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Glenn J. Treisman, MD, PhDEugene Meyer III Professor of Psychiatry and Medicine

Director, AIDS Psychiatry ServiceJohn Hopkins University School of Medicine

Baltimore, Maryland

Psychopharmacology For

Every HIV Clinician

FLOWED: 04/08/16

Washington, DC: April 15, 2016

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Financial Relationships With Commercial Entities

Dr Treisman has no relevant financial affiliations

to disclose. (Updated 04/15/16)

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Disclosures

• I have no relevant financial disclosures

• When a patient has not gotten better and comes to see me, if there is no evidence based treatment with good data, I prefer doing something rather than nothing, as they have already had nothing and it is not working.

• This experience may influence my discussion

• I will probably say lots of off-label things about psychotropics-lots!

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Classification of Drugs

–Chemical class

–Origin-plant family

–Condition usually treated

–Physiologic actions (sympatholytic, mimetic)

–Receptor activity

–Mechanism of action• Agonists, antagonists, partial agonists, reverse agonists

• Muscarinic, nicotinic,

• Reuptake blocker, precursor

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Classification by Condition

• Major depression-antidepressants

• Bipolar disorder-mood stabilizers

• Schizophrenia-antipsychotics

• Anxiety disorders-anxiolytics

• Insomnia-hypnotics

• ADHD-stimulants/others

• Dementia-cognitive enhancers

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Classification by Drug Class-Tricyclic Antidepressants

• Major depression

• Generalized anxiety disorder

• Social phobia

• Obsessive-compulsive disorder

• Panic disorder

• Post-traumatic stress disorder

• Body dysmorphic disorder

• Anorexia and bulimia

• Attention-deficit hyperactivity disorder

• Parkinson's disease

• Chronic pain

• Migraine

• Tourette syndrome

• Irritable bowel syndrome

• Interstitial cystitis

• Nocturnal enuresis

• Narcolepsy

• Insomnia

• Pathological laughter

• Chronic hiccups

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Psychopharmacology in the Clinic

• Rational therapeutics starts with diagnosis

• Pathophysiologic target and disease eradication

• Replacement

• Syndrome suppression

• Symptomatic suppression

• Cosmetic therapy

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Psychiatry

• Rarely has a specific disease to eradicate

• Replacement is uncommon

• Few syndromes

• Mostly symptom suppression

• Too much cosmetic psychiatry

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Therapeutic vs Symptomatic(In psychiatry we need to beware cosmetic psychopharmacology)

Therapeutic

• Drug effects try to counter or correct pathology

• Goal is to improve function

• Antidepressants

• Neuromodulators

Symptomatic

• Drugs block or activate pathways that produce symptoms

• Goal is to make people feel better

• Anxiolytics

• Opiates

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Antidepressants-uses

• Major depression

• Panic attacks-most

• Chronic pain-TCAs and SNRIs

• GI disturbance-TCAs inhibit, SSRIs activate

• Migraine-TCAs and some atypicals, SNRIs

• OCD-SSRIs, SNRIs, some TCAs

• Attention deficit disorder TCAs

• Generalized Anxiety disorder-SSRIs, SNRIs, TCAs

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Antidepressant-classes

• Tricyclic Antidepressants

• Monoamine Oxidase Inhibitors

• Selective Serotonin Reuptake Inhibitors SSRIs

• SNRIs

• Bupropion

• Mirtazapine

• Trazodone and Nefazodone (Vilazodone)

• Maprotiline

• Vortioxetine

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Depression

stressdemoralization

CNS inflammationsubstance abusesubcortical injury

cognitive impairment

HIV/Hep Cimpulsivity

hopelessnesscarelessness

demoralizationsubstance abuse

cognitive impairment

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Pharmacotherapy For Depression

• Poor sleep

• Weight loss

• Anxiety

• G.I. disturbance

DesipramineNortriptyline

(other TCAs)(Maprotiline)

• Hypersomnia

• Weight gain

• Suicide potential

• Chronicity

CitalopramEscitalopram FluoxetineFluvoxamineParoxetineSertralineVenlafaxineDuloxetineDesvenlafaxineMilnacipranLevomilnacipran

Failure from side effects

AugmentationAntipsychotics, Thyroid, Pindolol, Lamotrigine, Dopamine agonists

Failure after adequate trial

BupropionNefazodoneMAOIsTrazodoneMirtazapineVilazodoneVortioxetine

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Two Ways to Think About Depression

Major DepressionCategorical Demoralization(Sadness/Grief)

Dimensional

Major DepressionDemoralization(Sadness/Grief)

Severity

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Mean Standardized Improvement as a Function of Initial Severity

Kirsch I, et al. PLoS Med. 2008;5:e45.

