Update in
Clinical Psychopharmacology
Peter A. DeMaria, Jr., M.D., FASAM
Tuttleman Counseling Services
Temple University
Clinical Associate Professor of Psychiatry
Temple University School of Medicine
Philadelphia, PA
Disclosures
• I have no actual or potential conflict of
interest in relation to this educational
activity or presentation.
• Use of trade versus generic drug names
• Off-label use of drugs.
Treatment Planning
1. Medication
2. Psychotherapy
3. Combined medication and psychotherapy
Referral for Psychopharmacologic
Evaluation/Treatment
1. When to refer
2. Preparing the patient
3. What to expect
4. The challenge of split treatment
– Communication
– Dynamics
– Ethics
– Legal issues
5. What to expect
Neurotransmission
Taken from: Bloom FE, Neurotransmission in the Central Nervous System in
Goodman & Gilman’s Pharmacological Basis of Therapeutics, 9th Ed, p. 270
Pharmacokinetics
Taken from: Julien, R. A Primer of Drug Action. WH Freeman Co., New York, 1998. p. 25.
Drug Interactions
 Synergism (e.g. alcohol + sedative)
 Induction of enzymes and increased metabolism
 Inhibition of enzymes and delayed metabolism
 In vitro versus clinical significance
FDA approval vs. clinical use
(“Off-label use”)
Selecting a Psychotropic Agent
•
•
•
•
•
•
•
•
•
Diagnosis/symptom complex
Patient’s prior response
Family member’s experience
FDA approved indication
Pharmacologic actions
Documented efficacy
Side effect profile
Insurance coverage/finances
Patient preference
DSM-IV Classification of Depressive
Disorders
•
•
•
•
Adjustment disorder with depressed mood
Dysthymia
Major depression (MDD)
Premenstrual Dysphoric disorder (PMDD)
Pharmacotherapy options
• Monoamine oxidase inhibitors (MAOI)
• Tricyclic antidepressants (TCA)
– Amitriptyline (Elavil)
– Nortriptyline (Pamelor)
Imipramine (Tofranil)
Desipramine (Norpramin)
• Selective Serotonin Reuptake Inhibitors (SSRI)
• Serotonin and Norepinephrine Reuptake
inhibitors (SNRI)
• Atypical antidepressants
– Bupropion (Wellbutrin)
• On the horizon
Nefazodone (Serzone)
Selective Serotonin Reuptake Inhibitors (SSRI)
1. Examples
Sertraline (Zoloft)
Citalopram (Celexa)
Paroxetine (Paxil)
Fluoxetine(Prozac)
Escitalopram (Lexapro)
Fluvoxamine (Luvox)
2. Mechanism of Action
Blocks re-uptake of serotonin thereby increasing
serotonin in the synapse
SSRI - FDA Approved Indications
Sertraline (Zoloft)
Paroxetine (Paxil)
Fluoxetine (Prozac)
Citalopram (Celexa)
Escitalopram (Lexapro)
Fluvoxamine (Luvox)
MD
X
X
X
X
X
PMDD
X
X
X
OCD
X
X
X
PD
X
X
X
PTSD
X
X
GAD
X
SP
X
X
BN
X
X
X
Therapeutic Response
• Can take between 2 and 8 weeks
• Response is gradual
• Others may notice the response before the
patient does
SSRI/SNRI Side Effects
•
•
•
•
•
•
Gastrointestinal
Anxiety/insomnia
Flushing/night sweats
Vivid dreams
Weight change
Sexual dysfunction
Antidepressant-Induced Sexual Dysfunction
Desire  Decreased libido
Arousal  Difficulties w/ erection/lubrication
Orgasm  Delayed orgasm/anorgasmia
Management
–
–
–
–
Spontaneous resolution
Decrease dose
Change agent
Adjunctive medication
Selective PDE5 Inhibitor
Cyproheptadine (Periactin)
Bupropion (Wellbutrin)
“Poop-out” Effect
1. Definition
2. Explanation
– Placebo response
– Inadequate dose
– Potential changes in receptors
3. Management
–
–
–
–
Drug holiday
Increase dose
Change antidepressant
Add agent with NE or DA properties
Discontinuation Syndrome
• Develops after abrupt cessation of SSRI/SNRI
• Symptoms = washed-out, flu-like,
lightheaded, H/A, emotional liability, diarrhea
• Can occur with all SSRIs/SNRIs
• May be related to half-life
• Worse with paroxetine (Paxil) and venlafaxine
(Effexor)
• Abates with re-challenge of SSRI/SNRI
• Slow taper of SSRI/SNRI or change to longer
acting agent.
