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Psychotropic Medications. Dale Sanderson, PA-C Physician Assistant Seattle Mental Health. ► SSRI antidepressants ► Atypical antidepressants ► Tricyclic antidepressants ► MAOI antidepressants ► Older mood stabilizers ► Newer mood stabilizers ► Older antipsychotics

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psychotropic medications

Psychotropic Medications

Dale Sanderson, PA-C

Physician Assistant

Seattle Mental Health

overview
► SSRI antidepressants

► Atypical antidepressants

► Tricyclic antidepressants

► MAOI antidepressants

► Older mood stabilizers

► Newer mood stabilizers

► Older antipsychotics

► Newer antipsychotics

► Anticholinergics

► Benzodiazepines

► Other anxiolytic/hypnotics

► Stimulants

► Meds for dementia

► Meds for substance abuse

► Psychiatric uses of antihypertensives

Overview
introduction
SSRI antidepressants

Atypical antidepressants

Tricyclic antidepressants

MAOI antidepressants

Older mood stabilizers

Newer mood stabilizers

Older antipsychotics

Newer antipsychotics

Anticholinergics

Benzodiazepines

Other anxiolytic/hypnotics

Stimulants

Meds for dementia

Meds for substance abuse

Psychiatric uses of antihypertensives

FDA approval process

Advantages & limitations

driven by public’s concerns about safety

study population vs. “real world”

drug company agenda for approval

Indication vs. off-label use and dosing

1982 position report

Side-effect listing

cause & effect?

Introduction
introduction4
Choosing a medication

diagnosis

benefit vs. side-effects, toxicity, ease of use, drug-drug interactions (www.drug-interactions.com, www.drugs.com )

medication history, family history

Starting, stopping & changing

luxury of time

cross tapering

one change at a time

Response rate

response vs. remission

the right diagnosis

treatment failures

Introduction
ssri antidepressants
SSRI antidepressants

Atypical antidepressants

Tricyclic antidepressants

MAOI antidepressants

Older mood stabilizers

Newer mood stabilizers

Older antipsychotics

Newer antipsychotics

Anticholinergics

Benzodiazepines

Other anxiolytic/hypnotics

Stimulants

Meds for dementia

Meds for substance abuse

Psychiatric uses of antihypertensives

Selective Serotonin

Reuptake Inhibitor

1988 Prozac introduced

1992-93 Zoloft, Paxil, Luvox

1998 Celexa

2001 fluoxetine (Prozac generic)

2002 Lexapro (modified Celexa)

2006 STAR*D trial results published

http://www.nmha.org/research/star/faqs.cfm

Annual sales = $12 billion

Number of patient starts on Prozac, Paxil or Zoloft from 1988 to 2002 = 67.5 million (www.ahrp.org)

SSRI antidepressants
ssri antidepressants6
Mechanism of action

Inhibit serotonin reuptake so increase synaptic serotonin levels

Many SSRIs affect other receptors especially at high doses

Clinical effect usually takes weeks so mechanism goes beyond simply increasing synaptic serotonin levels

Several serotonin (5-HT) receptor subtypes

Serotonin receptors are located throughout the body (especially GI tract)

SSRI antidepressants
ssri antidepressants7
Indications & off-label uses

All except Luvox FDA approved to tx depression (major depressive d/o and dysthymia)

Various class members also approved to treat: generalized anxiety d/o, OCD, panic d/o, PTSD, eating disorders, premenstrual dysphoric d/o, social anxiety d/o

Off-label uses- ADHD, insomnia, chronic pain syndromes, seasonal affective d/o, behavioral problems in individuals with dementia and mental retardation, … other uses

SSRI antidepressants
ssri antidepressants8
Half-life

Short: paroxetine & fluvoxamine (missed doses can result in uncomfortable symptoms)

Moderate: sertraline, citalopram, escitalopram

Long: fluoxetine (good for people who may miss doses)

SSRI antidepressants
ssri antidepressants9
Side effects

Decreased sex drive and impaired sexual function tend not to resolve with time

Nausea, diarrhea, anorexia, vomiting

- all increase with dose and can resolve with time

Weight gain (esp. paroxetine) after initial GI effects

Headache, dizziness, anxiety (esp. fluoxetine), rash, insomnia, sedation, sweating, vivid dreams, tremor, dry mouth (esp. paroxetine), bruising, ↑ prolactin

SSRI antidepressants
ssri antidepressants10
Drug-drug interactions (DDI)

Luvox > Prozac > Paxil > Zoloft > Celexa > Lexapro

Interacting effects may be dose dependent (Zoloft)

SSRI levels tend not to be altered by other drugs but can potentially increase levels (inhibit metabolism) of certain drugs

Examples:

paroxetine > ↑ risperidone

fluoxetine > ↑ buspirone

fluvoxamine > ↑ olanzapine

(consult references such as www.drug-interactions.com , www.drugs.com, others)

SSRI antidepressants
ssri antidepressants11
Cautions

Suicidal ideation and ↑ suicide risk especially with children early in tx but significant debate

Serotonin syndrome (SSRI + MAOI, possibly lithium, others)