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16

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rove

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Initial Severity, baseline HRSD

Clinically significantdifference

20 32

1.5

1.0

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24 28

DrugPlacebo

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SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant.Walsh BT, et al. JAMA. 2002;287:1840-1847.

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1980 1985 1990 1995 2000

Placebo(n=75)

TCA(n=43)

SSRI(n=33)

Pro

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Publication Year

Patients With ≥50% Improvement on SSRI, TCA, or Placebo

Slide 17 of 51© 2014 by Lippincott Williams & Wilkins. Published by Lippincott Williams & Wilkins, Inc.

Placebo vs 10 mg of Escitalopram

Escitalopram Treatment of Depression in Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome: A Randomized, Double-Blind, Placebo-Controlled Study.Hoare, Jacqueline; MD, FCPsych; Carey, Paul; Joska, John; MMed, FCPsych; Carrara, Henri; Sorsdahl, Katherine; Stein, Dan; FCPsych, PhDJournal of Nervous & Mental Disease. 202(2):133-137, February 2014.

FIGURE 1 . MADRS improvement over time in both placebo and treatment group.

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Tricyclic Antidepressants (TCAs)• Imipramine and Amitriptyline (late 1950s)

• Nortriptyline, Desipramine, Doxepin, Protriptyline

• Need blood levels (but they predict therapy)

• Alpha blocking, Antimuscarinic

• Cause sedation, weight gain, dry mouth, constipation

• Cardiotoxicity (dangerous in overdose)

• EKG in overdose predicts lethality

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Tricyclic Antidepressants (TCAs) Common Uses

• Chronic pain

• Neuropathy

• Post-herpetic neuralgia

• Migraine

• GI spasm

• Diarrhea

• Insomnia (doxepin)

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SSRIs (Black Box for Suicidal Ideas)

• Fluoxetine- long half life, little sedation

• Sertraline- GI activating

• Paroxetine- sedating, weight gain, short half life (beware withdrawal syndrome) (CR formulation)

• Fluvoxamine- indication for OCD

• Citalopram- less activating but not sedating (black box for QT)

• Escitalopram- isomer of citalopram

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SSRIs

• Akathisia- restlessness, different than neuroleptics, very unpleasant, a suicide risk?

• Anorgasmia- decreased sex drive

• Apathy

• Suicidality? Children and Adolescents? Old data on antidepressants and activation

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SSRIs Common Uses

• Gastroparesis

• Chronic constipation

• Panic attacks

• Generalized anxiety

• OCD

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SNRIs

• Similar to SSRIs

• Efficacy in chronic pain on a par with TCAs

– Venlafaxine

– Duloxetine

– Desvenlafaxine

– Milnacipran

– Levomilnacipran

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Bupropion

• Least sexual side effects

• Least sedating

• Decreases nicotine craving

• Decreases Etoh craving

• Sometimes good for ADHD

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Heterocyclic Antidepressants

• Trazodone- very sedating, used mostly for sleep, effective for depression at high doses

• Nefazodone- specific liver toxicity, LSD like visual “trails” (great drug, no one uses it because of the liver issue)

• Vilazodone-?

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Mirtazapine

• Safer than TCAs with many similar advantages

• Sedation and improved sleep

• Pain efficacy

• Weight gain

• Did I mention weight gain?

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Monoamine Oxidase Inhibitors (MAOIs)

• Tyramine poisoning

• Serotonin syndrome

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For Newer Antidepressants

• Drug trials only have to be better than placebo at 9-12 weeks

• The trials are underdosed (in my opinion) and patients need higher doses, particularly for pain

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Other Drugs and Conditions that Everyone Will Encounter

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Psychosis

• Distinguish between delirium and psychotic states

• Delirium-waxing and waning, poor ability to attend, change in the level of consciousness, almost always organic and needs urgent workup

• Psychosis-almost always a product of schizophrenia, bipolar disease or depression, and in clear consciousness

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Agitation

• Must develop a differential diagnosis-delirium, psychosis, unreduced week old hip fracture, hunger, constipation

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Antipsychotics-Neuroleptics

• Used in

– Schizophrenia

– Bipolar and depression induced psychosis

– Sedation for agitation

• First generation (“typical”) (D-2 blockers)

• Second generation (“atypical”)

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Schizophrenia• Affects 1-2% of the world’s population

• 3.2 million Americans

• 25 % of all mental health costs (US)

• One third of psychiatric hospital beds

• U.S. $62.7 billion 2002

– $22.7 billion excess direct health care costs

– $7.0 billion outpatient

– $5.0 billion drugs

– $2.8 billion inpatient

– $8.0 billion long-term care

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Neuroleptic Side Effects (Less in Newer Drugs-Not None)