Serotonin-Norepinephrine Reuptake Inhibitors
(SNRI)
• Mechanism of Action
• Examples and Indications
• Side Effects
Desvenlafaxine (Pristiq)
Duloxetine (Cymbalta)
Mirtazapine (Remeron)
Venlafaxine (Effexor-XR)
MDD GAD
X
X
X
X
X
X
PD
SAD
FM
X
X
X
MDD = Major depressive disorder, GAD = Generalized anxiety disorder,
PD = Panic disorder, SAD = Social anxiety disorder, FM = Fibromyalgia.
Treatment Resistant Depression
1. Is the patient medication compliant?
2. Is the diagnosis correct?
3. Change agents-Within/between classes
4. Antidepressant combinations
-Complementary mechanisms of action
5. Add psychotherapy
6. Augmentation strategies
– Lithium
– Antipsychotic
Thyroid hormone
Estrogen
7. ECT/Focal Brain Stimulation
Focal Brain Stimulation
• Vagal Nerve Stimulation • Transcranial magnetic
(VNS)
stimulation (TMS)
– Pulse generator implanted in
the left chest wall
– Electrode wrapped around
the left vagus nerve
– Pulse on for 30 seconds and
off for 5 minutes
– Efficacy = ?
– Uses an electromagnetic
coil placed against the
scalp to create a rapidly
changing magnetic field
that depolarizes neurons.
– Outpatient procedure
– Safe and well tolerated
– Efficacy =?
How long to Treat?
• 6-12 months
• Longer if,
– Return of symptoms on discontinuation of AD
– Recurrent episodes of depression
– Severe depression (suicide attempt, psychosis)
Number of Prior Episodes of Depression
Recurrence Rate
1
< 50%
2
50-90%
3 or more
>90%
Taken from: Stahl S. Essential Psychopharmacology: Neuroscientific Basis and
Practical Applications. 2nd Ed., Cambridge University Press. 2000, p. 150.)
FDA Suicide Warning
• Black Box Warning
• All antidepressants
• Increased risk of suicidal thinking and
behaviors
• Affects 18-24 y/o
On the Horizon
• Corticotropin releasing factor-1 (CRF1)
antagonists
• Glucocorticoid receptor antagonists
• Substance P receptor antagonists
• NMDA receptor antagonists
• Melanocyte inhibiting factor (nemifitide)
• Omega -3 fatty acids
• Melatonin receptor antagonists
• Focal and deep brain stimulation therapies
STAR*D
• Largest (n=4041, age 18-75 y/o) study of treatment
of non-psychotic MDD
• Multiple real-world psychiatric and primary care
settings
• Conducted between July 2001 and April 2004
• Funded by National Institute of Mental Health
(NIMH)
• Goal was remission (< 5 on the QIDS-C16)
• Treatment involved 6 levels with patient ability to
choose options
• Available at www.star-d.org
N
Remission Response
Rate
Rate
3,671
36.8%
48.6%
1,439
30.6%
28.5%
Step 3
Switch to Mirtazapine, nortriptyline 390
OR augment with lithium or T3
13.7%
16.8%
Step 4
Switch to tranylcypromine or
venlafaxine plus mirtazapine
13%
16.3%
STAR*D Results
Step 1
Citalopram
Step 2
Switch to bupropion, sertraline,
venlafaxine, or CBT, OR augment
with bupropion, buspirone, or CBT
(Rush AJ
123
et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps:
a STAR*D report. Am J Psych 163:1905-1917, 2006.)
