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

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 publics 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

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 vs. remission the right diagnosis treatment failures

Response rate

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
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
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
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
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
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
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 Johns Wort, MDMA (ecstasy), LSD, many others

SSRI antidepressants

citalopram (Celexa)

Few drug-drug interactions (DDIs) High serotonin specificity Typical or less SSRI side effects Simple dosing S molecule of the S & R mirror-image mixture of citalopram molecules Very long half-life Significant DDIs Can be activating

escitalopram (Lexapro) no generic available

fluoxetine (Prozac, Sarafem, Symbyax- with Zyprexa)

SSRI antidepressants

fluvoxamine (Luvox)

OCD indication Multiple significant DDIs Significant DDIs Some reports of associated weight gain Withdrawal symptoms with missed doses Moderate DDIs Multi-step dosing

paroxetine (Paxil)

sertraline (Zoloft)

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
198119891993199419962004Desyrel (trazodone) Wellbutrin (bupropion) Effexor (venlafaxine) Serzone (nefazodone) Remeron (mirtazapine) Serzone discontinued although generics still available 2004- Duloxetine (Cymbalta)

Atypical antidepressants
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
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

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 SNRI profile minimally dose dependent Indicated for depression & chronic neuropathic pain

duloxetine (Cymbalta)

Atypical antidepressants

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) Complex serotonin, NE (2) & histamine activity Receptor activity changes with changes in dose Sedation & weight gain especially at lower dose Lipid abnormalities Minimal DDIs (except MAOIs)

mirtazapine (Remeron)

Atypical antidepressants

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 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)

trazodone (Desyrel)

Tricyclic antidepressants
SSRI antidepressants Atypical antidepressants

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. 1960s- multiple other TCAs developed and placed into use 1990s- significant reduction in use due to introduction of SSRIs which have fewer side effects

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 nonpsychotropic meds

Tricyclic antidepressants

Mechanism of action

Norepinephrine, serotonin, histamine, muscarinic (cholinergic) and -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

Drug-drug interactions (DDI)

Multiple significant interactions in each direction with potentially serious consequences Anticholinergic SE include: dry mouth, constipation, blurred vision and urinary retention Cardiac arrhythmias and conduction changes Orthostatic hypotension Sedation Weight gain Overdose is frequently fatal Pts with bipolar d/o may be pushed into mania or rapid cycling

Side effects (SE)

Cautions

Tricyclic antidepressants
NE amitriptyline (Elavil)low amoxapine (Asendin) high clomipramine (Anafranil). low desipramine (Norpramin) high doxepin (Sinequan). low imipramine (Tofranil). low maprotiline (Ludiomil) high nortriptyline (Pamelor).. mod protriptyline (Vivactil) high trimipramine (Surmontil).. low 5HT high low high low low low low low low low Ach Sed high high mod low high high low low mod high mod mod low mod mod mod mod low high high Comments pain, MgrHA tetracyclic tx OCD; SSRI-like activating used for insomnia pain; enuresis tetracyclic chronic pain most activating

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

Monoamine Oxidase Inhibitors

Abbreviated as MAOI
SSRI antidepressants Atypical antidepressants
Tricyclic antidepressants

1952-

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

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

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

Available formulations

phenylzine (Nardil); isocarboxazid (Marplan); tranylcypromine (Parnate) selegiline (Eldepryl)

Similar medications

used to treat Parkinsons 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)

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

Older Mood Stabilizers

SSRI antidepressants
Atypical antidepressants Tricyclic antidepressants MAOI antidepressants

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 valproates efficacy in treating mania 1978- significant studies demonstrate lithiums efficacy in bipolar disorder 1980 studies demonstrate effectiveness of carbamazepine in bipolar d/o

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

Older Mood Stabilizers

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

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

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

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

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

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

Newer Mood Stabilizers

SSRI antidepressants Atypical antidepressants Tricyclic antidepressants MAOI antidepressants Older mood stabilizers

lamotrigine, oxcarbazepine, topiramate, (levatiracetam, zonisamide)

