Transcript Mood Stabilizers

Medications &
Your Mental &
Physical
Wellbeing
Your Name
Your affiliation
Meeting name
Location, Date
© Drs. Andrea Murphy and David Gardner, 2013, Permission for use granted to More Than Meds Trainees
Welcome
Lets get to know each other!
About Me
Why am I here?
What if you stump me?
Target symptoms
Combining meds
Herbals and other
Stigma natural options Benefits of Rx Duration
Meds & alcohol & Treatment options Meds & driving
and working
other substances Side effects
Switching Rx Non-med
Stopping
Rx
Cost
Coverage
options
Missing doses / running out Working with your
doctor(s) etc.
Tools and resources
WHAT CAN WE TALK ABOUT TODAY?
Mental health and physical health are linked
Antidepressants
SSRI
Citalopram
Escitalopram
Fluvoxamine
Fluoxetine
Paroxetine
Sertraline
SNRI
Duloxetine
Venlafaxine
Desvenlafaxine
NaSSA
Mirtazapine
NDRI
Bupropion
Others
Tricyclics
MAOIs
Moclobemide
Trazodone
Antipsychotics
Antianxiety/sedative
2nd Generation
Benzodiazepines
Aripiprazole
Asenapine
Clozapine
Lurasidone
Olanzapine
Quetiapine
Paliperidone
Risperidone
Ziprasidone
Alprazolam
Bromazepam
Clonazepam
Diazepam
Lorazepam
Nitrazepam
Oxazepam
Temazepam
Triazolam
1st Generation
Chlorpromazine
Flupenthixol
Fluphenazine
Haloperidol
Loxapine
Perphenazine
Pimozide
Trifluoperazine
Zuclopenthixol
Others
Buspirone
Zopiclone
Zolpidem
Mood Stabilizers
Carbamazepine
Lamotrigine
Lithium
Oxcarbazepine
Topiramate
Valproic acid
(divalproex)
Other
Folic acid
Niacin
Omega-3 fish oils
SAMe
St. John’s wort
Valerian
Side Effect
modifiers
Stimulants
Amphetamine
mixed salts
Dextroamphetamine
Lisdexamfetamine
Methylphenidate
Modafinil
Others
Atomoxetine
Benztropine
Metformin
Propranolol
Tetrabenazine
Antidepressants
Antipsychotics
Mood Stabilizers
Sleeping pills
Q&A
Heart & Diabetes
meds
Stimulants
Side effect meds
Pain meds
Q&A
Antidepressants
SSRI
Citalopram
Escitalopram
Fluoxetine
Paroxetine
Sertraline
Celexa
Cipralex
Prozac
Paxil
Zoloft
Antidepressant
s
Benefits of treatment
Side effects, precautions, warnings
Cymbalta
SNRI
Effexor
Duloxetine
Pristiq
Venlafaxine
Desvenlafaxine
Remeron
NaSSA
Mirtazapine
Target symptoms
Duration of treatment
Adherence
Starting, combining, switching, stopping treatment
Alcohol & other substances
Wellbutrin
Herbal and other natural options
Non-medication options
Cost, insurance coverage
NDRI
Bupropion
Others
Tricyclics
MAOIs
Information tools & resources
Working with your doctor
Folic acid
St John’s wort
Antipsychotics
2nd Generation
Aripiprazole Abilify
Asenapine Saphris
Clozapine Clozaril
Lurasidone Latuda
Olanzapine Zyprexa
Quetiapine Seroquel
Paliperidone Invega
Risperidone Risperdal
Ziprasidone Zeldox
Q&A
Antipsychotics
Benefits of treatment
Side effects, precautions, warnings
Target symptoms
Duration of treatment
Starting, combining, switching, stopping treatment
Adherence
Largactil
Fluanxol
Modecate
1st Generation
Haldol
Chlorpromazine Loxapac
Trilafon
Flupenthixol
Fluphenazine Orap
Stelazine
Haloperidol
Clopixol
Loxapine
Perphenazine
Stigma
Alcohol & other substances
Natural options
Non-medication options
Cost, insurance coverage
Information tools & resources
Working with your doctor
Q&A
Sedative-hypnotics
Benzodiazepines
Alprazolam
Bromazepam
Clonazepam
Diazepam
Lorazepam
Nitrazepam
Oxazepam
Temazepam
Triazolam
Xanax
Rivotril
Valium
Ativan
Serax
Restoril
Halicion
SedativeHypnotics
Benefits of treatment
Side effects, precautions, warnings
Duration of treatment
Mixing with other medications, alcohol, etc.
Stopping
Many
Natural options
Non-medication options
Others
Diphenhydramine
Melatonin
Valerian
Zopiclone
Zolpidem
Imovane
Sublinox
Cost, insurance coverage
Information tools & resources
Working with your doctor and other health providers
Mood Stabilizers
Carbamazepine
Lamotrigine
Lithium
Oxcarbazepine
Valproic acid
(divalproex)
Tegretol
Lamictal
Trileptal
Epival
Omega-3 fatty acids
Q&A
Mood stabilizers
Treating different phases of treatment
Benefits of treatment
Side effects, precautions, warnings
Target symptoms
Duration of treatment
Starting , combining, switching, stopping treatment
Adherence
Stigma
Alcohol & other substances
Natural options
Non-medication options
Cost, insurance coverage
Information tools & resources
Working with your doctor
Stimulants & other ADHD
medications
Stimulants
Amphetamine
mixed salts
D-amphetamine
Lisdexamfetamine
Methylphenidate
Modafinil
Other
Atomoxetine
Clonidine
Adderall
Dexedrine
Vyvanse
Ritalin, …
Stimulants & other
ADHD
medications
Benefits of treatment
Side effects, precautions, warnings
Strattera
Target symptoms
Onset and duration of effect
Starting , combining, switching, stopping treatment
Adherence
Stigma
Cost, insurance coverage
Information tools & resources
Working with your doctor
http://morethanmeds.com
RECOMMENDED RESOURCES
http://medicationinfoshare.com
RECOMMENDED RESOURCES
A middle aged woman with
persistent insomnia is guided
BY HER PHARMACIST to an
effective online, evidencebased cognitive-behavioural
therapy program for chronic
insomnia. In 6 weeks she is
having restful, revitalizing
sleeps, the best she’s had in
years.
She’s much less stressed and
fatigued.
http://medicationinfoshare.com
Links We Like
Medications & Your Mental & Physical Wellbeing
Thank-you!
www.morethanmeds.com
www.facebook.com/CommunityPharmacyIsMoreThanMed
s
@medinfoshare
Additional content follows
Antidepressants and related
content
Foundations
Antidepressant for Major Depressive Episodes
The more severe the depressive
episode, the more the scale tips in
favour of using an antidepressant.
Switching and augmenting
antidepressants is usually safe,
except when it isn’t.
Antidepressants are more effective
for anxiety disorders than for
depression. For bipolar depression,
fuggeddaboudit.
Selecting an antidepressant is much
more about the process and less
about the decision.
At first try, the chance for achieving
remission of depression is < 50%.
For depression, antidepressants are
better at keeping people well vs.
getting them well.
(NNTKeep well < NNT Get well )
Early non-adherence is substantial
and can be mitigated.
http://medicationinfoshare.com
http://medicationinfoshare.com
Folic Acid for Depression
Women only?
DB, RCT, 10 weeks
Major depressive episode, 43±13 y.o.
Treatment
(fluoxetine + …)
Response rate
Absolute
difference
-3%
Men
Folic acid
61%
n=40
Placebo
64%
Women
Folic acid
94%
+33%
n=69
Placebo
61%
(p<0.005)
NNT=3
Fluoxetine 20 mg/day
Folic acid 0.5 mg/day
Coppen & Bailey. J Affective Dis 2000; 60: 121-30.
Support, Educate, & Plans
Expect more than meds from your pharmacist.
Antipsychotics and related
content
Mortality in Schizophrenia
Schizophrenia is a “life-shortening disease”
Life expectancy = schizophrenia – general population
= -9 to -12 years
De Hert et al. World Psychiatry 2011
Excess Mortality in Schizophrenia
Systematic review of mortality in schizophrenia
K=37
Countries: 25
Deaths: 22,296
2/3 Excess
Natural Causes SMRs
4.2
Respiratory
3.2
Endocrine
2.6
Schizophrenia mortality
Digestive
2.4
2-3x general population
CVD
1.8
Neoplastic
1.4
SMR 2.6
Overall
2.4
(M 3.0 F 2.4)
Compared to 1.8 with diabetes in NS
1/3 Excess
Unnatural Causes SMRs
Suicide
Saha et al. Arch Gen Psychiatry 2007
12.9
Accident
1.7
Overall
7.5
Double the rate of common causes of death.
2-13 times the rate of rare causes of death
Nervous
Prevalence of cardiometabolic risk factors in
schizophrenia
Modifiable risk factors
Diabetes
Prevalence
Relative risk
10-15%
>2
Obesity
45-55%
1.5-2
Smoking
50-80%
2-3
Hypertension
19-58%
2-3
Dyslipidemia
25-69%
≤5
Metabolic Syndrome
37-63%
2-3
Are you DRP
seeking?
De Hert et al. European Psychiatry 2009
Chance for benefiting with clozapine vs. other
antipsychotics when switching between antipsychotics
(my evidence/experience informed impression)
Undesirable
response
Desirable
response
Clinically Relevant Pharmacokinetics
Plasma halflife [metab]
h
Aripiprazole
75 [96]
Asenapine
24
Clozapine
Haloperidol
Loxapine
F
87
35% sl
2% po
Elimination
2D6, 3A4
Potent
inhibitor of:
Other
--
40% of AUC is metab at SS. PMs have 60% 
AUC & t1/2=150 hrs. Drug levels double with
2D6 inhibitors
UGT1A4>>CYP1A2
Sublingual admin.
5-16
~50
1A2 (metab: 2D6,3A4,
12-36*
~60
1A2, 2D6, 3A4
2D6
8-30
33
1A2, 2D6, 3A4
--
2C9, 2C19)
--
1A2 inducers (smoking) reduce CLZ levels.
Smk cessation  levels of CLZ 50%
 levels 2-4 fold in PMs
F = oral bioavailability * CSF half-life is significantly longer than plasma half-life PM: poor metabolizer SS: steady state AUC:
area under the curve (a measure of total body concentration of drug)
Meyer JM. Goodman & Gilman text, 2011.
Clinically Relevant Pharmacokinetics cont’d
Plasma halflife [metab]
h
F
Elimination
Potent
inhibitor of:
Other
Olanzapine
21-54
~65
1A2, 2D6, 2C9,
2C19
--
Paliperidone
23
28
60% renal
--
Perphenazine
9-21
25
2D6
2D6
Quetiapine
6-7 [12]
10
3A4
--
Potent 3A4 inhibitor can triple QTP levels
Risperidone
20-24
~70
2D6
--
Potent 2D6 inh’s  active components 75%.
Reduce dose if renal imp’t (<50%)
Ziprasidone
6-7
30% fasting
60% fed
3A4
--
500 kcal meal req’d for optimal F
Dose adjust if renal impairment (<75%)
F = oral bioavailability * CSF half-life is significantly longer than plasma half-life PM: poor metabolizer SS: steady state AUC:
area under the curve (a measure of total body concentration of drug)
Meyer JM. Goodman & Gilman text, 2011.
• Comprehensive
“monitoring” resource
– All adverse effects
• To support:
– Knowledge transfer regarding
antipsychotic adverse effects
– Treatment selection:
differentiate antipsychotics
based on AEs
– Treatment monitoring of APD
AEs
Atypical antipsychotics
Simplified adverse effect comparison
CV risk factors, weight
gain, dyslipidemia,
diabetes risk
Olanzapine
Clozapine
Risperidone
Quetiapine
Paliperidone
Ziprasidone
Aripiprazole
D2 potency:
EPS, sexual dysfunction,
galactorrhea, gynecomastia,
amenorrhea
Risperidone
Paliperidone
Olanzapine
Ziprasidone
Aripiprazole
Quetiapine
Clozapine
Tardive Dyskinesia
• An often irreversible involuntary movement disorder resulting from
long-term exposure to D2 blocking agents
• involves face (lip smacking, puckering, tongue protrusions, puffing,
frowning), hands & arms (choreoathetoid movements), feet, trunk
(writhing movements)
• 4-5%/year with conventional antipsychotics
• significantly less with novel agents
• risk increases with:
– dose, D2 potency, age (older), gender (female), intermittent use pattern,
mood disorders
• treatment:
– no antidotes
– switch to low risk medication (e.g., novel APs)
Estimated Annual Incidence of Tardive
Dyskinesia with Atypicals
Atypicals N=2,769
Similar patient
populations
(adults)
408
Correll et al, Am J Psychiatry 2004
Neuroleptic malignant syndrome
•
A rare but potentially life-threatening adverse effect associated with ALL
antipsychotics. High potency agents may afford higher risk.
Clinical Features:

hyperthermia

autonomic instability

altered mental status

muscular hypertonicity (rhabdomyolysis, very high CK)
Not a prominent
feature with NMS
related to atypicals
Management:
1. stop antipsychotic agent
2. supportive measures (most often requires treatment in an Intensive Care Unit)
3. monitor vital signs
4. if no improvement, pharmacological treatment: dantrolene and/or
bromocriptine
Standard overlap method
Methods of
Switching
1st antipsychotic
2nd antipsychotic
Extended overlap method
Days
1st antipsychotic
Weeks
2nd
antipsychotic
Abrupt washout method
Days
Weeks
1st antipsychotic
2nd antipsychotic
Days
Weeks
Switching antipsychotics: tools
For patient-specific guidance on switching visit
http://switchrx.ca and
http://wiki.psychiatrienet.nl/index.php/SwitchAntipsychotics
Co-medications
•
•
•
•
Benzodiazepines
– lorazepam, clonazepam
– multiple benefits:
• agitation, akathisia, anxiety, insomnia, tremor
Anticholinergics (benztropine, procyclidine, …)
– affects balance between dopamine and cholinergic activity in
nigrostriatal pathway
• Rx of parkinsonism (not akathisia)
Beta-blockers
– propranolol
• treatment of AP-induced akathisia, tremor
Others
– Metformin (weight management), statins (CV risk), psychostimulants
(sedation), sildenafil (impotence), sunscreen (phenothiazines,
thioxanthenes), etc.
Omega-3 for Psychosis mitigation
EPA 700 mg/d DHA 480 mg/d (other PUFA 220 mg/d)
Patients: Ultra-high risk for psychotic disorder (no AP or MS Rx)
Duration: 12 wks omega-3 then 40 wks follow-up
Design: DB, RCT n=81
Primary outcome: progression to psychotic disorder
Change in Total Symptoms
Age: 16.5 ± 2.0 y.o.
Change in Negative Symptoms
Amminger et al. Arch Gen Psychiatry 2010 (Feb)
Omega-3 for Psychosis mitigation
EPA 700 mg/d DHA 480 mg/d (other PUFA 220 mg/d)
Progression to a Psychotic Disorder
Progression to psychotic disorder:
Omega-3:
2/40 (
5.0%)
Placebo:
NNT = 4.4 (95% CI: 11/40
3 to 16)
(27.5%)
Amminger et al. Arch Gen Psychiatry 2010 (Feb)
Mood stabilizers and related
content
Bipolar disorder is a cyclical disorder with recurrent and irregular
fluctuations in mood, energy, and behavior encompassing the extremes of
human experiences.
Treatment
Prevention
Treatment
mania
hypomania
euthymia
depression
mixed
The previous slide is a gross over-simplification …
“Clinically, in particular phenomenologically, the fact that
bipolar disorder merges at its margins with schizophrenia,
borderline personality disorder, attention-deficit
hyperactivity disorder, and its most immediate neighbor,
major depression, has meant that tremendous effort has
been directed at defining the illness and, by doing so,
defining its therapeutic territory – but, alas, a solution is
not on the horizon.”
Malhi GS. Bipolar Disord 2013; 15: 54-7.
Bipolar Disorder
Psychiatric and Medical Comorbidities
Comorbidity
Mean Rate
Range
Any Axis I
disorder
65%
50 – 70%
Substance use
disorder
56%
34 – 60%
Alcohol abuse
49%
Other drug abuse
Mean Rate
Range
OCD
10%
2 – 21%
Binge-eating
disorder
13%
30 – 69%
Personality
disorder
36%
29 – 38%
44%
14 – 60%
Migraine
28%
15 – 40%
Anxiety disorder
71%
49 – 92%
Overweight
58%
Social phobia
47%
Obesity
21%
PTSD
39%
Type 2 diabetes
10%
Panic disorder
11%
Hypothyroidism
9%
3 – 21%
Comorbidity
Krishnan. Psychosom Med Jan 2005
Pharmacotherapy of BD
The Ideal Mood Stabilizer
Efficacy
Other characteristics
•
•
•
•
•
•
•
•
•
Antimanic
Antidepressant
Relapse prevention
Anti-suicidal
Reduced mortality
Tolerable
Safe
Convenient
Accessible
The Benefits of Mood Stabilizers (patients
should know this at least):
Mood stabilizers can:
• halt the turbulent course of
bipolar disorder
• significantly decrease the risk
for suicide (lithium)
• increase life expectancy
• increase productivity and
functioning
Prognosis:
• is improved by medication
adherence
• 40-75% of responders to mood
stabilizers become gainfully
employed & live independently
Consequences of stopping
medication:
• risk for suicide returns (lithium)
• early relapse, worse course of
illness, rehospitalization
• personal losses (job, family, future
plans)
Management of illness is made easier
by:
• good, regular sleep habits
• avoiding excessive caffeine,
nicotine, other stimulants
• avoiding alcohol, other substances
of abuse
• adherence to medications
Association between
adherence, plasma
levels, and hospital
admissions
Patients were categorized
by group prior to 18 mo.
follow-up.
Scott & Pope. Am J Psych 2002
Effect of the rate of discontinuation of effective
lithium treatment on relapse risk
N=59
N=85
p<0.0001
Baldessarini et al 1997
Treatment Paradigms:
Bipolar depression:
Mood stabilizer (MS)  antidepressant?
Atypical antipsychotic (QTP)
Euthymia (maintenance therapy)
MS alone or MS combination
MS + benzodiazepine (BZP)  antipsychotic (AP)
Hypomania
Increase MS dose, often add BZP (e.g., clonazepam), AP
Mania/Mixed
MS + AP + BZP (plus “side effect medications i.e., anti-cholinergics, beta-blockers)
ECT
See CANMAT Guidelines
Drug
Place in therapy Dosing
(mg/day)
Serum levels
Adverse effects
Lithium
Mania/hypomani
a
Maintenance
Depression
Rx & Px: 0.8-1.1
Geriatrics: 0.40.6
mmol/L
cog. imp’t, tremor,
acne, psoriasis,
polydipsia/uria, edema,
weakness, wt gain,
thyroid dysfxn, renal
dysfxn, teratogen
Toxicity: irr. brain
damage or death with
moderate overdoses
900-1800
Rx: acute treatment; BD depression: bipolar depression; Px: prophylactic treatment; Classical: mania then depression
then euthymia; BD: bipolar disorder; mixed: mixed episode with symptoms of mania and depression; RC: rapid cyclers
(4/yr); SA: comorbid substance abuse (alcohol, street drugs); 2nd BD: secondary bipolar disorder (medical or
neurological etiology, eg. closed head injury, chronic CNS infection (HIV)); LD: loading dose approach; cog imp’t:
cognitive impairment; GI: gastrointestinal; N: nausea; D: diarrhea; DR: dose related; LEs: liver enzymes (AST, ALT); Tx:
treatment; bv: blurred vision
Drug
Place in therapy
Dosing
(mg/day)
Serum levels
Adverse effects
Valproate
(divalproex,
valproic
acid)
Mania/hypoma
nia
Maintenance
Depression?
750-1750
350-700
mol/L
GI (N, D)(DR), sedation
(DR),
thrombocytopenia
(DR), leukopenia (DR),
LEs, hair loss, wt
gain, teratogen,
encephalopathy(hyper
ammonianemia)
Drug
Place in
therapy
Dosing
(mg/day)
Serum levels
Adverse effects
Lamotrigine
Maintenance
Depression
75-250
n/a
dizziness, ataxia,
sedation, headache,
diplopia, bv, N, V,
rash, serious rash
[LAM] with VPA
[LAM] with enzyme
inducers
? 34-50
mol/L
sedation, cog. imp’t,
WBC, GI distress,
dizziness, rash,
LEs, wt gain
Carbama- Mania/hypom 600-1200
zepine
ania
Maintenance
Depression?
Pharmacokinetics:
Lithium:
• renal clearance, no PB, linear kinetics, narrow therapeutic to
toxic ratio
Valproate:
• hepatic clearance, interesting kinetics, enzyme inhibitor (rule of
thumb), wide therapeutic to toxic ratio
Carbamazepine:
• hepatic clearance, auto-inducer (watch for PK interactions)
Lamotrigine:
• Hepatic clearance via glucuronidation (mean t½ 25 hrs alone,
70 hours with VPA)
Drug, Diet and Fluid Interactions with Standard Mood Stabilizers:
Lithium
[Li]: NSAIDs (ASA safe), COX-2 inhibitors
thiazide diuretics
indapamide (furosemide safer)
ACE inhibitors, ARBs
• if any of the above medications are required,  lithium x 50% prior to starting therapy then adjust
doses based on levels taken in 2-3 days
• adjust the dose based on levels 2-5 days after starting any of the above medications
Diet: large changes in Na+ (salt) intake can affect Li+ levels. A large decrease in Na intake
(eg.prescribed Low Na diet) can [Li] significantly.
Fluid: fluid and electrolyte balance affect [Li]:
[Li]: net water loss including, dehydration (V, D, fever), major surgery, diuresis, mammoth
exercising, renal dysfunction
Hold lithium for several days during acute illness
Lab Monitoring
Baseline
Labs
Levels
Lithium
electrolytes, TSH,
renal function (SCr,
urea), ECG (45 yo)
TSH, SCr q612 mo. and
ACI
Critical to monitor
Adults: 0.8-1.1 mmol/L
Elderly: 0.4-0.6 mmol/L
Valproate
CBC (PLT, WBC), liver Ditto at 1 & 3
fxn (AST, ALT)
mo. and ACI
To assess adherence.
Range: 350-700 ųmol/L
Not well correlated with
outcome-dose by clinical findings
Carbamaze
pine
CBC (WBC),
electrolytes (Na+ SIADH)
Ditto at 1 & 3
mo. and ACI
To assess adherence.
Range: 17-50 mmol/L
Not well correlated with
outcome-dose by clinical findings
Lamotrigin
e
Liver fxn (AST/ALT)
--
N/A
Quetiapine for Bipolar Depression:
Results
Response Rate
Response Time (median)
Quetiapine 600: 58% *
Quetiapine 600: 22 d *
Quetiapine 300: 58% *
Quetiapine 300: 22 d *
Placebo:
Placebo:
36%
Remission Rate
36 d
Remission Time (median)
Quetiapine 600: 53% *
Quetiapine 600: 27 d *
Quetiapine 300: 53% *
Quetiapine 300: 29 d *
Placebo:
Placebo:
28%
* p<0.001, ITT LOCF vs. placebo
65 d
Calabrese et al. Am J Psychiatry 2005
Sedatives & Hypnotics
Anxiolytics
Useful drugs include:
• benzodiazepines - for acute and short-term indications
• antidepressants - TCAs, SNRIs, SSRIs - for longer term
treatment
• buspirone - for longer term treatment of Generalized Anxiety
Disorder (GAD)
• Antipsychotics: augmentation (OCD; GAD?)