STAR*D
• MDD is a chronic and recurrent illness.
• Using objective measurements of symptoms and side
effects a can help with treatment decisions.
• Remission can take time (at least 8, but up to 14
weeks).
• Many steps may be needed to reach remission.
– Remission rate of 50% was reached after 2 steps.
– Remission rate of 70% was reached after 4 steps
• Remission results in better log-term outcomes.
• Participant attrition is high.
(Warden D et al. The STAR*D project results: a comprehensive review of
findings. Current Psychiatry Reports 9:449-459, 2007.)
DSM-IV Anxiety Disorders
1.Adjustment disorder
2.Generalized anxiety disorder (GAD)
3.Panic disorder
4.Obsessive-compulsive disorder (OCD)
5.Social anxiety disorder (social phobia)
6.Acute stress disorder
7.Post traumatic stress disorder (PTSD)
8.Specific phobia
Benzodiazepines
Benzodiazepine
Alprazolam (Xanax)
Chlordiazepoxide (Librium)
Clonazepam (Klonopin)
Clorazepate (Tranxene)
Diazepam (Valium)
Lorazepam (Ativan)
Oxazepam (Serax)
Half-life
(hr)
12
100
34
100
100
15
8
Active
metabolites
Yes
Yes
No
Yes
Yes
No
No
Anxiolytic dose
range (mg/day)
0.5-4
15-100
0.5-10
7.5-60
2-40
2-4
30-120
Approximate dose
equivalency (mg)
0.25
10
0.5
7.5
5
1
15
Taken from: Kaplan SI, Sadock BJ. Kaplan & Sadock’s Synopsis of Psychiatry, 8 th ed.,
Lippincott, Williams & Wilkins, Philadelphia, 1998, p. 996.
Advantages
-Rapid onset of action
-Highly effective
Disadvantages
-Physiologic dependence
-Addicting
-Impaired cognition
Anterograde amnesia
J of Clin. Psychiatry, 60(5), 252, May 1999
FDA Approved Indications MDD PD OCD SP PTSD GAD PMDD BN ND FM
SSRI
Citalopram (Celexa)
X
Escitalopram (Lexapro)
X
X
Fluoxetine (Prozac)
X
X
X
X
X
Paroxetine (Paxil/CR)
X
X
X
X
X
X
X
Sertraline (Zoloft)
X
X
X
X
X
X
SNRI
Duloxetine (Cymbalta)
X
X
X
Venlafaxine (Effexor/XL) X
X
X
X
Tricyclic Antidepressant
Fluvoxamine (Luvox)
X
Other
Bupropion (Wellbutrin)
X
X
Buspirone (BuSpar)
X
Mirtazapine (Remeron)
X
MDD=major depressive disorder, PMDD=peri-menstrual dysphoric disorder, PD = panic
disorder, PTSD=post-traumatic stress disorder, GAD=generalized anxiety disorder,
OCD=obsessive-compulsive disorder, SP=social phobia, BN = bulimia nervosa, ND =
nicotine dependence, FM = fibromyalgia
SSRI/SNRIs in Anxiety Disorders
Advantages
• High efficacy
• Non-addicting
• Effective for a number
of conditions
Disadvantages
• Can take 2-8 weeks or
longer to be effective
• Side effects
• Drug interactions
• Discontinuation
syndrome
Other Options for Anxiety Disorders
• Buspirone (BuSpar)
• Beta blockers
• Combinations
– SSRI/SNRI + Benzodiazepine
• Antipsychotics
– Trifluoperazine (Stelazine)
– Quetiapine (?)
• Pregabalin (?)
