Antianxiety Agents, Antianxiety Agents, Sedative-Hypnotics and Sedative-Hypnotics and

Antidepressants:Antidepressants:PharmacokineticsPharmacokineticsAdverse EffectsAdverse Effects

Drug InteractionsDrug Interactions

BIJU SOMAN M.Sc, MBABIJU SOMAN M.Sc, MBA

ASSISTANT PROFESSORASSISTANT PROFESSOR

MANIPAL UNIVERSITYMANIPAL UNIVERSITY

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GoalsGoals

Anxiolytic-Sedative-Hypnotics (ASHs)Anxiolytic-Sedative-Hypnotics (ASHs) Diagnostic indicationsDiagnostic indications Classification of ASHsClassification of ASHs Relevant PharmacokineticsRelevant Pharmacokinetics Serious Adverse EffectsSerious Adverse Effects Drug InteractionsDrug Interactions

Antidepressants (ADs)Antidepressants (ADs) