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7/27/2019 IPS 2012 - Psychiatry for PCP
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7/27/2019 IPS 2012 - Psychiatry for PCP
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Course Faculty
IPS 2012
Course 10
Psychopharmacology for Primary Care Providers and Other Non-Psychiatrists
Ronald J . Diamond, M.D.
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SATURDAY, OCTOBER 6, 2012
9:00 AM-4:00 PM
COURSE 10
PSYCHOPHARMACOLOGY FOR PRIMARY CARE PROVIDERS AND OTHER NON-
PSYCHIATRISTS
EDUCATIONAL OBJECTIVES:
At the conclusion of this session, the participant should be able to: 1) Understand themajor classes of psychiatric medication and how each can be used more effectively; 2)Develop target symptoms to follow the effectiveness of prescribed medication and 3)Balance risks and benefits and have a better understanding of how to optimize benefitswhile decreasing side effect burden.
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Proposed Agenda--subject to change based on audience interest:
Instant Psychopharmacology
9-9:45 Introduction to Psychopharmacology
9:45-10:45 Antipsychotic Meds
10:45-11 Break
11-12 Antidepressant Meds
12-1 Lunch
1-2 Mood stabilizers
2-3 Treatment of anxiety and insomnia
3-3:15 break
3:15-4 Medication with a person with borderline personality disorder
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Introduction to Psychopharmacology
Ronald J Diamond M.D.
diamond@wisc.edu
Rev 9/12
1
Instant Psychopharmacology
9-9:45 Introduction to
Psychopharmacology
9:45-10:45 Antipsychotic Meds
10:45-11 Break
11-12 Antidepressant Meds
12-1 Lunch
1-2 Mood stabilizers
2-3 Treatment of anxiety and insomnia
3-3:15 break
3:15-4 Medication with a person with borderline
personality disorder
The Rules of the Game
There are only four major classes of medications.AntipsychoticsAntidepressantsMood stabilizersSedative- hypnoticsMiscellaneous
Instant Psychopharmacology:
An Introduction to Psychiatric Medications
Same Dose = Same Serum Level
Frankie et al. Psych opharmacology Berl. Occupancy of dopamine D2 receptors by the atypical antipsychotic
drugs risperidone and olanzapine: theoretical implications 200 4: 175: 473- 480
Before starting any medication
Make a diagnosis first Obtain a careful medication history Develop target symptoms Adjust medication to target symptoms Actively look for side effects
Why take any medication?
To get better Because someone else wants us to
Because we are forced to take it
What do we mean by getting better?
Feel better Decrease symptoms Increase function Increase stability/stay out of hospital Improve subjective sense of well-being Improve quality of life
7/27/2019 IPS 2012 - Psychiatry for PCP
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Introduction to Psychopharmacology
Ronald J Diamond M.D.
diamond@wisc.edu
Rev 9/12
2
All medication has risks
Balance potential benefits Vs risksWhat risks or benefits are most importantQuestion of valuesWho gets to decide
When is a riskworth itWhat is the risk of NOT taking medication
Think about side effects from the clients
point of view
How much weight
gain would you
tolerate from a
medication
How much weight gain should a patient withschizophrenia tolerate from a medication that seems
to be helping?
The message is critical: What is the
good patient supposed to do?
Take an active role, or wait for meds to work? Adjust to current life, or actively change life? Instead of therapy, or with therapy
Need to develop target list
What is the target of the medication: whatbehavior/feeling or experience do we hope will
change?
What is the consumer hoping medication will doWhat are others hoping medication will do
Must be detailed, specific and concrete Based on observable behavior
Some targets better indicators of
medication effects than others
Intrusiveness of beliefs will change more thanbeliefs will change
Distress causes by voices will change even ifvoices do not go away
Decrease in suicidal ideation may be morelikely than complete absence
Improved behavior may occur beforeimprovement in subjective sense of mood
Where is medication effective, and
where not?
Panic frequency may decrease with medication,but the associated agoraphobia and anticipatory
anxiety requires behavioral therapy
Medication may help mood stability in someonewith bipolar, but listing of early warning signs,
risk situations, behavioral ways to support stability
are all important
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Introduction to Psychopharmacology
Ronald J Diamond M.D.
diamond@wisc.edu
Rev 9/12
3
Things that interfere with medication
working
Consumer not taking it Dose not correct Not taking it for long enough Substance use Medical illness Diagnosis incorrect Unrealistic expectations of what medication is
able to do
Medications do not work for everyone
Increase in Magnitude of Placebo Response in
Clinical Trials of Schizophrenia since 1993
Kinon, Potts and Watson 2011
Taking medication regularly
Medications only have a chance of working if they
are taken regularly: and most are not!!!
Non-compliance rates for common illness:
Arthritis 55-71 %
Bipolar 20-57%
Diabetes 19-80%
Hypertension 50% drop out at 1 year
Efficacy Vs Effectiveness
Efficacy: in controlled settings does it work Effectiveness: In the real world does it work
Effectiveness = Efficacy + tolerability + ease of use +
cost + willingness to take the medication
Health beliefs
How do we decide the nature of a problemDo we believe this problem is illness?Do we all agree on this definition of problem?
Is this the kind of problem that will respond tomedication?
Is there some part of the problem that mightrespond to mediation?
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Introduction to Psychopharmacology
Ronald J Diamond M.D.
diamond@wisc.edu
Rev 9/12
4
Beliefs about the problem
Why is John not working?
Lazy Unmotivated Stupid Unskilled Waiting Stressed out Pre-occupied
Looking for work
In school
Ill
Disabled
Alcoholic
Laid off
Wealthy-doesnt need to
Why is this person hearing voices?