Psychotropic Choices for Specific Conditions
Condition
Pharmacotherapy Option
Obsessive compulsive disorder SSRI
Clomipramine
Social anxiety disorder
SSRI/SNRI
Panic disorder
SSRI/SNRI
TCA
Benzodiazepine
PTSD
SSRI
Generalized anxiety disorder
SSRI/SNRI
Benzodiazepine
Buspirone
DSM-IV Psychotic Disorders
1.Schizophreniform disorder
2.Schizophrenia
3.Schizoaffective disorder
4. Brief psychotic disorder
The Disease Process
Positive Symptoms
• Hallucinations
• Delusions
• Disorganization
• Agitation
Negative symptoms
• Blunted affect
• Emotional withdrawal
• Social withdrawal
• Anhedonia
FDA Approved Indications for Atypical Antipsychotics
Indication
OLA
RIS ILO QUE
Schizophrenia
Schizoaffective
Disorder
X
X
X
X
Bipolar
Mania/Mixed
X
X
Bipolar
Depression
X
X
Adjunct in
MDD
X
X
ZIP
ARI ASEN
X
X
X
X
X
X
X
X
X
OLA = Olanzapine, RIS = Risperidone, ILO = Iloperidone, QUE = Quetiapine,
ZIP = Ziprasidone, ARI = Aripiprazole, ASEN = Asenapine
Atypical (2nd Generation) Antipsychotics
Side Effect
HL
CPZ
CLZ
RIS
OLZ
QTP
ZIP
-
+++
++++
-
+++
-
-
+++++
+++
+
++
+
+
++
Sedation
+
++++
+++++
+
+++
+++
++
Orthostasis
+
+++
++++
+
+
+
+
Weight gain
+
+++
++++
++
+++
+
-
Lipid increase
-
??
+++
??
++
??
-
+++
++
-
+++
+
-
+
Anticholinergic
EPS
Prolactin elevation
HL=haloperidol (Haldol), CPZ=chlorpromazine (Thorazine), CLZ=clozapine (Clozaril),
RIS=risperidone (Risperdal), OLZ=olanzapine (Zyprexa), QTP=quetiapine (Seroquel),
ZIP=ziprasidone (Geodon)
(Taken from: Jam, MW. Advances in the treatment of psychosis:
a multidisciplinary continuing education program. Power-Pak CE, New York, NY 2001, p. 8.)
Metabolic Syndrome & Atypical Antipsychotics
Medication
Clozapine
Olanzapine
Quetiapine
Risperidone
Aripiprazole
Ziprasidone
Weight Gain
+++
+++
++
++
0
0
↑FBS
+++
+++
++
++
0
0
Risk of adverse effects at therapeutic doses:
0 = None, ++ = Sometimes, +++ = Frequently
J. Clin. Psych 2004: 66; 267-272
↑ Lipids
+++
+++
++
++
0
0
CATIE
• 1460 “real-world” schizophrenics (no first-break
schizophrenics)
• NIMH funded
• Comparison of second generation antipsychotics to a
representative first generation antipsychotic
(perphenazine).
Agent
Time to Discontinuation
(months)
Olanzapine
9.2
Perphenazine 5.6
Quetiapine
4.6
Risperidone 4.8
Ziprasidone 3.5
All Cause
Discontinuation Rate
64%
75%
82%
74%
79%
CATIE
• Overall findings:
– Discontinuation rates for all agents were high.
– Olanzapine was the most efficacious
medication, however, it was associated with
the greatest weight gain, and the worst
metabolic profiles.
– For those patients changing drugs due to
tolerability, olanzapine and risperidone were
more efficacious second choice drugs.
– Ziprasidone had a better metabolic profile.
DSM-IV Mood Disorders
Bipolar disorder (manic-depressive disorder)
 Bipolar I
(recurrent major depression and mania)
 Bipolar II
(recurrent major depression with hypomania)
 Specifiers
 Rapid cycling (more than 4 episodes in a 12 month period)
 Seasonal pattern
Cyclothymia
The Heterogeneity of Bipolar Disorder
Taken from:
http://www.psychosisbipolar.com/information-aboutpsychoses-57.htmlTaken
Pharmacotherapy for Mood Disorders
1. Mood stabilizers
Lithium
2. Anticonvulsant Mood Stabilizers
Valproic acid (Depakote) Carbamazepine (Tegretol)
Oxcarbazepine (Trileptal) Lamotrigine (Lamictal)
Topiramate (Topamax)-?
