Update in Clinical Psychopharmacology

Peter A. DeMaria, Jr., M.D., FASAMTuttleman Counseling Services

Temple UniversityClinical Associate Professor of Psychiatry

Temple University School of MedicinePhiladelphia, 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 inGoodman & 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. ExamplesSertraline (Zoloft) Fluoxetine(Prozac) Citalopram (Celexa) Escitalopram

(Lexapro)Paroxetine (Paxil) Fluvoxamine

(Luvox)

2. Mechanism of ActionBlocks 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” Effect1. 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)

MDD GAD PD SAD FM

Desvenlafaxine (Pristiq) X

Duloxetine (Cymbalta) X X X

Mirtazapine (Remeron) X

Venlafaxine (Effexor-XR) X X X X

• Mechanism of Action

• Examples and Indications

• Side Effects

MDD = Major depressive disorder, GAD = Generalized anxiety disorder, PD = Panic disorder, SAD = Social anxiety disorder, FM = Fibromyalgia.

Treatment Resistant Depression1. 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

(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 =?

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

STAR*D Results N RemissionRate

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 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(hr)

Activemetabolites

Anxiolytic doserange (mg/day)

Approximate doseequivalency (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 cognitionAnterograde 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 SSRIClomipramine

Social anxiety disorder SSRI/SNRI

Panic disorder SSRI/SNRITCABenzodiazepine

PTSD SSRI

Generalized anxiety disorder SSRI/SNRIBenzodiazepineBuspirone

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 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

Atypical (2nd Generation) AntipsychoticsSide 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, +++ = FrequentlyJ. 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 (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%

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 Disorders1. Mood stabilizers

Lithium2. 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 antipsychoticCarbamazepine/oxcarbamazepineLi/VP + atypical antipsychoticElectroconvulsive therapy (ECT)

Depression Optimize mood stabilizerLamotrigineQuetiapineOlanzapine/fluoxetineMood 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 DisordersSymptom targeted

Symptom Spectrum Pharmacotherapy Option

Affective symptoms SSRI/SNRIAtypical antidepressantMood stabilizer

Mood dysregulation/impulsivity

Mood stabilizerAnticonvulsant mood stabilizerAtypical antipsychotic

Psychotic/para-psychotic symptoms

Atypical antipsychoticAntipsychotic

Pharmacotherapy in Severe Personality DisordersMeta-analysis of 21 retrieved studies-Borderline & Schizotypal P.D.

AP AD MSCognitive perceptual symptoms

S (++) NS NS

Impulsive behavioral dyscontrol

NS NS S (++++)

Affective dysregulation Depressed mood Anxiety Anger

NSNS

S (++/+++)

NSS (+/++)S (+/++)

S (++)HS (+++)S (++++)

Global functioning S (+/++) NS S (+++)

NS = Not significant, S = Significant, HS = Highly significant(+) = Small, (++) = Moderate, (+++) = Large, (++++) = Very largeIngehoven 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) - ?