Spiritual Parapsychological Normal (doesnt everyone) Neurological Symptom of stress or PTSD Drug related Caused by someone or something else Voices are real Mental illness--symptom of psychosis
What does it mean to take medications
Ill Disabled Dependent Damaged
Has a right to services
Limits are justified
Not your fault
Problem is real
Something can be
done/can be fixed
I Using medication as a tool to recovery
What is the problem that the consumer wantshelp with?
How has this problem interfered in thepersons life
How big is the problem
Modified from Pat Deegan
Using medication as a tool to recovery
Medication is something the consumer can doto take more control over his or her own life
Medication can make one feel dependent, out ofcontrol, or help to regain more control
Does it feel that it is something the consumer isdoing, or something being done to the
consumer
Modified from Pat Deegan
II Using medication as a tool to recovery
What else has the person tried to deal with this
problem
How much does the consumer want helpwith it
What will happen if this gets better?What will happen if this does not get better?
Modified from Pat Deegan
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Introduction to Psychopharmacology
Ronald J Diamond M.D.
diamond@wisc.edu
Rev 9/12
5
III Using medication as a tool to recovery
How might medication help with this problem
specific and concrete target goals for medication how would the consumer know medication is
helping
how would the consumer know that themedication is making things worse
how would other people know How long a time is reasonable to wait to see
Modified from Pat Deegan
IV Using medication as a tool to recovery
What else can the consumer do along with the
medication
What else does the consumer want from others,
along with the medication
Modified from Pat Deegan
Need for collaborative participation in
medication decisions
Consumers, psychiatrists, and other clinicianscan all learn how to facilitate this collaboration
Consumers can learn how to talk to theirpsychiatrist
Bring a friend or support personWrite down the most important questionsrole play the appointment
Medication can help make other
treatment more effective
Cognitive behavioral therapy Skill training Vocational training AODA treatment
Part of Wellness
Exercise Healthy good Sleep Activities and structure Friends
If the medication does not work
Is the diagnosis correct? Has a medical illness gone unrecognized? Has the dose been high enough for a longenough period of time? Is substance abuse interfering? Is the person taking the medication?
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Antipsychotic Medications
Ronald J Diamond M.D.
diamond@wisc.edu
Rev 9/12
1
Four out of five doctors
recommend. . .
Antipsychotic
Medications
Ron Diamond
diamond@wisc.edu
Relapse Rate on Placebo: Schizophrenia
MonthsCumulativePercentUnrelapsed
0!
20
40
60
80
100!
2!
4!
6!
8!
10
!12
!14
!16
!18
!22
!24
!
Prien, Cole and Belkin, 1969
8% Relapse / month over 24 months
Evidence Based Practice (Modified from
PORT Recommendations)
Family psycho-education ACT and Clubhouse psychosocial programs Integrated supported work programs Skill training Integrated Mental Health and AODA
Treatment
Cognitive Behavioral Therapy Cognitive RemediationDixon L, et al. Schizophr Bull. 2010;36:48-70.
Clubhouse not part of current PORT recommendations
Race and Ethnicity: CYP2D6
Cultural Issues in Medication Response
Smoking 45% of Egyptians smoke
Ave cig 1201 in egypt Greece 3230 Norway 739Caffeine; people from middle east prefer tea
rather than coffee
Tarek A. Okasha Egypt
Improvement Per Week
0%
2%
4%
6%
8%
10%
12%
14%
16%
18%
week 1 week 2 week 3 week 4
BPRS/PANSS
Core-Psychotic Symptoms
Agid et al Arch Gen Psych 2003
Meta-analysis of
114 trials with >
8000 patients
Refractory patients
and acute
emergency patientsexcluded
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Antipsychotic Medications
Ronald J Diamond M.D.
diamond@wisc.edu
Rev 9/12
2
Increase in Magnitude of Placebo Response in
Clinical Trials of Schizophrenia since 1993
Kinon, Potts and Watson 2011
Antipsychotic Dose-Response Curve
Clinical Response Curve
Toxicity Curve
Therapeutic window
Dose/Plasma level of antipsychotic medication
Antipsychotic Medications: Indications
Schizophrenia: + positive symptoms? Negative symptoms
? Cognitive dysfunction
Depression + psychotic depression? Some (quetiapine)
Bipolar disorder + antimanic + mood stabilizer (some) OCD Autism related behaviors Aggression
Antipsychotic Medications: other uses
(NOT FDA indicated)
Psychosis associated with dementia Black Boxwarning!
Borderline Personality Disorder Conduct disorder/childhood aggression Anti-anxiety Hiccups Nausea
Nigrostriatal
EPS
Infundibular
Prolactin elevation
Dopamine Pathways
Mesolimbic
psychosis
Mesocortical
Negative and
cognitive sx
Serotonin-Dopamine Receptor Blockers
Dopamine
Neuron
Serotonin
neuron
Blocking both serotonin and dopamine increases release of
dopamine some of which is then blocked at the dopamine receptor
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Antipsychotic Medications
Ronald J Diamond M.D.
diamond@wisc.edu
Rev 9/12
3
Clinical effects of various serotonin (5-HT) sub-receptors
5-HT 2A antagonism Increases dopamine release Decreases EPS Improves negative symptoms
5-HT 2C antagonism May increase dopamine/norepinephrine in cortex Improves cognitivesymptoms Improves affective symptoms
5-HT 1A agonism Improves cognition, anxiety anddepression
5-HT 1D antagonism Disinhibits presynapticserotonin release Antidepressant and antianxietyeffects
Stahl, S. & Shayegan, D.; J Clin Psych; 2003; 64 [suppl 19]: 6-12
1990 1995 2000 2005 2010
clozapine
risperidone
olanzapine
quetiapine
ziprazidone
aripirazole
risprasidone
microspheres
injection
paliperidone
paliperidone
monthly
Second Generation Antipsychotic Medications
asenapine
iloperidone
ClozapineVery complicated pharmacology
M1--anticholinergic
dry mouth constipation blurred vision drowsiness memory impairment
Alpha adrenergic
Low BP, dizzinessH1 Antihistamine
Drowsiness/sedation Weight gain5HT2C Blockers
Weight Gain
1
Adapted from StahlEssential Psychopharmacology
Clozapine Other side effects
Drooling Seizures Agranulocytosis Heat Related Deaths
Very effective positive and negative good mood stabilizer very low EPS very low TD
Clozapine Drug-Drug Interactions
Many important drug-drug interactions:
Increase clozapine levelsFluvoxamine (Luvox)Fluoxetine (Prozac) or paroxetine (Paxil)RisperidoneGrapefruit juice in large quantities
Decrease clozapine levelssmoking
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Antipsychotic Medications
Ronald J Diamond M.D.
diamond@wisc.edu
Rev 9/12
4
Lab tests suggested: clozapine {Clozaril]
PregnancyTest
X
CBC with
ANC
X X X
Fasting Lipid
& glucose
X X X X
Serum Level X
Weight
(BMI)
X X X
Waist
circumferenceX X X
At
beginning
1 wk x 6 mo, then
2 wks x 6 mo,
then 4 wks 3 moyearly
If
concerned
Risperidone (Risperdal)
Dose related EPS Less is better Prolactin Elevation Weight Gain Positive and negative
efficacy
Mood stabilizer Decreased TD
Adapted from Stahl
Essential Psychopharmacology
Paliperidone (Invega)
Major metabolite of risperidone More gradual release then risperidone [but
risperidone converted into paliperidone]
Fewer drug-drug interactions (metabolizedprimarily in kidneys, little P450 interaction)
More QTc prolongation [not significant] Similar prolactin elevation to risperidone
? Similar weight gain
Paliperidone Vs Risperidone
Risperidone Paliperidone
Tmax R: 1 hr 24 hrs9-OH-R: 3 hrs
Peak to Trough 38 125Ratio (%)
T 1/2 3 hrs 23 hrs
Steady State R: 1 day 4-5 days9-OH-R: 5 days
CYP450 enzyme 2D6 - extensive 4 enzymes
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Antipsychotic Medications
Ronald J Diamond M.D.
diamond@wisc.edu
Rev 9/12
6
Iloperidone (Fanapt): Problems
Dose dependent increase in QTc (9.1 msec at20-24mg/day) which may or may not be an issue
Must be titrated gradually to prevent dizzyness Start 1 mg BID, then increase 2mg/day til 12-24 mg 2D6 inhibitors can increase serum level (fluoxetine,
paroxetine)
Several negative effectiveness studies
Asenapine (Saphris)
Sublingual tablet35% bio-available sublingual
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Antipsychotic Medications
Ronald J Diamond M.D.
diamond@wisc.edu
Rev 9/12
7
Baseline 4 wks 8 wks 12 wks 3 mos 12 mos 5 yrs
Personal/Family
Hx
X X
Weight
(Body Mass Index)
X X X X X X X
Waist
Circumference
X X
BP X X X
Fasting Glucose X X X
Fasting lipid
profile
X X
Diabetic Care Feb 2004
Consensus Recommendations on
Diabetes MonitoringqAbdominal obesity
Waist circumference of > 40 inches in men
Waste circumference of > 35 inches in women
qHDL cholesterol (measured after 12 hours fast)[LDL = bad cholesterol : low HDL = good cholesterol]
HDL cholesterol < 40 mg/dl in men
HDL cholesterol < 50 mg/dl in women
qElevated triglycerides > 150 mg/dlqElevated blood pressure >130/85 mm HgqFasting blood glucose >110 mg/dl
NCEP III Circulation 2002 106: 3143-3421
Metabolic Syndrome: 3 or more following factors:
Traditional Antipsychotic Medications
Examples
fluphenazine (Prolixin)haloperidol (Haldol)
Both available as long acting injectionTraditional D2 blocker may (??) work better
in rare patients
Much less expensiveSemi-traditional medications
Loxapine (Loxitane)
Antipsychotic Side Effects
EPS (Extrapyramidal [muscle] side effects)
Dytonias (muscle cramps) Tremor--coarse Parkinsonian type tremor Akinisia--decreased movement/spontaneity Akathisia--motor restlessness Tardive Dyskinesia: MAY BE PERMANENT
NMS: Neuroleptic Malignant Syndrome
Usually within 30 days of new medication or dose
0.02-2.44% of people taking neuroleptic medications
Hyperthermia (fever) Muscle rigidity Mental Status Changes: Confusion, stupor Elevated CPK Increased heart rate, labile blood pressure Rapid breathing, shortness of breath Sweating, sialorrhea, incontinence
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Antipsychotic Medications
Ronald J Diamond M.D.
diamond@wisc.edu
Rev 9/12
8
Risperidone Consta
Paliperidone Palmitate after single IM injection
Cleton, P et. al.
Poster from
ASCPT, Orlando
Ap 2008
Dose Escalation:
Time
Medication Dose
Symptoms
The negative effects of medication
"Sure the drugs would do that (remove the auditory
and visual hallucinations) but my ability to
cognise was just totally impaired by drugs and
once my ability to cognise was destroyed I would
get deeper into psychosis. Yeah, deeper, less and
less able to recognize myself".
Tooth, Kalyansundaram and Glover. Recovery
from Schizophrenia: A consumer perspecti ve
1998
Second Generation Antipsychotics: are
they worth the cost?
CATIE CUTLESS Long-term VA study
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Antidepressant Medications
Ronald J Diamond M.D.
diamond@wisc.edu
Rev 9-12
1
Antidepressant
Medications
Ronald J Diamond
diamond@wisc.edu
Drug Effects and Depression Severity: A
Patient-Level Meta-analysis: JAMA 2010Fourrnier et al:
Antidepressant medications represent the bestestablished treatment for major depressive disorder, but
there is little evidence that they have a specific
pharmacological effect relative to pill placebo for
patients with less severe depression.
Data from 6 studies, 718 patients
Paroxetine and imipramine only medication studied
Hamilton used as outcome instruments
Efficacy of antidepressants: a re-analysis
and re-interpretation of the Kirsch data:
Fountoulakis and Moller 2010
Overall the results suggest that although a large
percentage of the placebo response is due to
expectancy this is not true for the active drug and
efects are not additive. The drug efect is always
present and is unrelated to depression severity,
while this is not true for placebo.
Treatment of
Illness
Vs
Enhancing Normal
Personality
Interaction between Genes and Experience Cultural/ethnic differences in attitudes towardsmedication
Study of depressed African-American and CaucasianVeterans in Primary Care
PHQ-9 scores 6.8 + 3.9 (mildly depressed) No racial differences in perceived barriers to medical care 79% of African-Americans and 46% of Caucasians felt
prayer would help with depression
23% of African-Americans and 37% of Caucasians feltthat medication would help
No difference in views of psychotherapyKascow et al Psych Services Ap 2011 62(4)
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Antidepressant Medications
Ronald J Diamond M.D.
diamond@wisc.edu
Rev 9-12
2
Antidepressant Medications: Indications Depression
When to use, and when notMajor depressive disorderDepressed phase of bipolar disorderDysthymiaDepression associated with axis II
disorder
Adjustment disorderGriefPost cocaine depression
Illness Vs enhancementHow to combine with other therapy
Antidepressant Medications: Other Indications
AnxietyGeneralized Anxiety GADPanicOCDPTSDSocial Phobia
Bulim Fibromyalgia Neurogenic pain Migraine headaches Smoking cessation Insomnia
Antidepressant Medications
They all take weeks to work, (perhaps ?) They can all induce mania They can all induce rapid cycling They all have withdrawal effects if stopped
suddenly
They are all [pretty much] equally effective, butmay work on different people
May increase neuron growth, especially inhippocampus
Antidepressants and manic switch
Adding antidepressant to mood stabilizer maynothelp with depression
Risk of switch to maniatricyclics>
SNRIs: [venlafaxine [Effexor>
SSRIs [sertraline [Zoloft] >
bupropion [Welbutrin]
Antidepressant Medication:
Risk of Suicidal Behavior varies by Age
Drug-Drug interactions
Pharmacokinetic: raises or lowers serum level of
another medication, ex fluvoxamine (Luvox) can
increase clozapine levels or fluoxetine (Prozac) can
increase amitriptyline levels
Phamacokinetic: interactions in action, ex tramadol
(Ultram) has major risk for serotonin syndrome
when given with MAOI, and some risk when given
with SSRI or SNRI
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Antidepressant Medications
Ronald J Diamond M.D.
diamond@wisc.edu
Rev 9-12
3
Treatment Goals for Patients With MDD
Adapted from Kupfer DJ.J Clin Psychiatry. 1991;52(suppl 5):28-34.
Symptoms
Syndrome
Treatment phases
Prog
ressio
n
todisord
er
Acute Continuation Maintenance
Recurrence+
ResponseNormalcy +
RecoveryRemission
+
Relapse
STAR-D Remission Data:
Fava et al Am J Psychiat 2008; 165: 342-351
Classes of antidepressant medications
SSRI/SNRI Presynaptic agonists Bupropion Tricyclic antidepressants MAOI other
SSRI (Selective Serotonin Re-uptake Inhibitor)
fluoxetine (Prozac) sertraline (Zoloft) paroxetine (Paxil) fluvoxamine (Luvox) citalopram (Celexa) escitalopram (Lexapro)
SSRIs: Relatively Selective, Not Completely Selective
Essential Psychopharmacology 2nd Ed Stephen Stahl
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Antidepressant Medications
Ronald J Diamond M.D.
diamond@wisc.edu
Rev 9-12
4
Essential Psychopharmacology 2nd Ed Stephen Stahl
Essential
Psychopharmacology 2nd Ed
Stephen Stahl
Different SSRIs have
different receptor bindings
SSRI
Clearly work through mechanisms other than just
blocking serotonin reuptake
Time course is too long Dose requirement is too high Differences in response to different medications
SSRI side effects
generally very safe, and very well tolerated
Transient but commonHeadache, nauseaAgitation, sleep disturbance, nightmaresEPS (extra pyramidal [motor] side effects)
Excessive Sweating Sexual side effects Weight gain--more over time Drug-Drug interactions
More with some SSRIs than othersSerotonin syndrome
Withdrawal syndrome from SSRIs Increased tendency to bruise/bleed
SSRI/SNRI and sexual side effects
40% of patients have some sexual dysfunction,
(desire, lubrication/erection,orgasm ) Antidotes without proven efficacy:
Mianserin, cyproheptadine, Ginkgo biloba,
amantadine, loratadine Antidotes with very limited research support
Buproprion, buspirone
Selective phosphodiasterase-5 inhibitorsSildenafil (Viagra)
Antidepressant induced sodium reduction
(Hyponatremia)
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Antidepressant Medications
Ronald J Diamond M.D.
diamond@wisc.edu
Rev 9-12
5
Serotonin Syndrome
Increased risk with two or more antidepressants
Clinical symptoms typically begin within 24 hrs ofstarting or increasing doseoften within 2 hours
1) cognitive or mental-status changes (e.g., agitation,
confusion, delirium, hallucinations,
2) neuromuscular abnormalities (clonus, hyperreflexia,
increased muscle tone, rigidity, shivering, tremor)
3) autonomic hyperactivity symptoms (diaphoresis,
diarrhea, fever, flushing, hypotension or hypertension,
mydriasis, increased respiratory rate, tachycardia
SSNRIselective serotonin and norepinephrine
re-uptake blocker Venlafaxine (Effexor)
May be more effective (probably not)Dual action only at higher dose rangeHigher incidence of high blood pressureGenerally starts low and increase dose over timeSSNRI probably more effective than SSRI in
pain
SSNRIselective serotonin and norepinephrine
re-uptake blocker
Duloxetine (Cymbalta)
May be more effective [little data to support this] Side effects (similar to other SSRIs and SSNRIs)
Hypertension, sexual side effects, GI sideeffects, insomnia
FDA indication for pain from diabeticneuropathy
SSNRIselective serotonin and norepinephrine
re-uptake blocker
Desvenlafaxine (Pristiq)
FDA approval March 2008
Metabolite of venlafaxine:
May ?????
less need for titration
less drug-drug interaction
more serotonin/norepinephrine balancethroughout dose range
Dual action medicationsindirect or pre-synaptic mechanism Trazodone:
Very short acting--Very sedating Rare risk of priapism [1:8000 men] Commonly used as sleep aid Dry mouth, weight gain
Nefazadone (Serzone) Rare but very serious liver problems Well tolerated: some sedation, some weight gain Few sexual side effects Twice a day, start low, increase dose over time Significant drug-drug interactions
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Antidepressant Medications
Ronald J Diamond M.D.
diamond@wisc.edu
Rev 9-12
6
Dual action medications: indirect or pre-
synaptic mechanism
Mirtazapine (remeron)
Very sedating less at higher dose than lower doseWeight gain early, then levels offMay have fewer sexual side effectsCan be used in combination with SSRIs
Vilazodone (Vibryd)
SSRI and 5HT1a partial agonistREPORTEDLY: no weight gain or sexual
dysfunction
Listed side effects nausea, insomnia,diarrhea, vomiting
2 controlled 8 wk trials using: improvementon MADRS 3.2 and 2.5
Titrated over 2 wks, 10 mg x 1 wk, the 20 mgx 1 wk, then 40 mg/day
Bupropion (Welbutrin)Mechanism of action unclear: no significant
effect on dopamine serotonin or norepinephrine
reuptake blockade:
No sexual side effects (and may reversesexual side effects of other medications)
Activating, not sedatingMay be less helpful in anxiety disordersUseful to decrease nicotine (?and other)
addictive craving
Slight increase risk of seizures
Tricyclic Antidepressants
Amitriptyline (Elavil) Imipramine (Tofranil) Nortriptyline (Pamelor) Desipramine (Norprmin) Doxepin (Sinequan) Clomipramine (Anafranil) [OCD]
Tricyclic Antidepressant Receptor Activity
Essential
Psychopharmacology
2nd Ed
Stephen Stahl
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Antidepressant Medications
Ronald J Diamond M.D.
diamond@wisc.edu
Rev 9-12
7
NE reuptakeblockade
5-HTreuptakeblockade
Muscarinicblockade
AntihistamineAdrenergicblockade
Tertiary Aminesamitriptyline ++ ++ +++ ++ ++
clomipramine ++ +++ + ++ ++
doxepine ++ ++ ++ +++ ++
imipramine +++ +++ ++ + ++
trimipramine + + ++ +++ ++
Secondary Aminesdesipramine +++ + + + +
nortriptyline ++ ++ + + ++
protryptiline +++ + +++ + +
Tetracyclics amoxapine ++ + + + ++
maprotiline ++ + + ++ ++
trazodone - + - - +++
Tricyclic Antidepressants
Zajecka 2005
Tricyclic Antidepressants
Primarily norepinephrine reuptake blocker,but very messy: blocks many receptors
As effective in depression as SSRIs: may workwhen other medications do not
Useful with headache and some other pain(often in very low dose)
Data with pain from fibromyaligia
Tricyclic Antidepressants: side effects
Anticholinergic: dry mouth, constipation,confusion, urinary retention
Weight gain (more than with SSRIs) Neurological: seizures Cardiovascular: pulse, orthostatic BP drops Sexual side effects Sedating: can help sleep, add to lethargy
Lethal in overdose:
Sedating Antidepressants for Insomnia
trazodone doxepine (in VERY low dose) amitriptyline
MAOIs: Monoamine Oxidase InhibitorsAction on Sertonin, Norepinephrine and Dopamine
Phenelzine (Nardil)
Tranylcypromine (Parnate)
May may work when other medications do not Many many food and drug interactionsvCan cause high blood pressure crisis if a
tyramine containing food is eaten
vRisk of serotonin syndrome with drug-druginteraction
Orthostatic BP drop, weight gain, sexual side effects
MAOIs: drug-drug interactions
Can be used with trazodone, antipsychotics,benzodiazepines, other hypnotics
Medications formally contra-indicated, but data
suggests risk may be less
Sympathomimetics (pseudofed, cold meds) Decongestant nasal sprays Carbamazepine/oxcarbazepine (similar to tricylics) Bupropion may be worth cautiously considering in
special cases: other antidepressants more
dangerous
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Antidepressant Medications
Ronald J Diamond M.D.
diamond@wisc.edu
Rev 9-12
8
Relative Overdose Toxicity
Doxepin 2.6
Clomipramine 1.4
Trimipramine 1.7
Imipramine 1.5
Nortriptyline 1.3
Venlafaxine 0.29
Mirtazapine 0.22
Citalopram 0.12
Sertraline 0.05
Fluoxetine 0.03
Paroxetine 0.03
Ratio of fatal/
non-fatal
overdose relative
to amitriptyline
Hawton et al
Brit J Psych
2010; 196
May 354-358
Augmentation Strategies: the art
beyond the science
Two (or more) antidepressantsBupropion or mirtazapine + SSRI or SSNI
Antipsychotic + antidepressantGood data in psychotic depressionFair data in refractory depression and OCD
Lithium Other mood stabilizers Misc: buspirone (buspar), pindolol (Viskin),
stimulants, atomoxetine (Strattera)
Folic Acid and depression
Other Biological Treatment for Depression
Sleep deprivation: effective but not practical ECT: effective, safe, probably underused
Problem with politics and stigmaProblem with relapseMaintenance ECT an outpatient option
VNS: Vagal Nerve StimulationNow FDA approvedSurgical procedureTakes months to be effective, up to 30 % of
very treatment resistant patients
Tis better to hunt in fields for health unbought,
Than fee the doctor for nauseous draught
God never meant his works for man to mend.
The wise for cure on exercise depend.
Dryden
Other Biological Treatment for Depression
Exercise: effective for mild to moderate depressionFew side effectsLow costCompliance an issue
St Johns Wort: [most prescribed antidepressant inGermany]Recent controlled trials did not support useMany drug-drug interactions
Stimulants: amphetamines, modafanil, etc Light therapy (for seasonal affective disorder)
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Antidepressant Medications
Ronald J Diamond M.D.
diamond@wisc.edu
Rev 9-12
9
STAR*D
Federally funded, multi-site Practical clinical trial, broad inclusion trial Equipoise stratified randomization Primary outcome = Depression Remission
STAR*D Results
30%
25%
30%
20%
12%
16%
25%
14%
7%
0%
5%
10%
15%
20%
25%
30%
35%
Level I
citalopram
Level II
Switch to Bupropioin,
Sertraline, EffexorAugment: Bupropion,Buspiron
Level III
Switch: Nortriptyline
Switch: Mirtazapine
Augment Lithium
Augment T3
Level IV
Efexor + Mirtazapine
Trancyclopromine
Level IILevel I Level III Level IV
Michael Thase 2011
When treatment does not work,
THINK
Alcohol and other substance abuse Medical Illness Other prescribed or OTC medication Non-adherence with prescribed medication
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Medication for Bipolar Disorder
Ronald J Diamond M.D.
diamond@wisc.edu
Rev 9-12
1
Mood Stabilizing Medications
3
The Prevalence of Bipolar Disorder
Estimated Prevalence in the USBipolar I.5%1.0%13Females Males4
Bipolar II.5%1.1%23Females > Males4
1. Kessler RC et al.Psychol Med. 1997;27(5):10791089.2. Weissman MM et al. Affective Disorders. In: Robins LN, Resier, DA, eds. Psychiatric Disorders in
America.1991:5380.
3. Merikangas KR et al.Arch Gen Psychiatry. 2007;64:543552.4. Diagnostic and Statistical Manual of Mental Disorders,4th ed., text revision. Washington, DC:
American Psychiatric Publishing, Inc; 2000.
Mood Stabilizers
Decrease the frequency and intensity of mood shifts
Medications for Bipolar Disorder: FDA approved
Acute
Mania
Maintenance
Mania
Bipolar
Depression
Lithium carbonate x x
Sodium valproate (Depakote) x
Carbamazepine (Tegretol x
Risperidone (Risperdal) x x
Quetiapine (Seroquel) x x x
Olanzapine (Zyprexa) x x
Ziprasidone (Geodon) x x
Lamotrigine (Lamictal) x
Lithium Carbonate
Specifics of Use
Usually start twice a day, but most people cansafely take once a day
Half-life 24 hours If someone starts and then stops, may not work
as well when restarted
Need for blood tests to measure lithium level Need for blood test to follow kidney function
Lithium Carbonate
Side Effects
Kidney Thyroid Common, uncomfortable
Tremor, nausea, thirst, increased urination, metallictaste, weight gain
Feeling fuzzy or less creative, memory problems Toxic side effects
Confusion, ataxia, muscle twitching, convulsions Possible Birth Defects: Warning to women who could
get pregnant
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Medication for Bipolar Disorder
Ronald J Diamond M.D.
diamond@wisc.edu
Rev 9-12
2
Lab tests suggested: lithium [Eskalith,
Lithobid, lithium carbonate]
Pregnancy Test X
Kidney
function (BUN/
creatine)
X X X X
Sodium X X
Serum Level X X X
Weight (BMI) X X
Thyroid (TSH) ?X X
At
beginning 1 wk 6 moyearly
If
concerned
Anticonvulsant Mood Stabilizers
divalproex sodium (valproic acid) (Depakote) Carbamazepine (Tegretal) Oxcarbazepine (Trileptal) Gabapentin (Neurontin) Pregabalin (Lyrica) Topirimate (Topamax) Lamotrigine (Lamictal) Tiagabine (Gabitril) Zonisamide (Zonagram) Levetiracetam (Keppra) Tiagabine (Gabitril)
Divalproex sodium (Depakote)
Can rapid load, get to full dose rapidly Start twice/day, most people can take once/day
Half-life 6-16 hours Many drug-drug interactions Potential serious problems with
Liver problemsPancreatitis? Polycystic ovaries
Birth Defects (women should take folic acidand be warned)
Divalproex sodium (Depakote):
Risk of Birth Defects
3 %-8% risk of spinal bifida Craniofacial Heart defects Behavioral teratogenicity Increased risk of cognitive problems in babies
born to mothers on divalproex
Lee Cohen 2006
Divalproex sodium (Depakote)
Dose related GI upset, nausea Sedation, tiredness, decreased energy, cognitive
problems Decreased platelets (thrombocytopenia) Tremor Weight gain (?)
Not dose related Hair loss (alopecia)
Divalproex sodium (Depakote)
Drug-Drug interactionsCan inhibit metabolism of carbemazepine,
lamotrigine, tricyclic antidepressants,
warfarinAspirin (increases free valproate level 4x)
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Medication for Bipolar Disorder
Ronald J Diamond M.D.
diamond@wisc.edu
Rev 9-12
3
Divalproex sodium (Depakote)
Polycystic Ovarian Syndrome (PCOS)
1.4 %
10.5 %
0.0%
2.0%
4.0%
6.0%
8.0%
10.0%
12.0%
No
Valproate
Joffe et al 2006
Mentral irregulaties[
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Medication for Bipolar Disorder
Ronald J Diamond M.D.
diamond@wisc.edu
Rev 9-12
5
Lamotrigine (Lamictal) Rash
Highest risk in first 2-8 weeks Involvement of mucous membranes Head/neck, palm/soles Blistering/burn like Swollen lymph glands, fever, increase WBCs Very rare reports of hypersensitivity without
rash--early signs are fever and swollen lymphglands
Atypical Antipsychotics are all good
mood stabilizers
All indicated for mania
Quetiapine has best data for bipolar depression Risperidone Olanzapine Quetiapine Ziprasidone Aripiprazole Clozapine
Quetiapine in acute bipolar depression:
Bolder I and Bolder II studies
Calabrese et al: Am J Psychiat 2005: 162: 1351-1360
Thase et al J Clin Psychopharmacology 26(6) Dec 2006
Antidepressants: risk of manic switch
Gijsman et al 2004 meta-analysis of 12 studies
3.8 % (vs 4.7% for placebo)1088 subjects, only treated 4-10 wks8 % of TCA vs 0% of SSRI (3 studies)Post et al 2003, 2006
10 wk study of 174 subjects10% of pts taking bupropion9 % of pts taking sertraline29 % of pts taking venlafaxine
Gijsman et al Am J Psychiat 2004: 161
Post et al Bipolar Dis 2003; 5
Antidepressants: do they work in
bipolar depression?
Gijsman: meta-analysis of placebo Vs active
More likely to respond to active treatment RR 1.9 [95% confidence 1.5-2.3] NNT 5 [95% 4-7]Sachs et al (2007) n = 366
no benefit from adding antidepressant to moodstabilizer
Sachs et al NEJM 2007:161
FDA approval for mood disorder
Acute Main Acute Main Depressionaugment
Aripiprazole x x x
Quetiapine x x x x x
Olanzapine x x x
Risperidone x
Ziprasidone x
Bipolar Mania Bipolar Depression
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Medication for Bipolar Disorder
Ronald J Diamond M.D.
diamond@wisc.edu
Rev 9-12
6
Thoughts on treatment of bipolar patients
Manic-depressive disease can be as disabling asschizophrenia
Virtually no bi-polar patient is on only one medication Most people live more of their time in the down, but
most treatment is focused on the up
All of the 2nd generation antipsychotic medicationsseem to have robust mood stabilizing properties
Cognitive behavioral or other psychological ways tomanage symptoms can be very useful
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Ronald J Diamond M.D.diamond@wisc.eduMedications and Borderline Personality Disorder
Revised 4/121
Prescribing Medications for People with
Borderline Personality DisorderNovember 2010
Ronald J Diamond M.D.Department of PsychiatryUniversity of Wisconsin
Personality DisorderA. Pervasive, persistent maladaptive behavior
Not attributable to Axis I Medical illness Or cultural role difficulties.
B. We all have different ways of protecting ourselves C. We all have bits and pieces of effective as well as
maladaptive behaviorD. Any label gives very incomplete information
We react negatively to the borderline
diagnosis Having that diagnosis resulted in my getting treated
exactly the way I was treated at home. The minute I
got the diagnosis people stopped treating me as
though what I was doing had a reason.
Judith HermanTrauma and Recovery
No Medications are approved for BPD 81 % of cohort in collaborative borderline follow up
project taking medication (CLPS study) Zanarina 78 % of BPD on meds > 75 % of time over
37 % of BPD on > 3 meds Cochrane review suggested some meds may be
effective (Brit J Psychiat 2010 (196: 4-12 NICE guidelines discount much of this info (National
Collaborating Centre for Mental Health)
What is biological?Temperment social learning TraitMedication can turn down the noise and allow one touse other therapies
Deficits in People with Borderline Disorder
(Temperament)A. Affective Instability B. Impulsivity and low frustration toleranceC. Cognitive perceptual dysfunctionD. Anxiety inhibition problems
Dimensions of Personality (Siever and Davis (1991)
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Ronald J Diamond M.D.diamond@wisc.eduMedications and Borderline Personality Disorder
Revised 4/122
Deficits in People with Borderline Disorder
(Character)A. Sense of self as being damaged/defective/not goodB. Difficulty maintaining their own sense of identity/
poor object constancyC. Poor understanding of rules of normal
interpersonal relationships
The goal is to stay in a long term, stable
relationship: Know the limits of your responsibility Be aware of your own feelings Monitor and regulate interpersonal distance Be aware of "splitting"--being "right" may be less
important than being a team
Be clear about the therapy contractA. What does the client want
What are the clients treatment goals What would doing better or doing worse mean What commitment is the client willing/able to make
B. What do you want? What are you able to deliver What can you not tolerate
Behavior Risk
Core Strategies for Therapy Validation Problem solving Skills training
Marsha Lenihan
Assumptions about borderline patients and
therapy (from Lenihan) Patients are doing the best they can Patient want to improve Patients need to do better, try harder and be moremotivated to change Patients may not have caused all of their own
problems but they have to solve them anyway
Assumptions about borderline patients and
therapy (cont) The lives of suicidal, borderline individuals are
unbearable as they are currently being lived Patients must learn new behaviors in all relevant
contexts Patients cannot fail in therapy Therapists treating borderline patients need support
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Ronald J Diamond M.D.diamond@wisc.eduMedications and Borderline Personality Disorder
Revised 4/123
Consider that problem behavior is
exacerbated by: Treatable medical illness Co-existing mental illness Sequela of trauma Always consider substance abuse
Obtain a careful history What has been tried What has worked What has not worked.
Pharmacological Treatment: Difficult to prescribe for a patient who is
impulsive, angry, and tends to have major
issues with control. Patient may be abusing alcohol or drugs.
Elements of a medication trial: Collaborative relationship with shared
treatment goals Identify specific target symptoms Discontinue medication if target symptoms do
not improve
Monitor whether medication is working What does getting better mean? What does getting worse mean? Encourage use of daily chart or calendar
Identify 2 or 3 feelings/behaviors/activities that aretreatment targets
Use a 1-10 scaleRate every day
Medication decisions are never an emergency!Patient education is criticalGet clear agreement on what, for how longNever want a client to take medication more than
the client wants to take the medication
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Ronald J Diamond M.D.diamond@wisc.eduMedications and Borderline Personality Disorder
Revised 4/124
Crisis Intervention is CriticalCrisis Vs ongoing life chaos
Is this a crisis? Whom is this a crisis for?
Do not get overwhelmed by the client's sense of crisis.
Target of Medication Symptom Behavior Interpersonal strategy
Silk
Medication in Borderline Personality Disorder:
Mood stabilizersA. Divalproex Sodium (Depakote)B. Carbamazepine (Tegretal)C. Oxcarbazepine (Trileptal)C. Gabapentin (Neurontin)D. Lamotrigine (Lamactil)E. Lithium F. Topiramate (Topamax)
Medication in Borderline Personality Disorder:
AntidepressantsSSRIsSalzman et al 1992 fluoxetine Vs placebo n = 24 improvement in depression, mood lability, anger, irritabilityOther studies showed decrease impulsivity and self-mutilationMAOIs
Suggested for atypical depression or hysteroid dysphoriaParsons et al 1989: phenelzine, imipramine, Vs placebobetter response, and better response with more BPD sxMAOI use not very problematic despite pt population
Risk ofrapid cycling
Antidepressants and Borderline Disorder Recent meta-analysis show little effect from antidepressants SSRIs may have modest effect on anger, anxiety, depression
and possibly affective lability Very limited effect on depression with SSRIs
Ripoll LH, Clinical Psychopharmacology of Borderline Peronality Disorder CurrOpin Psychiatry 2012;25 (1) 52-58
Medication in Borderline Personality Disorder:
Traditional AntipsychoticsGoldberg et al 1986: random control of 50 patients withthiothixene 5 -40 mg No overall difference, but decrease in psychotic like
symptoms + phobic anxiety and OCD sxSoleff et al 1986: NTZ Vs haloperidol Vs placebo:haloperidol mean = 7.2 mg Improvement in both psychotic like and depression Some patients seemed to get worse All studies had large drop out ratesTypically use very low dose-may be less effective at full dose
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Ronald J Diamond M.D.diamond@wisc.eduMedications and Borderline Personality Disorder
Revised 4/125
Medication in Borderline Personality Disorder:
Atypical Antipsychotics Second generation agents better tolerated, better mood
stability and help cognition relative to older medications Not FDA indicated. Research supporting the use of
antipsychotics very limited Open studies and chart reviews generally much more
positive than double blind random controlled studies
Alpha 2 Adrenergic Agonists Clonidine Guanfacine
Can decrease startle and overreaction symptoms ofPTSD
Alpha 1 Adrenergic Antagonist Prasosin (Minipress) Terazosin (Hytrin)
Can decrease startle and overreaction symptoms ofPTSD
Medication in Borderline Personality Disorder:
BenzodiazepinesUse very rarely and very carefully Addiction Aggressive dyscontrol and rage reactions
Medication in Borderline Personality Disorder:
Medications for alcohol abuse Antabuse Naltrexone (ReVia)
Roth et. Al 1996: open trial with 7 patients without
ETOH problems with analgesia and dysphoria:
11 week follow-up: 6/7 stopped self-injurious behavior
Acamprosate (Campral)
Medication in Borderline Personality Disorder:
Stimulants
Comorbidity of Borderline and ADD
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Ronald J Diamond M.D.diamond@wisc.eduMedications and Borderline Personality Disorder
Revised 4/126
BPD describes a very heterogeneous group
of people Treatment planning is critical.A. Can allow the clinician to be proactive B. Involve the client
Its easy to arrive at polypharmacy They want more meds They want new meds They have lots of symptoms They want to be fixed We feel that we need to do something Polypharmacy not always wrong, but it is not always
wise
Medication as transitional object Very sensitive to weight gain and other side effects But patients also get very attached to their medication
The sufferer who frustrates a keen therapist by failingto improve is always in danger of meeting primitive
human behavior disguised as treatment Main--theAilment
Risk There is no way to treat clients with borderline
personality disorder without taking risks Need to balance short term Vs long term risks
High lifetime risk of suicide. Responding to each suicidal event may make it
more difficult for people to stabilize their lives.
Balancing risks Discussed carefully with the client The clients family Other members of the treatment team and supportsystem
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Ronald J Diamond M.D.diamond@wisc.eduMedications and Borderline Personality Disorder
Revised 4/127
Clinical Suggestions:
When you are stuck, enlarge the field Support the client's own competence
whenever possible
Maintain Hope
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Diamond RJ Instant Psychopharmacolog 3rd
edition: A Guide for the Nonmedical Mental Health
Professional WW Norton & Co, New York 3rd
edition 2009
Diamond RJ The Medication Question: Weighing Your Mental Health Treatment Options For Patients
and Their Families WW Norton & Co, New York 2011
Recommended