>> diarrhea, tremor, sweating, restlessness, hyperreflexia

progression of symptoms if untreated► ► ►

>> disorientation, rigidity, fever >> coma, seizures >> >> death (approximately 10% mortality rate)

Many medications/substances have serotonin activity:

dextromethorphan, fentanyl, meperidine, sumatriptan,

St John’s Wort, MDMA (ecstasy), LSD, many others…

SSRI antidepressants
ssri antidepressants12
citalopram (Celexa)

Few drug-drug interactions (DDIs)

High serotonin specificity

Typical or lessSSRI side effects

escitalopram (Lexapro) – no generic available

Simple dosing

“S” molecule of the “S” & “R” mirror-image mixture of citalopram molecules

fluoxetine (Prozac, Sarafem, Symbyax-with Zyprexa)

Very long half-life

Significant DDIs

Can be activating

SSRI antidepressants
ssri antidepressants13
fluvoxamine (Luvox)

OCD indication

Multiple significant DDIs

paroxetine (Paxil)

Significant DDIs

Some reports of associated weight gain

“Withdrawal” symptoms with missed doses

sertraline (Zoloft)

Moderate DDIs

Multi-step dosing

SSRI antidepressants
atypical antidepressants
SSRI antidepressants

Atypical

antidepressants

Tricyclic antidepressants

MAOI antidepressants

Older mood stabilizers

Newer mood stabilizers

Older antipsychotics

Newer antipsychotics

Anticholinergics

Benzodiazepines

Other anxiolytic/hypnotics

Stimulants

Meds for dementia

Meds for substance abuse

Psychiatric uses of antihypertensives

Newer antidepressants that are not/less serotonin specific or affect serotonin differently than SSRIs

1981- Desyrel (trazodone)

1989- Wellbutrin (bupropion)

1993- Effexor (venlafaxine)

1994- Serzone (nefazodone)

1996- Remeron (mirtazapine)

2004- Serzone discontinued although generics still available

2004- Duloxetine (Cymbalta)

Atypical antidepressants
atypical antidepressants15
Mechanism of action

venlafaxine and duloxetine are both serotonin and norepinepherine reuptake inhibitors- “SNRIs”

mirtazapine has serotonin subtype & norepinephrine activity

trazodone, nefazodone have different serotonin activity than SSRIs

bupropion has dopamine and norepinephrine activity

Atypical antidepressants
atypical antidepressants16
Indications & off-label uses

All have FDA approval to treat depression

SNRIs shown effective in chronic neuropathic pain

Nicotine addiction (bupropion)

Augment SSRIs, reduce (?) SSRI sexual side effects

Insomnia (mirtazepine, trazodone)

Many similar uses to SSRIs

bupropion, mirtazepine, trazodone & nefazodone do not usually have associated sexual dysfunction

Atypical antidepressants
atypical antidepressants17
venlafaxine (Effexor)

Similar to TCAs with less safety & side effect concerns

FDA approval for depression and generalized anxiety d/o & social anxiety d/o

SNRI- activity depends on dose

Minimal DDI

SE with missed doses

duloxetine (Cymbalta)

SNRI profile minimally dose dependent

Indicated for depression & chronic neuropathic pain

Atypical antidepressants
atypical antidepressants18
bupropion (Wellbutrin, Zyban)

NE, dopamine reuptake inhibition

Can be activating

Zyban to tx smoking addiction

Seizure risk in certain patients (↑ risk at ↑ dose)

Potential DDIs not often significant (except MAOIs)

mirtazapine (Remeron)

Complex serotonin, NE (α2) & histamine activity

Receptor activity changes with changes in dose

Sedation & weight gain especially at lower dose

Lipid abnormalities

Minimal DDIs (except MAOIs)

Atypical antidepressants
atypical antidepressants19
nefazodone (Serzone)

Rarely used due to irreversible liver toxicity

Pulled from market by initial manufacturer in 2004 although still available as generic

Still popular with some patients

trazodone (Desyrel)

Sedation, weight gain, low blood pressure

Used most commonly (off label) for insomnia

Rare reports of sustained painful erection (priapism) that should be treated in ER (can lead to impotence)

Atypical antidepressants
tricyclic antidepressants
SSRI antidepressants

Atypical antidepressants

Tricyclic antidepressants

MAOI antidepressants

Older mood stabilizers

Newer mood stabilizers

Older antipsychotics

Newer antipsychotics

Anticholinergics

Benzodiazepines

Other anxiolytic/hypnotics

Stimulants

Meds for dementia

Meds for substance abuse

Psychiatric uses of non-psychotropic meds

Describes a group of drugs with similar structure and function (abbreviated as TCA)

1958- imipramine failed investigation as an antipsychotic but found to have antidepressant properties.