3. Atypical Antipsychotics
Olanzapine (Zyprexa)
Risperidone (Risperdal)
Quetiapine (Seroquel)
Aripiprazole (Abilify)
Ziprasidone (Geodon)
4. Combination
Olanzapine/fluoxetine (Symbyax)
Treating Bipolar Disorder
• Use mood charting.
• Combination pharmacotherapy is the rule
rather than the exception.
• Mood stabilizers are the cornerstone of
therapy.
• Optimize therapeutic effect and tolerability
while minimizing side effects.
• Antidepressants mat worsen the disease
course.
• Anticonvulsants & FDA suicide warning
Pharmacotherapy for Bipolar Disorder
Phase
Mania
Treatment Options
Lithium (Li)
Valproate (VP)
Atypical antipsychotic
Carbamazepine/oxcarbamazepine
Li/VP + atypical antipsychotic
Electroconvulsive therapy (ECT)
Depression
Optimize mood stabilizer
Lamotrigine
Quetiapine
Olanzapine/fluoxetine
Mood stabilizer + antidepressant
Maintenance
In general, continue regimen that is working,
however, simplify as clinically indicated.
Insomnia
•
•
•
•
•
A symptom, not a diagnosis
Evaluate for underlying cause
Promote good sleep hygiene
Use a sleep log
Pharmacotherapy
– 10 days or less
– Options
•
•
•
•
•
Non-benzodiazepine hypnotics
Benzodiazepine hypnotics
Sedating antihistamines
Sedating antidepressants
Sedating antipsychotics
Attention Deficit Hyperactivity Disorder
1. Stimulants
–
–
–
–
Amphetamine salts (Adderall)
Methylphenidate (Ritalin, Concerta, Focalin)
Dextroamphetamine (Dexedrine)
Pemoline (Cylert)
2. Non-stimulants
– Atomoxetine (Strattera)
– Guanfacine extended release (Intuniv)
– Others
• Bupropion(Wellbutrin)
• Tricyclic antidepressants
• Venlafaxine (Effexor)
3. New Delivery Systems
– Methylphenidate patch (Daytrana)
– Pro-drug: lisdexamfetamine (Vyvanse)
Pharmacotherapy for Eating Disorders
1. Classification
Anorexia nervosa
Bulimia nervosa
Eating disorder NOS
2. Pharmacotherapy options
SSRIs for bingeing/purging
Topiramate for binging/purging - ?
Treatment for co-morbid disorders
Pharmacotherapy for Personality Disorders
Symptom targeted
Symptom Spectrum
Affective symptoms
Mood dysregulation/
impulsivity
Psychotic/para-psychotic
symptoms
Pharmacotherapy Option
SSRI/SNRI
Atypical antidepressant
Mood stabilizer
Mood stabilizer
Anticonvulsant mood
stabilizer
Atypical antipsychotic
Atypical antipsychotic
Antipsychotic
Pharmacotherapy in Severe Personality Disorders
Meta-analysis of 21 retrieved studies-Borderline & Schizotypal P.D.
Cognitive perceptual
symptoms
Impulsive behavioral
dyscontrol
Affective dysregulation
Depressed mood
Anxiety
Anger
Global functioning
AP
AD
MS
S (++)
NS
NS
NS
NS
S (++++)
NS
NS
S (++/+++)
S (+/++)
NS
S (+/++)
S (+/++)
NS
S (++)
HS (+++)
S (++++)
S (+++)
NS = Not significant, S = Significant, HS = Highly significant
(+) = Small, (++) = Moderate, (+++) = Large, (++++) = Very large
Ingehoven T et al. J. Clinical Psychiatry 71(1):14-25, 2010
Pharmacotherapy for Substance Use Disorders
• Drugs for intoxication/withdrawal
• Aversive agents
– Disulfiram (Antabuse)
• Maintenance agents
– Methadone
– Buprenorphine (Suboxone/Subutex)
• Anticraving agents
– Nicotine replacement therapy (NRT)
– Naltrexone (ReVia. Vivitrol)
– Acamprosate (Campral)
– Varenicline (Chantix)
– Topiramate (Topamax) - ?