Effect size vs. placebo in GAD
Hidalgo et al. J Psychopharm 2007
Effect Size: Active vs. Active in
GAD
Effect size
Venlafaxine
Buspirone
0.20
Venlafaxine
Diazepam
0.07
Hydroxyzine
Buspirone
0.26
Pregabalin
Lorazepam
0.16
0.22
Hidalgo et al. J Psychopharm 2007
All clinicians (incl. pharmacist) should do a sleep
assessment and discuss Sleep Hygeine
Therapeutic
Choices
e-Therapeutics
Benzodiazepines
Short acting
 Alprazolam
 Oxazepam
 Triazolam
Intermediate acting
 Clonazepam
 Lorazepam
 Temazepam
Long acting
 Chlordiazepoxide
 Diazepam
 Flurazepam
Differentiating the BZPs:
Clinical Applications
General indications:
anxiety
insomnia
phobias
panic attacks
hypo/mania
epilepsy
preop anaesthesia alcohol withdrawal
chemo-related emesis
muscle relaxant
Panic Disorder: alprazolam, clonazepam, lorazepam
Hypo/mania: lorazepam, clonazepam
Status epilepticus: IV diazepam
Myoclonic epilepsy: clonazepam, clorazepate
Alcohol withdrawal: diazepam, chlordiazepoxide
Muscle relaxant: diazepam
Antidepressant: alprazolam
Differentiating the BZPs:
Pharmacokinetics
PK Parameter
• onset
Clinical Correlates:
• hypnotic utility
• abuse potential
•
lipophilicity
•
•
duration of effect
onset/offset of effect
•
half-life
•
•
•
dosing frequency
risk for accumulation
withrawal syndrome
•
hepatic metabolism/ active
metabolistes
•
special populations: elderly, hepatic
impairment
•
•
interchanging agents
withdrawal syndrome
•
potency
Benzodiazepine:
Side Effects & Toxicity
Side Effects:
• sedation
• dizziness, weakness, ataxia
• psychomotor impairment
• cognitive impairment
• retrograde amnesia
• nausea, slight hypotension
Traffic accidents:
Special Populations:
OR = 2-5
• behavior dyscontrol
• falls: elderly
• resiratory suppression: apnea
Toxicity:
• very safe in mono-substance ODs.
• enhance toxicity of other CNS depressants in multi-drug ODs (eg. alcohol, TCAs, barbs)
Benzodiazepine Issues:
Overuse, misuse, abuse
BZP use in general population:
“in past year”: 8%
“for > 1 year”: 2%
Risk Factors for Abuse/Misuse:
People factors
- multiple drug abuse
- alcohol abuse
- ‘need’ for large doses
- recent abrupt BZP d/c
Drug factors
- rapid onset
- rapid offset
- euphoriant effects
Specific agents:
Triazolam: rapid onset/offset, euphoriant
Alprazolam: rapid offset, sig. withdrawal effects
Diazepam: most rapid onset, euphoriant
Benzodiazepine Issues
Adverse behavioral effects
Incidence: < 1%
Description:
• hostility
• aggressiveness
• rage reactions
• paroxysmal excitement
• irritability
• behavioral dyscontrol
Risk factors:
• not predictive (eg. pre-existing conduct disorder, aggressiveness)
• children, MR, ADHD
Benzodiazepine Issues:
Physical Dependence/Withdrawal
Symptoms of the BZP Withdrawal Syndrome:
GI distress
diaphoresis
tremor
lethargy
dizziness headache
increased sensory acuity (hearing, visual)
restlessness
insomnia irritability
anxiety
tinnitus
depersonalization
seizure
psychosisdelirium
Risk Factors:
• short-acting agents (T1/2)
• magnitude of daily dose
• duration of use
• rate of discontinuation taper
• dependent personality
Benzodiazepine Issues:
Stopping Treatment
How and When To Taper:
• short-duration, high dose, short-intermediate acting BZP
• long-duration, any dose, any BZP
daily dose
Quartiles:
100-75%: fast
75-25%: slow
25-0%: very slow
> 6 weeks
Fundamentals for a successful taper:
•asymptotic taper (decrease doses by 10-20% of current dose q3-7 days)
•flexible schedule
•patient involvement in drafting the taper schedule
•adequate duration of > 6 weeks
•have a treatment plan for emergence of symptom
•switch to long-acting BZP prior to taper (e.g. clonazepam or diazepam)
Comparison of Antidepressant and Benzodiazepine Use in Nova Scotia,
Canada and Australia from 2000 through 2003
160
140
DDDs/1000 beneficiaries/day
120
100
80
NS All Benzos
NS All Antidepressants
Oz All Benzos
60
Oz All Antidepressants
40
20
0
2000
2001
2002
2003
Year
Smith et al. A comparison of benzodiazepine use in Nova
Scotia, Canada and Australia. Can J Psychiatry 2008.