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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
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
Response rate
response vs. remission the right diagnosis treatment failures
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
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
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
SSRI antidepressants
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
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
duloxetine (Cymbalta)
SNRI profile minimally dose dependent Indicated for depression & chronic neuropathic pain
Atypical antidepressants
mirtazapine (Remeron)
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)
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
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)
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
Tricyclic antidepressants
Cautions
Overdose is frequently fatal Pts with bipolar d/o may be pushed into mania or rapid cycling
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
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
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
Drug-drug interactions
Multiple prescribed and over-the-counter medications can be potentially lethal. Serotonin syndrome with SSRIs & many others.
Available formulations
phenylzine (Nardil); isocarboxazid (Marplan); tranylcypromine (Parnate)
Similar medications
selegiline (Eldepryl)
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
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
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
Topiramate (Topamax)
Research questions its use as a mood stabilizer although scattered reports suggest possible benefit weight loss, cognitive dulling, kidney stones, metabolic acidosis
Zonisamide (Zonegran)
Efficacy in bipolar disorder unsubstantiated although scattered reports suggest possible benefit Side effects similar to topiramate including weight loss
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
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
Older Antipsychotics
Side effect terminology:
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
Side effect terminology contd:
Parkinsonism
tremor, muscle stiffness, slowed movement, drooling generally occurs beyond 1 week after starting medication
Older Antipsychotics
Side effect terminology contd:
Anticholinergic effects
dry mouth, blurred vision, constipation, urinary retention, mydriasis (dilated pupils)
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
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
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
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
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
Newer Antipsychotics
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
Anticholinergics (AC)
benztropine (Cogentin)
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
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
Librium (chlordiazepoxide) 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
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)
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
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
Miscellaneous
buspirone (BuSpar)- subtle anxiolytic, slow response chloral hydrate (Noctec)- hypnotic, rapid tolerance, toxicity in overdose
Antihistamines
hydroxyzine pamoate (Vistaril) diphenhydramine (Benadryl)
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
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, Tourettes syndrome, others
pemoline (Cylert)
rarely used stimulant due to liver toxicity
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
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 2004 Detailed British study questions efficacy of cholinesterase inhibitors
Prevent relapse
deterrents, craving control
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
naltrexone (ReVia)
opioid antagonist COMBINE study demonstrates effectiveness in reducing relapse with medical management sessions (JAMA
2006;295:2003-2017)
potential liver toxicity Vivitrol injectable naltrexone lasts 30 days www.vivitrol.com not part of the COMBINE study
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
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
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
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.