IPS 2012 - Psychiatry for PCP

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.

[email protected]

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


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[email protected]

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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[email protected]

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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[email protected]

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


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?



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[email protected]

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


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


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


[email protected]

Rev 9/12

1

Four out of five doctors

recommend. . .

Antipsychotic

Medications

Ron Diamond

[email protected]

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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[email protected]

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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[email protected]

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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[email protected]

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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[email protected]

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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[email protected]

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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[email protected]

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


[email protected]

Rev 9-12

1

Antidepressant

Medications

Ronald J Diamond

[email protected]

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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[email protected]

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


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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[email protected]

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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[email protected]

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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[email protected]

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


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


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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[email protected]

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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[email protected]

Rev 9-12

7

NE reuptakeblockade

5-HTreuptakeblockade

Muscarinicblockade

AntihistamineAdrenergicblockade

Tertiary Aminesamitriptyline ++ ++ +++ ++ ++

clomipramine ++ +++ + ++ ++

doxepine ++ ++ ++ +++ ++

imipramine +++ +++ ++ + ++

trimipramine + + ++ +++ ++

Secondary Aminesdesipramine +++ + + + +

nortriptyline ++ ++ + + ++

protryptiline +++ + +++ + +

Tetracyclics amoxapine ++ + + + ++

maprotiline ++ + + ++ ++

trazodone - + - - +++


Zajecka 2005


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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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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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


[email protected]

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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[email protected]

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


Dose related GI upset, nausea Sedation, tiredness, decreased energy, cognitive

problems Decreased platelets (thrombocytopenia) Tremor Weight gain (?)

Not dose related Hair loss (alopecia)


Drug-Drug interactionsCan inhibit metabolism of carbemazepine,

lamotrigine, tricyclic antidepressants,

warfarinAspirin (increases free valproate level 4x)


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[email protected]

Rev 9-12

3


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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[email protected]

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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[email protected]

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 [email protected] 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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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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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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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)


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


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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Revised 4/125


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


BenzodiazepinesUse very rarely and very carefully Addiction Aggressive dyscontrol and rage reactions


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)


Stimulants

Comorbidity of Borderline and ADD


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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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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

IPS 2012 - Psychiatry for PCP

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