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Psychotropic Medications Dale Sanderson, PA-C Physician Assistant Seattle Mental Health.

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1 Psychotropic Medications Dale Sanderson, PA-C Physician Assistant Seattle Mental Health

2 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

3 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?

4 Introduction Choosing a medication  diagnosis  benefit vs. side-effects, toxicity, ease of use, drug-drug interactions (www.drug-interactions.com, )www.drug-interactions.comwww.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

5 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 Zoloft, Paxil, Luvox 1998 Celexa 2001 fluoxetine (Prozac generic) 2002 Lexapro (modified Celexa) 2006 STAR*D trial results published Annual sales = $12 billion Number of patient starts on Prozac, Paxil or Zoloft from 1988 to 2002 = 67.5 million (www.ahrp.org)www.ahrp.org

6 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)

7 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

8 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)

9 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

10 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 others)www.drug-interactions.comwww.drugs.com

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

12 SSRI antidepressants citalopram (Celexa)  Few drug-drug interactions (DDIs)  High serotonin specificity  Typical or less SSRI 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

13 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

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

15 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

16 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

17 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

18 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) 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)

19 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)

20 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) 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

21 Tricyclic antidepressants 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

22 Tricyclic antidepressants 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

23 Tricyclic antidepressants NE 5HT Ach Sed Comments amitriptyline (Elavil)………low high high highpain, MgrHA amoxapine (Asendin)…… high low mod lowtetracyclic clomipramine (Anafranil). low high high hightx OCD; SSRI-like desipramine (Norpramin) high low low lowactivating doxepin (Sinequan)……. low low mod highused for insomnia imipramine (Tofranil)……. low low mod mod pain; enuresis maprotiline (Ludiomil)…… high low low mod tetracyclic nortriptyline (Pamelor)….. mod low mod modchronic 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

24 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 First MAOI found with antidepressant properties in process of looking for an antituberculosis drug 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 Transdermal selegiline patch (Emsam) approved to treat depression

25 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.

26 Monoamine Oxidase Inhibitors 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)

27 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

28 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 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 significant studies demonstrate lithium’s efficacy in bipolar disorder 1980studies demonstrate effectiveness of carbamazepine in bipolar d/o

29 Older Mood Stabilizers Lithium- f eatures  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)

30 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

31 Older Mood Stabilizers Carbamazepine (Tegretol)- f eatures  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

32 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

33 Older Mood Stabilizers Valproic acid (valproate, Depakote)- f eatures  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

34 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

35 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 lamotrigine approved for bipolar I maintenance

36 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 (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

37 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

38 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

39 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 1950Chlorpromazine synthesized as a sedating antihistamine 1952 Chlorpromazine reported to be beneficial in psychosis & mania 1953First reports of chlorpromazine- associated movement disorders 1958Haloperidol developed 1962 Long-acting injectable fluphenazine developed 1970Dopamine hypothesis of schizophrenia suggested 2005CATIE trial shows positive outcome for perphenazine compared to newer antipsychotics

40 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” Typical, traditional, conventional antipsychotics  differentiates these drugs from newer “atypical” antipsychotics Dopamine receptor antagonist  highlights strong dopamine activity and tight binding at D2 receptors

41 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 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

42 Older Antipsychotics 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

43 Older Antipsychotics 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)

44 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

45 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

46 Older Antipsychotics 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 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)

47 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 1990clozapine introduced in US after long delay related to safety concerns 1994risperidone 1996olanzapine 1997quetiapine 2000ziprasidone 2003aripiprazole 2004ADA/APA consensus report on obesity & diabetes in those taking antipsychotics

48 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

49 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

50 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 olanzapine (Zyprexa, Zydis)  significant weight, diabetes and lipid abnormality risk  levels reduced by smoking

51 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

52 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

53 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

54 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

55 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

56 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-midmin DDI oxazepam (Serax) short-midmin DDI temazepam (Restoril) midmin DDI triazolam (Halcion) shortcommon procedure presedate

57 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 chloral hydrate first used Ambien approved 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

58 Other anxiolytic/ hypnotics 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)

59 Other anxiolytic/ hypnotics 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)

60 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

61 Stimulants / ADHD Drugs 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

62 Stimulants / ADHD Drugs 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

63 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 1993Cognex (tacrine) approved 1996Aricept (donepezil) approved 1997Generalizability of approval studies questioned (J Am Ger Soc 1997;45:923) 2003Namenda approved for moderate to severe Alzheimer’s Dementia 2004Detailed British study questions efficacy of cholinesterase inhibitors

64 Medications for Dementia 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.

65 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

66 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

67 Meds to Tx Substance Abuse 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

68 Meds to Tx Substance Abuse naltrexone (ReVia)  opioid antagonist  COMBINE study demonstrates effectiveness in reducing relapse with “medical management” sessions (JAMA 2006;295: )  high response for placebo cause some to question study design   potential liver toxicity  Vivitrol injectable naltrexone lasts 30 days not part of the COMBINE study

69 Meds to Tx Substance Abuse 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:

70 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

71 Psychiatric uses of antihypertensives 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

72 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.


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