluoxetine (nor) fluoxetine moclobemide ketoconazole sertraline nefazadone paroxetine fluvoxamine venlafaxine grapefruit moclobemide haloperidol Effects of combined antidepressant and BZD treatments on driving performance of depressed outpatients (N=) 3 33 Fluoxetine Moclobemide 3 1 B1 B 1 3 Treatment (wks) Ramaekers et al Patients receiving BZDs and potential drug/drug interaction at Cytochrome P5 enzymes Fluoxetine (N=19) # patients Substrate for isozyme 3A3/ Moclobemide (N=) # patients Substrate for isozyme C19 rdiazepam Clotiazepam Yes Yes Bromazepam Alprazolam 3 Yes Yes 1 1 Oxazepam Lorazepam Total cases 15 1 Ramaekers et al. 1997

7 Δ SD Lateral Position (cm) SD Lateral Position (cm) Effects of combined antidepressant and BZD treatments on driving performance of depressed outpatients 33 comedication compatible BZD comedication incompatibele BZD comedication 3 1 Moclobemide Fluoxetine B 1 3 B 1 3 Treatment (wks) Ramaekers et al Effects of combined antidepressant and BZD treatments on driving performance of depressed outpatients FLU FLU FLU MOC MOC MOC BZD Comp BZD Inc BZD BZD Comp BZD Inc BZD Week 1 Week 3 Week Equivalent effect of BAC (mg/ml) If a antidepressant with sedative properties has to be prescribed, how can possible driving impairment be avoided? behavioral tolerance ascending dose regimens nocturnal vs daytime dosing 7

8 Δ SD Lateral Position (cm) Driving after nocturnal doses of sedating antidepressants - - Mirtazapine Mirtazapine Mirtazapine Mianserin Dothiepin 15 mg / 3mg hs 3 mg/ 5 mg hs 3 mg hs 3mg /mg hs 75mg / 15mg hs Equivalent effect of BAC (mg/ml) Day 1 Day 7 / Day 15 Day But even nocturnal doses can cause unexpected residual impairment Poor vs Extensive metabolizers H 3C Mianserin Mirtazapine Esmirtazapine maleate (enantiomer) Antidepressant mg tid Antidepressant 3-5 mg nocte Insomnia? mg nocte

9 Δ SDLP (cm) Δ SDLP (cm) CYPD phenotyping Subjects received one tablet of dextromethorphan before bedtime Excretion ratio dextrometorphan/dextrorphan was determined in morning urine Poor metabolizers: excretion ratio >=.3 (N=7) Extensive metabolizers : excretion ratio <.3 (N=5) SDLP - overall,5 3,5,5 Single dose Multiple doses Equivalent effect BAC.5 mg/ml 1,5,5 n inferiority margin -,5-1,5 ESM ESM ZOP ESM ESM Mean (95% CI) SDLP difference from placebo after single doses of esmirtazapine (ESM) and zopiclone (ZOP) and after multiple doses of ESM. ( = non-inferiority not shown, upper bound of the 95% CI is above the non-inferiority margin of. cm) SDLP CYPD Poor metabolizers Extensive metabolizers Equivalent effect BAC 1. mg/ml. mg/ml.5 mg/ml 1 n inferiority margin Single dose Multiple doses Single dose Multiple doses ESM ESM ESM ESM ESM ESM ESM ESM Mean (95% CI) SDLP difference from placebo after single doses of esmirtazapine (ESM) and zopiclone (ZOP) and after multiple doses of ESM in poor (N=7) and extensive metabolizers (N=5). ( = non-inferiority not shown, upper bound of the 95% CI is above the non-inferiority margin of.cm) 9

10 Do healthy volunteers studies apply to depressed patients? Depressed patients are ill, and symptom reduction by antidepressant treatment might actually improve their driving capacity! parallel groups Study design (1) Depressed patients without antidepressants Characteristics: active depression (HAM<17) no antidepressants Depressed patients with -5 weeks antidepressants Healthy controls 1-5 years 5 km/year past 3 years From previous study (Ramaekers et al. 1997) parallel groups Study design () Depressed patients without antidepressants Depressed patients with -5 weeks antidepressants Healthy controls Characteristics: diagnosis depression (DSM-IV criteria) receiving SSRI-type antidepressant for -5 weeks 1-5 years 5 km/year past 3 years