Newer mood stabilizers

Older antipsychotics Newer antipsychotics Anticholinergics Benzodiazepines Other anxiolytic/hypnotics Stimulants Meds for dementia Meds for substance abuse Psychiatric uses of antihypertensives

1990s- lamotrigine investigated for mood stabilizing properties after pts on it for seizure disorders report benefits 1990s- most newer approved anticonvulsants are investigated for mood stabilizing properties 2003- lamotrigine approved for bipolar I maintenance

Newer Mood Stabilizers

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 (StevensJohnson 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

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

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

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 chlorpromazineassociated 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

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 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 differentiates these drugs from newer atypical antipsychotics highlights strong dopamine activity and tight binding at D2 receptors

Major tranquilizer

Typical, traditional, conventional antipsychotics

Dopamine receptor antagonist

Older Antipsychotics
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 sustained muscular contraction of neck, eyes, throat generally occurs soon after starting medication
uncomfortable continuous motor restlessness can occur any time in treatment but generally in first week(s) easily misdiagnosed as the underlying psychiatric disorder

Acute dystonia

Akathisia

Older Antipsychotics
Side effect terminology contd:

Parkinsonism

tremor, muscle stiffness, slowed movement, drooling generally occurs beyond 1 week after starting medication
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

Tardive dyskinesia (TD)

Older Antipsychotics
Side effect terminology contd:

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

Anticholinergic effects

Older Antipsychotics
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
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
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 Med molindone (Moban) Med perphenazine (Trilafon) good outcome in CATIE trial High pimozide (Orap) cardiac risk Low thioridazine (Mellaril) high cardiac risk High thiothixene (Navane) High trifluoperazine (Stelazine)
Low

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

Terminology

Atypical antipsychotics, Second-generation antipsychotics, Serotonin-dopamine antagonists 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 schizophrenia and other psychotic disorders acute bipolar mania & maintenance augmentation of antidepressants & mood stabilizers aggression & impulsivity

Mechanism

Indications/uses

Newer Antipsychotics

Features

less risk of EPS/movement disorders greater effect on negative symptoms of schizophrenia 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

Cautions

Newer Antipsychotics

aripiprazole (Abilify)

unique complex mechanism can be either activating or sedating, nausea common 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 significant weight, diabetes and lipid abnormality risk levels reduced by smoking

clozapine (Clozaril)

olanzapine (Zyprexa, Zydis)

Newer Antipsychotics

quetiapine (Seroquel)

approved dose range considered low by many low EPS risk used commonly as sedating agent most like typical antipsychotics at higher doses available in long acting injection (Consta) approved dose range considered low by many initial cardiac concerns appear insignificant for most must be taken with fat-containing meal/snack

risperidone (Risperdal)

ziprasidone (Geodon)

Anticholinergics (AC)
benztropine (Cogentin)
SSRI antidepressants
Atypical antidepressants Tricyclic antidepressants MAOI antidepressants Older mood stabilizers Newer mood stabilizers Older antipsychotics Newer antipsychotics

least sedating, most commonly used

biperiden (Akineton) diphenhydramine (Benadryl) trihexyphenidyl (Artane) amantadine (Symmetrel)

not an AC, used rarely to treat EPS

Anticholinergics
Benzodiazepines Other anxiolytic/hypnotics Stimulants Meds for dementia Meds for substance abuse Psychiatric uses of antihypertensives

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

Benzodiazepines
SSRI antidepressants Atypical antidepressants Tricyclic antidepressants MAOI antidepressants Older mood stabilizers Newer mood stabilizers Older antipsychotics Newer antipsychotics Anticholinergics

1957

Librium (chlordiazepoxide)

1970s
1986 1990s

Valium (diazepam) top selling drug in US

Xanax (alprazolam) top selling drug in US SSRIs replace some chronic benzodiazepine use for anxiety

