“CNS prescription drugs and
their ability to impair”, y
JG Ramaekers, Dept Neuropsychology & Psychopharmacology Maastricht University, The Netherlands
(j.ramaekers@maastrichtuniversity.nl)
FACTA 2014
Antidepressants
•
TCAs imipramine, amitriptyline, desipramine,
doxepin
•
RIMAs moclobemide
•
SSRIs fluoxetine, paroxetine, sertraline,.
.
(es)citalopram, fluvoxamine
•
SNRIs venlafaxine, milnacipran
•
SARIs trazodone, nefazodone
•
NaSSA mirtazapine
•
vortioxetine
Indications for the existence of
behavioral toxicity of antidepressants
•
Epidemiological surveys
•
Basic pharmacology
Antidepressants Authors Cases vs Controls Odds Ratio TCAs SSRIs TCA+SSRIs TCAs+MAO-A Leveille et al (1994) Ray et al (1992) Rapoport (2011) Barbone et al (1998) Ravera et al (2012) Rapoport (2011) Meuleners et al (2011) Ravera (2012) 234-447 5418-33283 7393 19386 3963-18828 7393 616 (elderly) drivers with chronic condition !
3963-18828 2.3 2.2 1.03 (NS) 0.9 (NS) 2.02 1.1 1.8 4.1 1.45 (NS)
Epidemiological data
Crash risk? NS = not significantSynaptic Effects of Antidepressants
Reuptake inhibition Receptor blockade TCA NE 5HT DA H1 α1 AcM D2 5HT2 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 XSynaptic Effects of Antidepressants
Reuptake inhibitors M A O Receptor agonist Receptor blockade SNRIs NE 5HT DA A 5HT1 H1 α1 α2 5HT2 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 XModels Antidepressants Results Psychomotor tests
Cognition Actual driving
All individual ADs Impairment after sedative ADs
Experimental data
Driver impairment?
Schematic representation of the
Road Tracking Test
Left lane right lane
+5V 0 -5V
Calculation
and meaning
of the
“weaving
index”
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 = 18 – 24)
•
cross-over, double-blind, placebo controlled
•
driving test at Tmax on Day 1 (acute effect)
•
driving test after 1 or 2 weeks of treatment
(subchronic effect)
•
therapeutic doses ( 1 or 2 dose regimens)
•
active control to demonstrate sensitivity
-4 -2 0 2 4 6 8 10
Day 1 Day 7/8 Day 15
DOX DOX AMI AMI IMI MIA MIA MIA 25mg td 25 mg td 25 mg td 50+25mg 50 mg bd 10mg td 10mg td 10 / 20mg td 1.0 0.8 0.5
Equivalent effect
of BAC (mg/ml)
Δ
S
D
L
at
er
al
P
os
it
ion
(
cm
)
*
*
*
*
*
*
*
*
*
*
*
*
TCAs and mianserin
MOC FLU PAR PAR NEF NEF VENL VENL VOR ESC 200mg bd 20mg hs 20mg qam 40mg qam 100mg bd 200mg bd 37,5/75mg bd 37,5mg bd 10mg hs 10/20 mg hs 1.0 0.8 0.5
Equivalent effect
of BAC (mg/ml)
Δ
S
D
L
at
er
al
P
os
it
ion
(
cm
)
*
*
*
RIMAs, SSRIs, SARIs and SNRIs
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
Antidepressant effects
at P450 isozymes
CYP1A2 CYP2C19 CYP2D6 CYP2E1 CYP3A3/4
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=40)
18 23 28 33 38 B1 B2 1 3 6 Fluoxetine Moclobemide Treatment (wks) SD La tera l P o si ti o n (cm ) Ramaekers et al. 1997
Patients receiving BZDs and potential drug/drug
interaction at Cytochrome P450 enzymes
Fluoxetine (N=19) Moclobemide (N=22)
# patients Substrate for
isozyme 3A3/4
# patients Substrate for
isozyme 2C19 Nordiazepam Clotiazepam Bromazepam Alprazolam Oxazepam Lorazepam 2 - 4 3 3 3 No No Yes Yes No No 7 1 1 1 5 1 Yes Yes No No No No Total cases 15 6 16 8 Ramaekers et al. 1997
Treatment (wks) SD La tera l P o si ti o n (cm ) Ramaekers et al. 1997
Effects of combined antidepressant and BZD treatments
on driving performance of depressed outpatients
18 23 28 33 B 1 3 6 B 1 3 6 No comedication compatible BZD comedication incompatibele BZD comedication Fluoxetine Moclobemide
Effects of combined antidepressant and BZD treatments
on driving performance of depressed outpatients
-4 -2 0 2 4 6 8 10
Week 1 Week 3 Week 6
FLU FLU FLU MOC MOC MOC No BZD Comp BZD Inc BZD No BZD Comp BZD Inc BZD
1.0 0.8 0.5
Equivalent effect
of BAC (mg/ml)
Δ
S
D
L
at
er
al
P
os
it
ion
(
cm
)
*
*
*
*
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
-4 -2 0 2 4 6 8 10
Day 1 Day 7 / 8 Day 15 Day 22
Mirtazapine Mirtazapine Mirtazapine Mianserin Dothiepin
15 mg / 30mg hs 30 mg/ 45 mg hs 30 mg hs 30mg /60mg hs 75mg / 150mg hs 1.0 0.8 0.5
Equivalent effect
of BAC (mg/ml)
Δ
S
D
L
at
er
al
P
os
it
ion
(
cm
)
*
*
*
*
Driving after nocturnal doses of sedating
antidepressants
*
But even nocturnal doses can cause
“unexpected” residual impairment
• Poor vs Extensive metabolizers
Mianserin Mirtazapine Esmirtazapine maleate (enantiomer) H3C
Antidepressant
10 mg tid
Antidepressant
30-45 mg nocte
Insomnia?