1960’s- multiple other TCA’s developed and placed into use

1990’s- significant reduction in use due to introduction of SSRIs which have fewer side effects

Tricyclic antidepressants
tricyclic antidepressants21
Mechanism of action

Norepinephrine, serotonin, histamine, muscarinic (cholinergic) and α-adrenergic receptor activity although in differing ratios

Anticholinergic activity leads to many of the side effects of these drugs

Indications & off-label uses

Depression and similar spectrum of disorders as SSRIs

Especially helpful with chronic pain and depression secondary to medical conditions such as AIDS

enuresis, narcolepsy, premature ejaculation, insomnia, migraine prophylaxis

Blood levels: May be obtained to monitor dose effectiveness

Tricyclic antidepressants
tricyclic antidepressants22
Drug-drug interactions (DDI)

Multiple significant interactions in each direction with potentially serious consequences

Side effects (SE)

Anticholinergic SE include: dry mouth, constipation, blurred vision and urinary retention

Cardiac arrhythmias and conduction changes

Orthostatic hypotension

Sedation

Weight gain

Cautions

Overdose is frequently fatal

Pts with bipolar d/o may be pushed into mania or rapid cycling

Tricyclic antidepressants
tricyclic antidepressants23
NE 5HT Ach Sed Comments

amitriptyline (Elavil)………low high high high pain, MgrHA

amoxapine (Asendin)…… high low mod low tetracyclic

clomipramine (Anafranil). low high high high tx OCD; SSRI-like

desipramine (Norpramin) high low low low activating

doxepin (Sinequan)……. low low mod high used for insomnia

imipramine (Tofranil)……. low low mod mod pain; enuresis

maprotiline (Ludiomil)…… high low low mod tetracyclic

nortriptyline (Pamelor)….. mod low mod mod chronic pain

protriptyline (Vivactil)…… high low mod low most activating

trimipramine (Surmontil).. low low high high

NE- noropinephrine activity; 5HT- serotonin activity (5-hydroxy-tryptamine); OCD:Obsessive-compulsive d/o

Ach- anticholinergic effects; Sed- sedation; mod-moderate; MgrHA- migraine headache prophylaxis

Tricyclic antidepressants
monoamine oxidase inhibitors
SSRI antidepressants

Atypical antidepressants

Tricyclic antidepressants

MAOI antidepressants

Older mood stabilizers

Newer mood stabilizers

Older antipsychotics

Newer antipsychotics

Anticholinergics

Benzodiazepines

Other anxiolytic/hypnotics

Stimulants

Meds for dementia

Meds for substance abuse

Psychiatric uses of antihypertensives

Abbreviated as MAOI

1952- First MAOI found with antidepressant properties in process of looking for an antituberculosis drug

1962- Investigation of a death from hypertensive crisis by someone ingesting tyramine rich food while taking an MAOI

1960’s- Institution of strict dietary restriction of tyramine containing foods and other interacting substances.

1960’s- Significant reduction in use due to introduction of TCAs which do not have the severe restrictions of MAOIs.

2006- Transdermal selegiline patch (Emsam) approved to treat depression

Monoamine Oxidase Inhibitors
monoamine oxidase inhibitors25
Features

Effective antidepressant for those who can adhere to the necessary restrictions and tolerate many other side effects

Very long duration requiring caution when mixing with restricted substances or medications

Tyramine containing foods (not a complete list)

Certain ones may be consumed in moderation

Many cheeses, chocolate, soybeans, hot dogs, dry sausage, caffeine, beer, wine, pickles, olives, … etc.

Drug-drug interactions

Multiple prescribed and over-the-counter medications can be potentially lethal. Serotonin syndrome with SSRIs & many others.

Monoamine Oxidase Inhibitors
monoamine oxidase inhibitors26
Available formulations

phenylzine (Nardil);

isocarboxazid (Marplan);

tranylcypromine (Parnate)

Similar medications

selegiline (Eldepryl)

used to treat Parkinson’s symptoms

selective “B” inhibitor at low doses so restrictions not critical

at higher doses acts like typical MAOI and so need restrictions

recently available as transdermal patch (Emsam) to tx depression and not needing food restrictions at low dose although still DDI

reversible selective “A” inhibitors not available in US (no restrictions)

Monoamine Oxidase Inhibitors
mood stabilizers introduction
Treat bipolar disorder (manic-depressive disorder)

Many used to treat various seizure d/o types, migraines, chronic pain syndromes, aggression, impulsivity, augmentation of antidepressants and antipsychotics

Other classes of meds also used in bipolar treatment usually in combination with mood stabilizers

Treatment of acute mania vs. prophylaxis vs. depression

Mood Stabilizers- Introduction
older mood stabilizers
SSRI antidepressants

Atypical antidepressants

Tricyclic antidepressants

MAOI antidepressants

Older mood stabilizers

Newer mood stabilizers

Older antipsychotics

Newer antipsychotics

Anticholinergics

Benzodiazepines

Other anxiolytic/hypnotics

Stimulants

Meds for dementia

Meds for substance abuse

Psychiatric uses of antihypertensives

Lithium, carbamazepine & valproic acid

1949- lithium recognized as antimanic

1949- lithium toxicity identified after being used as substitute for sodium in salt

1966- French researchers demonstrate valproate’s efficacy in treating mania

1978- significant studies demonstrate lithium’s efficacy in bipolar disorder

1980 studies demonstrate effectiveness of carbamazepine in bipolar d/o

Older Mood Stabilizers
older mood stabilizers29
Lithium- features

Only mood stabilizer without significant anticonvulsant properties

up to 70% response rate

demonstrated effectiveness in reducing suicidality

less effective in rapid cycling and mixed bipolar states

full clinical effect may take up to 1-2 months

serum levels guide dosing

lab draw 8-12 hrs after last dose

excreted through the kidneys

minimal liver mediated drug-drug interactions (but see next slide for other medication issues)