Benzodiazepines
Other anxiolytic/hypnotics Stimulants Meds for dementia Meds for substance abuse Psychiatric uses of antihypertensives

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 sedation, cognitive impairment, anterograde amnesia respiratory depression at high dose or with alcohol may worsen obstructive sleep apnea symptoms disinhibition in susceptible individuals

Side effects

Benzodiazepines (BZ)
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
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

Other anxiolytic/ hypnotics

SSRI antidepressants
Atypical antidepressants Tricyclic antidepressants MAOI antidepressants Older mood stabilizers Newer mood stabilizers Older antipsychotics Newer antipsychotics Anticholinergics Benzodiazepines

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

Stimulants Meds for dementia Meds for substance abuse Psychiatric uses of antihypertensives

Other anxiolytic/ hypnotics

Miscellaneous

buspirone (BuSpar)- subtle anxiolytic, slow response chloral hydrate (Noctec)- hypnotic, rapid tolerance, toxicity in overdose hydroxyzine pamoate (Vistaril) diphenhydramine (Benadryl) gabapentin (Neurontin) pregabalin (Lyrica) tiagabine (Gabatril)

Antihistamines

Anticonvulsants- mildly sedating and calming

Other anxiolytic/ hypnotics

Selective benzodiazepine receptor activity (GABA 1)hypnotics

eszopiclone (Lunesta) - long-term use approval zaleplon (Sonata) - short half-life zolpidem (Ambien)
ramelteon (Rozeram)

Melatonin receptor agonist

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

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

Meds for dementia Meds for substance abuse Psychiatric uses of antihypertensives

Stimulants / ADHD Drugs

atomoxetine (Strattera)

non-stimulant treatment for ADHD recent caution about suicidal ideation rare liver function impairment antihypertensive alpha 2 agonist used for ADHD, substance withdrawal, Tourettes syndrome, others

clonidine (Catapres)

pemoline (Cylert)

rarely used stimulant due to liver toxicity

Stimulants / ADHD Drugs

dextroamphetamine (Dexedrine)

multiple long-acting forms insomnia, headache, tremor, exacerbation of tics, nausea, weight loss, blurred vision, overstimulation see notes above for dextramphetamine non-stimulant poorly understood mechanism of action used for sleepiness related to narcolepsy, obstructive sleep apnea, depression, multiple sclerosis use for ADHD being investigated

methylphenidate (Ritalin)

modafinil (Provigil)

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

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 Alzheimers Dementia

Meds for dementia

Meds for substance abuse Psychiatric uses of antihypertensives

2004 Detailed British study questions efficacy of cholinesterase inhibitors

Medications for Dementia

General characteristics

The search for a treatment for Alzheimers 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

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

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

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 (??) deterrents, craving control

Meds to treat substance abuse

Psychiatric uses of antihypertensives

Prevent relapse

Meds to Tx Substance Abuse

disulfiram (Antabuse)

deterrent requires motivated patient craving control TID dosing, minimal DDI efficacy shown in some studies with more severe alcoholics although other studies question efficacy

acamprosate (Campral)

Meds to Tx Substance Abuse

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.com not part of the COMBINE study

Meds to Tx Substance Abuse

buprenorphine/naloxone (Suboxone)

treatment for opioid dependence contains both an agonist & antagonist identical to Wellbutrin treats nicotine craving several anticonvulsants (topiramate, etc.) have been used for craving reduction

bupropion (Zyban)

Others:

Disabilities & alcoholism resource:

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

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

The uses of these drugs are offlabel 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 antihypertensives

alpha (2) adrenergic agonists

clonidine, guanfacine, prazosin used in ADHD, Tourettes syndrome, PTSD prazosin found helpful in reducing PTSD related nightmares 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 diltiazem, verapamil, nimodipine may be helpful as additional agent in bipolar maintenance multiple DDIs and precautions

beta blockers

calcium channel blockers

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 & Sadocks 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 prescribers guide. Cambridge: Cambridge University Press.