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) Imipramine (Tofranil)
– Nortriptyline (Pamelor) Desipramine (Norpramin)
• Selective Serotonin Reuptake Inhibitors (SSRI)
• Serotonin and Norepinephrine Reuptake
inhibitors (SNRI)
• Atypical antidepressants
– Bupropion (Wellbutrin) Nefazodone (Serzone)
• On the horizon
Selective Serotonin Reuptake Inhibitors (SSRI)
1. Examples
Sertraline (Zoloft) Fluoxetine(Prozac)
Citalopram (Celexa) Escitalopram
(Lexapro)
Paroxetine (Paxil) Fluvoxamine
(Luvox)

2. Mechanism of Action
Blocks re-uptake of serotonin thereby
increasing serotonin in the synapse
 SSRI - FDA Approved Indications
MD PMDD OCD PD PTSD GAD SP BN
Sertraline (Zoloft) X X X X X X
Paroxetine (Paxil) X X X X X X X
Fluoxetine (Prozac) X X X X X
Citalopram (Celexa) X
Escitalopram (Lexapro) X X
Fluvoxamine (Luvox) 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 Bupropion (Wellbutrin)
Cyproheptadine (Periactin)
“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
MDD GAD PD SAD FM
Desvenlafaxine (Pristiq) X
Duloxetine (Cymbalta) X X X
Mirtazapine (Remeron) X
Venlafaxine (Effexor-XR) X 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 Thyroid hormone
– Antipsychotic Estrogen
7. ECT/Focal Brain Stimulation
 Focal Brain Stimulation
• Vagal Nerve Stimulation • Transcranial magnetic
(VNS) stimulation (TMS)
– Pulse generator implanted – Uses an electromagnetic
in the left chest wall coil placed against the
– Electrode wrapped around scalp to create a rapidly
the left vagus nerve changing magnetic field
– Pulse on for 30 seconds and that depolarizes neurons.
off for 5 minutes – Outpatient procedure
– Efficacy = ? – 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
STAR*D Results Rate Rate
Step 1
Citalopram 3,671 36.8% 48.6%
Step 2
Switch to bupropion, sertraline, 1,439 30.6% 28.5%
venlafaxine, or CBT, OR augment
with bupropion, buspirone, or CBT
Step 3
Switch to Mirtazapine, nortriptyline 390 13.7% 16.8%
OR augment with lithium or T3
Step 4
Switch to tranylcypromine or 123 13% 16.3%
venlafaxine plus mirtazapine

(RushAJ 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 Half-life Active Anxiolytic dose Approximate dose
(hr) metabolites range (mg/day) equivalency (mg)
Alprazolam (Xanax) 12 Yes 0.5-4 0.25
Chlordiazepoxide (Librium) 100 Yes 15-100 10
Clonazepam (Klonopin) 34 No 0.5-10 0.5
Clorazepate (Tranxene) 100 Yes 7.5-60 7.5
Diazepam (Valium) 100 Yes 2-40 5
Lorazepam (Ativan) 15 No 2-4 1
Oxazepam (Serax) 8 No 30-120 15
Taken from: Kaplan SI, Sadock BJ. Kaplan & Sadock’s Synopsis of Psychiatry, 8 th ed.,
Lippincott, Williams & Wilkins, Philadelphia, 1998, p. 996.

Advantages Disadvantages
-Rapid onset of action -Physiologic dependence
-Highly effective -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 Disadvantages
• High efficacy • Can take 2-8 weeks or
• Non-addicting longer to be effective
• Effective for a number • Side effects
of conditions • 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 Negative symptoms

• Hallucinations • Blunted affect
• Delusions • Emotional withdrawal
• Disorganization • Social withdrawal
• Agitation • Anhedonia
 FDA Approved Indications for Atypical Antipsychotics

Indication OLA RIS ILO QUE ZIP ARI ASEN

Schizophrenia X X X X X X X
Schizoaffective X
Disorder
Bipolar X X X X X X
Mania/Mixed
Bipolar X X
Depression
Adjunct in X X X
MDD

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
Anticholinergic - +++ ++++ - +++ - -
EPS +++++ +++ + ++ + + ++
Sedation + ++++ +++++ + +++ +++ ++
Orthostasis + +++ ++++ + + + +
Weight gain + +++ ++++ ++ +++ + -
Lipid increase - ?? +++ ?? ++ ?? -
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 Weight Gain ↑FBS ↑ Lipids
Clozapine +++ +++ +++
Olanzapine +++ +++ +++
Quetiapine ++ ++ ++
Risperidone ++ ++ ++
Aripiprazole 0 0 0
Ziprasidone 0 0 0
Risk of adverse effects at therapeutic doses:
0 = None, ++ = Sometimes, +++ = Frequently
J. Clin. Psych 2004: 66; 267-272
 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 All Cause
(months) Discontinuation Rate
Olanzapine 9.2 64%
Perphenazine 5.6 75%
Quetiapine 4.6 82%
Risperidone 4.8 74%
Ziprasidone 3.5 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.psychosis-
bipolar.com/information-about-
psychoses-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 Treatment Options
Mania 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 Pharmacotherapy Option
Affective symptoms SSRI/SNRI
Atypical antidepressant
Mood stabilizer
Mood dysregulation/ Mood stabilizer
impulsivity Anticonvulsant mood
stabilizer
Atypical antipsychotic
Psychotic/para-psychotic Atypical antipsychotic
symptoms Antipsychotic
 Pharmacotherapy in Severe Personality Disorders
Meta-analysis of 21 retrieved studies-Borderline & Schizotypal P.D.

AP AD MS
Cognitive perceptual S (++) NS NS
symptoms
Impulsive behavioral NS NS S (++++)
dyscontrol
Affective dysregulation
Depressed mood NS NS S (++)
Anxiety NS S (+/++) HS (+++)
Anger S (++/+++) S (+/++) S (++++)
Global functioning S (+/++) NS 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) - ?