Older Mood Stabilizers
older mood stabilizers30
Lithium- side effects

fine tremor, weight gain, nausea

increased thirst and urination

more severe toxicities include coarse tremor, gait instability, vomiting, diarrhea, confusion

increased risk of toxicity with fluid or salt restriction, hot weather/sweating, use of anti-inflammatory drugs, ace inhibitors & angiotensin receptor blockers, diuretics

may cause kidney and thyroid dysfunction so regular monitoring of creatinine, BUN and TSH are necessary

females are at much greater risk of lithium related thyroid dysfunction

Older Mood Stabilizers
older mood stabilizers31
Carbamazepine (Tegretol)- features

used in acute mania and bipolar maintenance

more effective than lithium in rapid cycling & mixed states

less effective in bipolar related depression

serum levels can be helpful in guiding dosing

lab draws 8-12 hours after last dose

multiple significant drug-drug interactions (DDI) affecting both other medications (reducing their levels) & other medications affecting it (increasing carbamazepine levels)

induces its own metabolism so may need to adjust dose over several weeks

Older Mood Stabilizers
older mood stabilizers32
Carbamazepine (Tegretol)- side effects

GI: nausea, constipation, diarrhea, appetite loss

CNS: sedation, dizziness, unsteadiness, confusion

benign rashes common, catastrophic rashes rare

many possible serious abnormalities in CBC

may reduce sodium levels (hyponatremia)

liver function abnormalities rare but possible

toxic metabolite (10-11-carbamazepine epoxide) can create problems via DDI (valproate, lamotrigine and phenobarbital) independent of carbamazepine levels and can be checked separately

Older Mood Stabilizers
older mood stabilizers33
Valproic acid (valproate, Depakote)- features

can be dosed rapidly to treat acute mania

more effective than lithium in rapid cycling & mixed states

used by some to treat aggression and impulsivity in other psychiatric disorders

approved for migraine prophylaxis

serum levels can be helpful in guiding dosing

lab draws 8-12 hours after last dose

commonly used at top or above levels stated for seizure control

some suggest supplementation with carnitine, selenium and others to reduce side effects

Older Mood Stabilizers
older mood stabilizers34
Valproic acid (Depakote)- side effects

nausea, weight gain, unsteadiness (ataxia), hair loss, tremor

liver dysfunction, decreased platelets (thrombocytopenia)

pancreatitis (rare but potentially serious)

polycystic ovary disease suggested by some reports

ammonia levels can be increased particularly in those rare individuals with genetic metabolic deficits

drug-drug interactions by various mechanisms with numerous other anticonvulsants, aspirin and others

Older Mood Stabilizers
newer mood stabilizers
SSRI antidepressants

Atypical antidepressants

Tricyclic antidepressants

MAOI antidepressants

Older mood stabilizers

Newer mood stabilizers

Older antipsychotics

Newer antipsychotics

Anticholinergics

Benzodiazepines

Other anxiolytic/hypnotics

Stimulants

Meds for dementia

Meds for substance abuse

Psychiatric uses of antihypertensives

lamotrigine, oxcarbazepine, topiramate, (levatiracetam, zonisamide)

1990’s- lamotrigine investigated for mood stabilizing properties after pts on it for seizure disorders report benefits

1990’s- most newer approved anticonvulsants are investigated for mood stabilizing properties

2003- lamotrigine approved for bipolar I maintenance

Newer Mood Stabilizers
newer mood stabilizers36
Lamotrigine (Lamictal)

Minimally sedating unlike most other mood stabilizers

Appears to be especially effective in treated bipolar depression but unproven to treat mania

Early use as an anticonvulsant in children raised concerns about potentially life-threatening rash (Stevens-Johnson syndrome, toxic epidermal necrolysis).

Initiating lamotrigine is done very slowly to decrease rash risk

valproate greatly increases lamotrigine levels

carbamazepine greatly decreases lamotrigine levels

Newer Mood Stabilizers
newer mood stabilizers37
Oxcarbazepine (Trileptal)

Used primarily in combination with other mood stabilizers although efficacy not clearly substantiated

Modified carbamazepine with potentially less side effects and drug-drug interactions than carbamazepine

10,11-carbamazepine epoxide not a metabolite so higher dose required if switching from carbamazepine

Topiramate (Topamax)

Research questions its use as a mood stabilizer although scattered reports suggest possible benefit

weight loss, cognitive dulling, kidney stones, metabolic acidosis

Newer Mood Stabilizers
newer mood stabilizers38
Levatiracetam (Keppra)

Efficacy in bipolar disorder unsubstantiated although scattered reports suggest possible benefit

Minimal drug-drug interactions

Zonisamide (Zonegran)

Efficacy in bipolar disorder unsubstantiated although scattered reports suggest possible benefit

