Update in Clinical Psychopharmacology

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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

2
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.

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Treatment Planning

• 1. Medication
• 2. Psychotherapy
• 3. Combined medication and psychotherapy

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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

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Neurotransmission
Taken from Bloom FE, Neurotransmission in the
Central Nervous System in Goodman Gilmans
Pharmacological Basis of Therapeutics, 9th Ed, p.
270
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Pharmacokinetics
Taken from Julien, R. A Primer of Drug Action.
WH Freeman Co., New York, 1998. p. 25.
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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)

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Selecting a Psychotropic Agent

• Diagnosis/symptom complex
• Patients prior response
• Family members experience
• FDA approved indication
• Pharmacologic actions
• Documented efficacy
• Side effect profile
• Insurance coverage/finances
• Patient preference

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DSM-IV Classification of Depressive Disorders

• Adjustment disorder with depressed mood
• Dysthymia
• Major depression (MDD)
• Premenstrual Dysphoric disorder (PMDD)

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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

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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

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SSRI - FDA Approved Indications

• Therapeutic Response
• Can take between 2 and 8 weeks
• Response is gradual
• Others may notice the response before the
• patient does

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SSRI/SNRI Side Effects

• Gastrointestinal
• Anxiety/insomnia
• Flushing/night sweats
• Vivid dreams
• Weight change
• Sexual dysfunction

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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)

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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

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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.

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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.
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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

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Focal Brain Stimulation

• Vagal Nerve Stimulation (VNS)
• 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 ?

• Transcranial magnetic stimulation (TMS)
• 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 ?

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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 lt 50
2 50-90
3 or more gt90
Taken from Stahl S. Essential Psychopharmacology
Neuroscientific Basis and Practical
Applications. 2nd Ed., Cambridge University
Press. 2000, p. 150.)
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FDA Suicide Warning

• Black Box Warning
• All antidepressants
• Increased risk of suicidal thinking and behaviors
• Affects 18-24 y/o

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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

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STARD

• Largest (n4041, 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 (lt 5 on the QIDS-C16)
• Treatment involved 6 levels with patient ability
  to choose options
• Available at www.star-d.org

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STARD Results N Remission Rate Response Rate
Step 1 Citalopram 3,671 36.8 48.6
Step 2 Switch to bupropion, sertraline, venlafaxine, or CBT, OR augment with bupropion, buspirone, or CBT 1,439 30.6 28.5
Step 3 Switch to Mirtazapine, nortriptyline OR augment with lithium or T3 390 13.7 16.8
Step 4 Switch to tranylcypromine or venlafaxine plus mirtazapine 123 13 16.3
(Rush AJ et al. Acute and longer-term outcomes
in depressed outpatients requiring one or several
treatment steps a STARD report. Am J Psych
1631905-1917, 2006.)
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STARD

• 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 STARD project results a
  comprehensive review of findings. Current
  Psychiatry Reports 9449-459, 2007.)

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Break Time
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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

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Benzodiazepines
Taken from Kaplan SI, Sadock BJ. Kaplan
Sadocks Synopsis of Psychiatry, 8th ed.,
Lippincott, Williams Wilkins, Philadelphia,
1998, p. 996.
Advantages Disadvantages -Rapid onset of
action -Physiologic dependence -Highly
effective -Addicting -Impaired
cognition Anterograde amnesia
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J of Clin. Psychiatry, 60(5), 252, May 1999
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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                  
MDDmajor depressive disorder, PMDDperi-menstrual
dysphoric disorder, PD panic disorder,
PTSDpost-traumatic stress disorder,
GADgeneralized anxiety disorder,
OCDobsessive-compulsive disorder, SPsocial
phobia, BN bulimia nervosa, ND nicotine
dependence, FM fibromyalgia
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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

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Other Options for Anxiety Disorders

• Buspirone (BuSpar)
• Beta blockers
• Combinations
• SSRI/SNRI Benzodiazepine
• Antipsychotics
• Trifluoperazine (Stelazine)
• Quetiapine (?)
• Pregabalin (?)

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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
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DSM-IV Psychotic Disorders

• 1. Schizophreniform disorder
• 2. Schizophrenia
• 3. Schizoaffective disorder
• 4. Brief psychotic disorder

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The Disease Process

• Positive Symptoms
• Hallucinations
• Delusions
• Disorganization
• Agitation

• Negative symptoms
• Blunted affect
• Emotional withdrawal
• Social withdrawal
• Anhedonia

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FDA Approved Indications for Atypical
Antipsychotics
Indication OLA RIS ILO QUE ZIP ARI ASEN
Schizophrenia X X X X X X X
Schizoaffective Disorder X
Bipolar Mania/Mixed X X X X X X
Bipolar Depression X X
Adjunct in MDD X X X
OLA Olanzapine, RIS Risperidone, ILO
Iloperidone, QUE Quetiapine, ZIP Ziprasidone,
ARI Aripiprazole, ASEN Asenapine
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Atypical (2nd Generation) Antipsychotics
HLhaloperidol (Haldol), CPZchlorpromazine
(Thorazine), CLZclozapine (Clozaril),
RISrisperidone (Risperdal), OLZolanzapine
(Zyprexa), QTPquetiapine (Seroquel),
ZIPziprasidone (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.)
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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
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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) All Cause Discontinuation Rate
Olanzapine 9.2 64
Perphenazine 5.6 75
Quetiapine 4.6 82
Risperidone 4.8 74
Ziprasidone 3.5 79
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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.

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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

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The Heterogeneity of Bipolar Disorder
Taken from http//www.psychosis-bipolar.com/infor
mation-about-psychoses-57.htmlTaken
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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)

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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

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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.
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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

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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)

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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

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Pharmacotherapy for Personality DisordersSymptom
targeted
Symptom Spectrum Pharmacotherapy Option
Affective symptoms SSRI/SNRI Atypical antidepressant Mood stabilizer
Mood dysregulation/ impulsivity Mood stabilizer Anticonvulsant mood stabilizer Atypical antipsychotic
Psychotic/para-psychotic symptoms Atypical antipsychotic Antipsychotic
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Pharmacotherapy in Severe Personality
DisordersMeta-analysis of 21 retrieved
studies-Borderline Schizotypal P.D.
AP AD MS
Cognitive perceptual symptoms S () NS NS
Impulsive behavioral dyscontrol NS NS S ()
Affective dysregulation Depressed mood Anxiety Anger NS NS S (/) NS S (/) S (/) S () HS () 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
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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) - ?

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