11 parallel groups Study design (3) Depressed patients without antidepressants Characteristics: healthy, no medication 1-5 years Depressed patients with -5 weeks antidepressants 5 km/year past 3 years matched for age, gender, IQ and driving experience Healthy controls Allowed SSRI- medication Citalopram (Cipramil ): - mg/day Fluoxetine (Prozac ): - mg/day Paroxetine (Seroxat ): -5 mg/day Sertraline (Zoloft ): 5- mg/day Venlafaxine (Efexor ): mg/day Fluvoxamine (Fevarin ): -3 mg/dag Road Tracking Test Standard Deviation Lateral Position medication free SSRI -5 Weeks Healthy controls 11

12 Global driving ability scores of depressed patients receiving AD treatment Brunnauer et al, General conclusions from experimental driving studies Sedative antidepressants such as TCAs severely impair driving performance when taken over the day The impairing effects on performance of antidepressants with sedative properties are reduced to minimal levels when administered as a nocturnal dose. vel antidepressants such as RIMAs, SSRIs, SARIs and SNRIs generally do not affect driving performance when given in therapeutic doses Combinations of antidepressants and BZDs or other drugs may produce PK interactions giving rise to serious driving impairment Depression induced driving impairment is only partly ameliorated by succesfull antidepressant therapy BZD anxiolytics Long acting, long-elimination half life Daytime use GABA agonists GABA, major inhibitory NT in CNS By definition, BZD anxiolytics must be very sedative 1

13 Change in SDLP (cm) A pharmacoepidemiological study in 7 hypnotic users, anxiolytic users and 9 controls Relative risk of injurious traffic accidents as functions of cumulative elapsed time after prescription of hypnotics (RRH ) and anxiolytics(rra). Based on data from Neutel (1995) Diazepam effects on SDLP in anxiolytic patients Van Laar, 1995 Summary of diazepam and lorazepam effects on SDLP diazepam lorazepam 1 E quivalent effects of alcohol while BAC is 1. mg/ml. mg/ml.5 mg/ml Day: Dose (mg): 5 Regimen: o.d. t.i.d. t.i.d. per day t.i.d. t.i.d. t.i.d. b.i.d. b.i.d. Subjects: HV HV HV AP HV/AP HV HV HV AP Study nr: Acute (black bars) and subchronic (grey bars) effects of diazepam and lorazepam in various doses on Standard Deviation Lateral Position (SDLP) in the highway driving test in separate studies with healthy volunteers (HV) and/or anxious patients (AP). Vermeeren et al, 9 13

14 concentration Change in SDLP (cm) Other anxiolytics and SDLP E quivalent effects of alcohol while BAC is 1. mg/ml. mg/ml.5 mg/ml - Day: Dose (mg): XR 1IR 1IR Regimen: b.i.d.. b.i.d. per day o.d. t.i.d. t.i.d. b.i.d. b.i.d. o.d. o.d. Drug: RIT OND BUS BUS CLO OXA ALPI SUR ALPR ALPR Study nr: Acute (black bars) and subchronic (grey bars) effects of ritanserin (RIT), ondansetron (OND), buspirone (BUS), clorazepate (CLO), oxazepam (OXA), alpidem (ALPI), suriclone (SUR) and alprazolam (ALPR) in various doses on Standard Deviation Lateral Position (SDLP) in the highway driving test in separate studies Vermeeren et al, 9 Actual driving in healthy volunteers after immediate and controlled release formulations of alprazolam 1mg (Leufkens et al 7) Subjects: Design: - 1 healthy subjects (9 males, 9 females) - Mean (±SE) age: 3.3 (±.) - Range -5 Treatments: - Double blind, placebo-controlled, 3-way crossover study - placebo - alprazolam IR 1 mg - alprazolam XR 1 mg alprazolam IR alprazolam XR time Adapted from Wright, Curr Ther Res 1995 Tmax alprazolam IR:.7 1. hrs Tmax alprazolam XR: 5-1 hrs alprazolam XR: delayed absorption fewer and less severe side effects (Rickels, Expert Opin Pharmacother ) 1

15 Δ SDLP (cm) Mean SDLP (cm) SDLP (-5 hrs post dose) placebo alprazolam XR alprazolam IR Increment SDLP (cm) from placebo Tests prematurely terminated 3 (out of 1) 7 (out of 1) A case study: driving under the influence of alprazolam (movie) Equivalent effect of BAC (mg/ml) 15