Side effects similar to topiramate including weight loss

Olanzapine/fluoxetine combination (Symbyax)

approved to treat bipolar depression

Newer Mood Stabilizers
older antipsychotics
SSRI antidepressants

Atypical antidepressants

Tricyclic antidepressants

MAOI antidepressants

Older mood stabilizers

Newer mood stabilizers

Older antipsychotics

Newer antipsychotics

Anticholinergics

Benzodiazepines

Other anxiolytic/hypnotics

Stimulants

Meds for dementia

Meds for substance abuse

Psychiatric uses of antihypertensives

1950 Chlorpromazine synthesized as a sedating antihistamine

1952 Chlorpromazine reported to be beneficial in psychosis & mania

1953 First reports of chlorpromazine- associated movement disorders

1958 Haloperidol developed

1962 Long-acting injectable fluphenazine developed

1970 Dopamine hypothesis of schizophrenia suggested

2005 CATIE trial shows positive outcome for perphenazine compared to newer antipsychotics

www.nimh.nih.gov/healthinformation/catie.cfm

Older Antipsychotics
older antipsychotics40
Neuroleptic

“seize the neuron” referring to the tendency to cause stiffness and other neurologic symptoms

early methods of dosing would achieve “neurolepsis” and then back dose down to relieve this effect

Major tranquilizer

refers to the tendency to sedate, quiet and create a “blandness” in patients similar to the “negative” symptoms of schizophrenia

differentiates from the benzodiazepines (Valium etc.) which were referred to as “minor tranquilizers”

Typical, traditional, conventional antipsychotics

differentiates these drugs from newer “atypical” antipsychotics

Dopamine receptor antagonist

highlights strong dopamine activity and tight binding at D2 receptors

Older Antipsychotics
older antipsychotics41
Side effect terminology:

Extrapyramidal symptoms (EPS)

pyramidal system- responsible for voluntary movement

extrapyramidal system- responsible for involuntary muscle action

includes dystonias, Parkinsonism, akathisia & tardive dyskinesia

Acute dystonia

sustained muscular contraction of neck, eyes, throat

generally occurs soon after starting medication

Akathisia

uncomfortable continuous motor restlessness

can occur any time in treatment but generally in first week(s)

easily misdiagnosed as the underlying psychiatric disorder

Older Antipsychotics
older antipsychotics42
Side effect terminology cont’d:

Parkinsonism

tremor, muscle stiffness, slowed movement, drooling

generally occurs beyond 1 week after starting medication

Tardive dyskinesia (TD)

spastic facial distortions and tongue movements

may extend to neck, trunk, and extremities

delayed effect, usually beyond 6 months from starting medication

risk increases with duration of exposure to antipsychotic

known to occur without antipsychotic therapy

may be permanent, occur on discontinuation or resolve on own

is worsened by medications used to treat other EPS symptoms

Older Antipsychotics
older antipsychotics43
Side effect terminology cont’d:

Neuroleptic malignant syndrome (NMS)

pipe-like rigidity, fever, tremor, altered level of consciousness

hypotension, tachycardia

laboratory abnormalities- elevated WBC & CK

mortality 10-20%

can occur any time in course of treatment

Anticholinergic effects

dry mouth, blurred vision, constipation, urinary retention, mydriasis (dilated pupils)

Older Antipsychotics
older antipsychotics44
Methods of classification: Structure

aliphatic phenothiazine - chlorpromazine

piperazine phenothiazine - perphenazine, trifluoperazine, fluphenazine

piperidine phenothiazine - thioridazine, mesoridazine

thioxanthene- thiothixene

dibenzodiazepine- loxapine

indolone- molindone

butyrophenone- haloperidol

diphenylbutylpiperidine- pimozide

Older Antipsychotics
older antipsychotics45
Methods of classification: Clinical effect/potency

Low potency: chlorpromazine, mesoridazine, thioridazine

medium-high sedation, low-medium EPS, high AC

Medium potency: perphenazine, loxapine, molindone

low-medium sedation, high EPS, low-medium AC

High potency: fluphenazine, trifluoperizine, thiothixene, haloperidol, pimozide

medium-low sedation, high EPS, low AC

EPS: extrapyramidal symptoms

AC: anticholinergic effects

Older Antipsychotics
older antipsychotics46
Low chlorpromazine (Thorazine) cardiac risk, weight gain

High fluphenazine (Prolixin) long-acting injection available

High haloperidol (Haldol) long-acting injection available

Med loxapine (Loxitane)

Low mesoridazine (Serentil) cardiac risk

Medmolindone (Moban)

Medperphenazine (Trilafon) good outcome in CATIE trial

High pimozide (Orap) cardiac risk

Low thioridazine (Mellaril) high cardiac risk

Highthiothixene (Navane)

High trifluoperazine (Stelazine)

Older Antipsychotics
newer antipsychotics
SSRI antidepressants

Atypical antidepressants

Tricyclic antidepressants

MAOI antidepressants

Older mood stabilizers

Newer mood stabilizers

Older antipsychotics

Newer antipsychotics

Anticholinergics

Benzodiazepines

Other anxiolytic/hypnotics

Stimulants

Meds for dementia

Meds for substance abuse

Psychiatric uses of antihypertensives

1990 clozapine introduced in US after long delay related to safety concerns

1994 risperidone

1996 olanzapine

1997 quetiapine

2000 ziprasidone

2003 aripiprazole

2004 ADA/APA consensus report on obesity & diabetes in those taking antipsychotics

http://care.diabetesjournals.org/cgi/content/full/27/2/596

Newer Antipsychotics
newer antipsychotics48
Terminology

“Atypical antipsychotics”, “Second-generation antipsychotics”, “Serotonin-dopamine antagonists”