1.5-4.5 mg nocte
CYP2D6 phenotyping
• Subjects received one tablet of dextromethorphan before bedtime • Excretion ratio dextrometorphan/dextrorphan was determined in morning urine • Poor metabolizers: excretion ratio >= 0.3 (N=7)
• Extensive metabolizers : excretion ratio < 0.3 (N=25)
-1,5 -0,5 0,5 1,5 2,5 3,5 4,5 Δ SD L P (cm )
ESM ESM ZOP ESM ESM 1.5 4.5 7.5 1.5 4.5
Single dose Multiple doses
Equivalent effect BAC 0.5 mg/mL Non inferiority margin * *
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 2.4 cm)
SDLP - overall
-4 -3 -2 -1 0 1 2 3 4 5 6 7 8 1 Equivalent effect BAC 1.0 mg/mL 0.8 mg/mL 0.5 mg/mL Non inferiority margin Poor metabolizers Extensive metabolizersSingle dose Multiple doses Single dose Multiple doses
Δ S DL P ( cm) * * * *
SDLP – CYP2D6
Do healthy volunteers studies apply
to depressed patients ?
Depressed patients are ill, and symptom
reduction by antidepressant treatment might
actually improve their driving capacity !
24 Depressed patients without antidepressants
24 Depressed patients with 6-52 weeks
antidepressants
24 Healthy controls
Characteristics:
• active depression (HAM<17)
• no antidepressants
• 21-65 years
• 5000 km/year past 3 years
• From previous study
(Ramaekers et al. 1997)
parallel groups
Study design (1)
24 Depressed patients without antidepressants
24 Depressed patients with 6-52 weeks antidepressants 24 Healthy controls Characteristics: • diagnosis depression (DSM-IV criteria) • receiving SSRI-type antidepressant for 6-52 weeks • 21-65 years
• 5000 km/year past 3 years
Study design (2)
24 Depressed patients without antidepressants
24 Depressed patients with 6-52 weeks antidepressants 24 Healthy controls Characteristics: • healthy, no medication • 21-65 years
• 5000 km/year past 3 years
•matched for age, gender, IQ
and driving experience
Study design (3)
parallel groups
Allowed SSRI- medication
•
Citalopram (Cipramil®): 20-60 mg/day
• Fluoxetine (Prozac®): 20-60 mg/day
• Paroxetine (Seroxat®): 20-50 mg/day
• Sertraline (Zoloft®): 50-200 mg/day
• Venlafaxine (Efexor®): 75-375 mg/day
• Fluvoxamine (Fevarin®): 100-300 mg/dag
17.9 20.3 24.0 5 10 15 20 25 30
*
***
Standard Deviation Lateral Position
+
Global driving ability scores of depressed patients
receiving AD treatment
Brunnauer et al, 2008
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.
• Novel 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
•Long acting, long-elimination half life
•Daytime use
•GABA agonists
•GABA, major inhibitory NT in CNS
•By definition, BZD anxiolytics must be very sedative
BZD anxiolytics
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)
A pharmacoepidemiological study in 78000 hypnotic
users, 148000 anxiolytic users and 98000 controls
Diazepam effects on SDLP in
anxiolytic patients
Van Laar, 1995 0 2 4 6 8 10 12 14 16 18 20 1 1 1 1 8 7 14 21 28 1 1 2 9 1 7 1 8 C h a n g e i n S D L P ( cm ) Day: Dose (mg): 5 10 5 5 15 20 20 20 0.5 0.5 1 1.5 2 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: 1 2 6 5 3 7 2 4 8 E quivalent effects of alcohol while BAC is 1.0 mg/ml 0.8 mg/ml 0.5 mg/ml diazepam lorazepam-2 0 2 4 6 8 10 12 14 16 18 1 181 8 7 14 21 28 11 1 11 18 29 11 1 C h a n g e i n S D L P ( cm ) Day:
Dose (mg): 5 1 1 4 4 15 20 20 20 5 10 5 10 50 0.2 1XR 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: 4 6 5 2 3 3 8 7 10 9 E quivalent effects of alcohol while BAC is 1.0 mg/ml 0.8 mg/ml 0.5 mg/ml
Other anxiolytics and SDLP
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 8 separate studies
Vermeeren et al, 2009
Actual driving in healthy volunteers after
immediate and controlled release formulations of
alprazolam 1mg (Leufkens et al 2007)
Subjects:
- 18 healthy subjects (9 males, 9 females) - Mean (±SE) age: 32.3 (±2.0) - Range 20-45
Design:
- Double blind, placebo-controlled, 3-way crossover study Treatments: - placebo - alprazolam IR 1 mg - alprazolam XR 1 mg time co n ce n tr ati o n alprazolam IR alprazolam XR
Tmax alprazolam IR: 0.7 – 1.8 hrs Tmax alprazolam XR: 5-12 hrs
alprazolam XR:
delayed absorption fewer and less severe side effects (Rickels, Expert Opin Pharmacother 2004)
Adapted from Wright, Curr Ther Res 1995
SDLP (4-5 hrs post dose)
15 20 25 30
placebo alprazolam XR alprazolam IR
Mean SDLP (cm)
Increment SDLP (cm)
from placebo +3.9 +8.2
*
*
Tests prematurely terminated 3 (out of 18) 7 (out of 18)
A case study: driving under the
influence of alprazolam (movie)
Δ S D LP (c m )
***
Equivalent effect of BAC (mg/ml) 1.0 0.8 0.5 0 2 4 6 8 10