• EPS: Acute dystonic reactions, akathisia, parkinsonism

• Tardive dyskinesia

• Neuroleptic malignant syndrome

• Seizures, dry mouth, blurred vision, urinary retention, constipation, orthostatic hypotension, slowed cardiac conduction, hyperprolactinemia, weight gain, predispose to heat stroke, photosensitivity, lupus-like reactions, cholestatic jaundice, agranulocytosis

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Problems with Neuroleptics

• Poor patient adherence/acceptance• Weight gain• Insulin resistance (and other markers of metabolic disorder)• Increased lipid levels• QT prolongation • Sedation • Akathisia• Apathy • Cognitive impairment (patients describe a zombie-like effect)• Dystonia and movement difficulty (Parkinson’s-like features)• Marked differences in therapeutic effectiveness that is patient specific

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Atypical Neuroleptics

Clozapine Agranulocytosis, weight gain, alpha blockade, sedation, salivation

Risperidone Weight gain, dystonia, tardive dyskinesia

Olanzapine Weight gain, sedation, weight gain, weight gain, insulin resistance

Quetiapine Sedation, transaminitis, cataracts, weight gain, insulin resistance

Ziprasidone Less sedation, little weight gain, more motor effects

Aripiprazole Less sedation, little weight gain, more motor effects

Asenapine High sedation but short half life, sublingual only

Lurasidone Less sedation, better tolerated?

IloperidoneBrexpiprazoleCariprazine

Too new

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Managing Side Effects

• Acute dystonia: Diphenhydramine 25-50 mg I.V., benztropine mesylate 1-2 mg I.V. or I.M.

• Akathisia: unpleasant sensation of motor restlessness most in legs, pts may appear agitated or pace, careful not to mistake it for worsened psychosis- beta blockers or benzo

• Parkinsonism: oral anticholinergics or dopamine agonists (amantadine)

• Tardive dyskinesia: risk factors- elderly, female, diabetic, high dosage, long duration treatment, concomitant mood disorder.

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Injected Long-Acting Antipsychotics

• Fluphenazine decanoate (fluphenazine)

• Haloperidol decanoate (haloperidol)

• Risperidone microspheres (risperidone)

• Olanzapine pamoate (olanzapine)

• Aripiprazole extended release (aripiprazole)

• Aripiprazole lauroxil (aripiprazole lauroxil)

• Paliperidone palmitate, 4-week (paliperidone)

• Paliperidone palmitate, 12-week (paliperidone)

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Neuroleptics vs Benzodiazepines for Agitation

• Few studies of benzodiazepines show efficacy for treatment of agitation

• The positive studies mostly used the endpoint of sedation

• The use of benzodiazepines for agitation remains contentious

• Many studies show that it is possible to decrease neuroleptic dose with benzo augmentation

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The Drugs Everyone Wants

• There are drugs with less than 100% compliance and drugs with more than 100% compliance

• This is the 2nd group

• Sedative-Hypnotics and anxiolytics

• Stimulants

• Opiates

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Anti-Anxiety Agents (Sedative-Hypnotics)

• Alcohol

• Bromides (potassium bromide) mid 1800s

• Chloral Hydrate 1869

• Phenobarbital (1912)

• Meprobamate (1955)

• Chlordiazepoxide (1960)

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Anti-Anxiety Agents (Sedative-Hypnotics)

• Non-specifically decrease anxiety (symptomatic rather than therapeutic)

• Produce euphoria and are positively reinforcing

• Produce tolerance, dependence and withdrawal

• Withdrawal can be life threatening

• Are “addictive”

• Are widely used for “cosmetic” reasons

• This includes the “z-drugs”– Eszopiclone

– Zaleplon

– Zolpidem

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Sedative Hypnotics

• Abortive for panic attacks but not good for chronic treatment

• Great for sleep but not good for chronic treatment

• These drugs are very useful when used sparingly

• It is very difficult to get the patient off of them

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Stimulants

• I have ADHD and need my …

• Stimulants are powerful reinforcers

• ADHD is a real disorder, but many patients get started on it for cosmetic reasons

• In clinical trials, TCAs and atomoxetine are as effective, but have no street value

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What do I do when my patients are already on narcotics, benzodiazepines or stimulants?

• Gradual taper over a year

• Use the drug to increase function

• Sometimes you have to say no

• Get expert advice when you get stuck

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Increased Patient Satisfaction Correlates with Increased Mortality

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leastsatisfied

2 3 mostsatisfied

all patients

patients in good health

The cost of satisfaction: a national study of patient satisfaction, health care utilization, expenditures, and mortality. Fenton JJ, Jerant AF, Bertakis KD, Franks P. Arch Intern Med. 2012 Mar 12;172(5):405-11.