Mechanism

adds serotonin (5HT 2A) activity

binds more loosely to dopamine receptors

clozapine initially rejected as an antipsychotic because of its seemingly reduced dopamine impact and lack of EPS

Indications/uses

schizophrenia and other psychotic disorders

acute bipolar mania & maintenance

augmentation of antidepressants & mood stabilizers

aggression & impulsivity

Newer Antipsychotics
newer antipsychotics49
Features

less risk of EPS/movement disorders

greater effect on “negative” symptoms of schizophrenia

Cautions

greater risk of obesity, diabetes and lipid abnormalities

clozapine > olanzapine > quetiapine, risperidone > ziprasidone, aripiprazole

requires regular monitoring of metabolic parameters

potential stroke, mortality risk in elderly

EPS, movement disorders and NMS all can still occur although (much) less than typical antipsychotics

Newer Antipsychotics
newer antipsychotics50
aripiprazole (Abilify)

unique complex mechanism

can be either activating or sedating, nausea common

clozapine (Clozaril)

most effective antipsychotic

risk of agranulocytosis (decreased neutrophil WBCs)

CBC weekly x 6 mos, bi-weekly x 6 mos, then monthly

multiple other side effects & DDI

levels reduced by smoking

olanzapine (Zyprexa, Zydis)

significant weight, diabetes and lipid abnormality risk

levels reduced by smoking

Newer Antipsychotics
newer antipsychotics51
quetiapine (Seroquel)

approved dose range considered low by many

low EPS risk

used commonly as sedating agent

risperidone (Risperdal)

most like typical antipsychotics at higher doses

available in long acting injection (Consta)

ziprasidone (Geodon)

approved dose range considered low by many

initial cardiac concerns appear insignificant for most

must be taken with fat-containing meal/snack

Newer Antipsychotics
anticholinergics ac
SSRI antidepressants

Atypical antidepressants

Tricyclic antidepressants

MAOI antidepressants

Older mood stabilizers

Newer mood stabilizers

Older antipsychotics

Newer antipsychotics

Anticholinergics

Benzodiazepines

Other anxiolytic/hypnotics

Stimulants

Meds for dementia

Meds for substance abuse

Psychiatric uses of antihypertensives

benztropine (Cogentin)

least sedating, most commonly used

biperiden (Akineton)

diphenhydramine (Benadryl)

trihexyphenidyl (Artane)

amantadine (Symmetrel)

not an AC, used rarely to treat EPS

Treats extrapyramidal symptoms (EPS)

tremor, stiffness, drooloing, dystonias

akathisia may not respond to ACs

tardive dyskinesia may worsen with ACs

Dry mouth, constipation, blurred vision

EPS thought to be cholinergic/ dopamine imbalance

Anticholinergics (AC)
benzodiazepines
SSRI antidepressants

Atypical antidepressants

Tricyclic antidepressants

MAOI antidepressants

Older mood stabilizers

Newer mood stabilizers

Older antipsychotics

Newer antipsychotics

Anticholinergics

Benzodiazepines

Other anxiolytic/hypnotics

Stimulants

Meds for dementia

Meds for substance abuse

Psychiatric uses of antihypertensives

1957 Librium (chlordiazepoxide)

1970’s Valium (diazepam) top selling drug in US

1986 Xanax (alprazolam) top selling drug in US

1990’s SSRI’s replace some chronic benzodiazepine use for anxiety

Benzodiazepines
benzodiazepines bz
General characteristics

Differ in action, duration, drug-drug interactions & side effects based on differences in absorption rate, lipid solubility & metabolism.

Indications/uses include anxiety d/o, panic d/o, mania, seizure d/o, phobias, insomnia, alcohol withdrawal, muscle spasm, agitation, catatonia, akathisia

hospital use (IV/IM) in sedation for procedures

Side effects

sedation, cognitive impairment, anterograde amnesia

respiratory depression at high dose or with alcohol

may worsen obstructive sleep apnea symptoms

disinhibition in susceptible individuals

Benzodiazepines (BZ)
benzodiazepines bz55
Abuse and dependence

Risk of abuse is small in individuals who are not abusing other substances

Withdrawal symptoms and physical dependence are not in themselves problematic if reductions are done gradually to minimize symptoms

use of longer acting agents to minimize between-dose breakthrough and avoiding “PRN” dosing are helpful

symptoms of “withdrawal” may represent breakthrough of the underlying anxiety disorder

needing to increase the dose (tolerance) not generally an issue at therapeutic doses

Benzodiazepines (BZ)
benzodiazepines56
alprazolam (Xanax) short-mid

chlordiazepoxide (Librium) long

clonazepam (Klonopin) mid-long serotonergic?

clorazepate (Tranxene) long

diazepam (Valium) long

estazolam (ProSom) mid

flurazepam (Dalmane) long

lorazepam (Ativan) short-mid min DDI

oxazepam (Serax) short-mid min DDI

temazepam (Restoril) mid min DDI

triazolam (Halcion) short common procedure presedate

Benzodiazepines
other anxiolytic hypnotics
SSRI antidepressants

Atypical antidepressants

Tricyclic antidepressants

MAOI antidepressants

Older mood stabilizers

Newer mood stabilizers

Older antipsychotics

Newer antipsychotics

Anticholinergics

Benzodiazepines

Other anxiolytic/ hypnotics

Stimulants

Meds for dementia

Meds for substance abuse

Psychiatric uses of antihypertensives

1869- chloral hydrate first used

1992- Ambien approved

2006- zolpidem (Ambien) generic

Hypnotics = medications to induce sleep

Non-benzodiazepine anxiolytics include buspirone & antihistamines.

Newer anticonvulsants are used “off-label” as both anxiolytics and hypnotics although efficacy is unproven.

Trazodone and some tricyclic antidepressants are used as hypnotics

Newer hypnotics active at GABA 1 receptor except ramelteon

Other anxiolytic/ hypnotics
other anxiolytic hypnotics58
Miscellaneous

buspirone (BuSpar)- subtle anxiolytic, slow response

chloral hydrate (Noctec)- hypnotic, rapid tolerance, toxicity in overdose

Antihistamines

hydroxyzine pamoate (Vistaril)

diphenhydramine (Benadryl)

Anticonvulsants- mildly sedating and calming

gabapentin (Neurontin)

pregabalin (Lyrica)

tiagabine (Gabatril)

Other anxiolytic/ hypnotics
other anxiolytic hypnotics59
Selective benzodiazepine receptor activity (GABA 1)- hypnotics

eszopiclone (Lunesta) - long-term use approval

zaleplon (Sonata) - short half-life

zolpidem (Ambien)

Melatonin receptor agonist

ramelteon (Rozeram)

Other anxiolytic/ hypnotics
stimulants adhd drugs
SSRI antidepressants

Atypical antidepressants

Tricyclic antidepressants

MAOI antidepressants

Older mood stabilizers

Newer mood stabilizers

Older antipsychotics

Newer antipsychotics

Anticholinergics

Benzodiazepines

Other anxiolytic/hypnotics

Stimulants/

ADHD Drugs

Meds for dementia

Meds for substance abuse

Psychiatric uses of antihypertensives

1956- Ritalin approved

10% of 10 yr old boys in US are on stimulants

2.5 million children in US are on stimulants

Recent FDA warning about increased cardiovascular risk (sudden death) for patients on stimulants

Stimulants / ADHD Drugs
stimulants adhd drugs61
atomoxetine (Strattera)-

non-stimulant treatment for ADHD

recent caution about suicidal ideation

rare liver function impairment

clonidine (Catapres)

antihypertensive alpha 2 agonist

used for ADHD, substance withdrawal, Tourette’s syndrome, others

pemoline (Cylert)

rarely used stimulant due to liver toxicity

Stimulants / ADHD Drugs
stimulants adhd drugs62
dextroamphetamine (Dexedrine)

multiple long-acting forms

insomnia, headache, tremor, exacerbation of tics, nausea, weight loss, blurred vision, overstimulation

methylphenidate (Ritalin)

see notes above for dextramphetamine

modafinil (Provigil)

non-stimulant

poorly understood mechanism of action

used for sleepiness related to narcolepsy, obstructive sleep apnea, depression, multiple sclerosis

use for ADHD being investigated

Stimulants / ADHD Drugs
medications for dementia
SSRI antidepressants

Atypical antidepressants

Tricyclic antidepressants

MAOI antidepressants

Older mood stabilizers

Newer mood stabilizers

Older antipsychotics

Newer antipsychotics

Anticholinergics

Benzodiazepines

Other anxiolytic/hypnotics

Stimulants

Meds for dementia

Meds for substance abuse

Psychiatric uses of antihypertensives

1993 Cognex (tacrine) approved

1996 Aricept (donepezil) approved

1997 Generalizability of approval studies questioned (J Am Ger Soc 1997;45:923)

2003 Namenda approved for moderate to severe Alzheimer’s Dementia

2004 Detailed British study questions efficacy of cholinesterase inhibitors

Medications for Dementia
medications for dementia64
General characteristics

The search for a treatment for Alzheimer’s Dementia is driven by intense human suffering & immense demographic numbers.

Studies that support use of these medications generally find subtle benefit or slowing of decline.

There is significant debate about the benefit vs. cost ($$ & side effects) of using these medications.

Treatment for behavioral issues in dementia has been complicated by FDA warnings about the risk of using antipsychotics in the elderly.

Medications for Dementia
medications for dementia65
Cholinesterase inhibitors

address one theorized mechanism of this complex disease

donepezil (Aricept)

galantamine (Reminyl)

rivastigmine (Exelon)

tacrine (Cognex)

rarely used due to liver toxicity

___________________________________

memantine (Namenda)

complex activity via NMDA (glutamate mediated) receptor

may have more broad psychiatric application

Medications for Dementia
meds to tx substance abuse
SSRI antidepressants

Atypical antidepressants

Tricyclic antidepressants

MAOI antidepressants

Older mood stabilizers

Newer mood stabilizers

Older antipsychotics

Newer antipsychotics

Anticholinergics

Benzodiazepines

Other anxiolytic/hypnotics

Stimulants

Meds for dementia

Meds to treat

substance abuse

Psychiatric uses of antihypertensives

Use of medications in substance abuse:

Treat withdrawal symptoms

benzodiazepines (BZ), anticonvulsants, clonidine

Treat comorbid psychiatric disorders

anxiety & depression are common

both primary & secondary etiologies

SSRIs, mood stabilizers, BZ (??)

Prevent relapse

deterrents, craving control

Meds to Tx Substance Abuse
meds to tx substance abuse67
disulfiram (Antabuse)

deterrent

requires motivated patient

acamprosate (Campral)

craving control

TID dosing, minimal DDI

efficacy shown in some studies with more severe alcoholics although other studies question efficacy

Meds to Tx Substance Abuse
meds to tx substance abuse68
naltrexone (ReVia)

opioid antagonist

COMBINE study demonstrates effectiveness in reducing relapse with “medical management” sessions (JAMA 2006;295:2003-2017)

high response for placebo cause some to question study design

http://www.niaaa.nih.gov/NewsEvents/NewsReleases/COMBINERelease.htm

potential liver toxicity

Vivitrol injectable naltrexone lasts 30 days www.vivitrol.comnot part of the COMBINE study

Meds to Tx Substance Abuse
meds to tx substance abuse69
buprenorphine/naloxone (Suboxone)

treatment for opioid dependence

contains both an agonist & antagonist

bupropion (Zyban)

identical to Wellbutrin

treats nicotine craving

Others:

several anticonvulsants (topiramate, etc.) have been used for craving reduction

Disabilities & alcoholism resource:

http://pubs.niaaa.nih.gov/publications/social/module10idisibilities/module10i.html

Meds to Tx Substance Abuse
psychiatric uses of antihypertensives
SSRI antidepressants

Atypical antidepressants

Tricyclic antidepressants

MAOI antidepressants

Older mood stabilizers

Newer mood stabilizers

Older antipsychotics

Newer antipsychotics

Anticholinergics

Benzodiazepines

Other anxiolytic/hypnotics

Stimulants

Meds for dementia

Meds for substance abuse

Psychiatric

uses of

antihypertensives

The uses of these drugs are “off-label” and carry additional potential side effects from their cardiovascular actions.

Potential psychiatric benefits have often been discovered while these agents were used for their primary indication.

Monitor blood pressure

Psychiatric uses of antihypertensives
psychiatric uses of antihypertensives71
alpha (α2) adrenergic agonists

clonidine, guanfacine, prazosin

used in ADHD, Tourette’s syndrome, PTSD

prazosin found helpful in reducing PTSD related nightmares

beta blockers

propranolol (Inderal) used for akathisia, lithium-induced tremor, performance anxiety & aggressive behavior (hyperarousal)

pindolol has been considered for antidepressant augmentation

multiple DDIs

avoid in asthma, diabetics on insulin, certain cardiovascular diseases

calcium channel blockers

diltiazem, verapamil, nimodipine

may be helpful as additional agent in bipolar maintenance

multiple DDIs and precautions

Psychiatric uses of antihypertensives
references
Albers, L. J., Hahn, R. K., & Reist, C. (2005). Handbook of psychiatric drugs. Laguna Hills, CA: Current Clinical Strategies Publishing.

Carlat, D.J. (2005). Benzodiazepines and hypnotics in psychiatry. The Carlat Report on Psychiatric Treatment, 3(9),1-6.

Carlat, D.J. (2006). Medication treatment of anxiety. The Carlat Report on Psychiatric Treatment, 4(3),1-6.

Carlat, D.J. (2006). Treating substance abuse. The Carlat Report on Psychiatric Treatment, 4(6),1-6.

Fuller, M. A., & Sajatovic, M. (2005). Psychotropic Drug Information Handbook, (5th ed.). Hudson, OH: Lexi-Comp.

Keltner, N. L., & Folks, D. G. (2005). Psychotropic drugs. St. Louis: Elsevier Mosby.

Sadock, B. J., & Sadock, V. A. (2003). Kaplan & Sadock’s Synopsis of Psychiatry, (9th ed.). Philadelphia: Lippincott Williams & Wilkins.

Schatzberg, A. F., Cole, J. O., & DeBattista, C. (2005). Manual of Clinical Psychopharmacology, (5th ed.). Washington, D.C.: American Psychiatric Press.

Shader, R. I. (2003). Manual of psychiatric therapeutics, (3rd ed.). Philadelphia: Lippincott Williams & Wilkins.

Shiloh, R., Nutt, D., & Weizman, A. (2001). Essentials in clinical psychiatric pharmacotherapy. London: Martin Dunitz.

Stahl, S. M. (2005). Essential Psychopharmacology: The prescriber’s guide. Cambridge: Cambridge University Press.

References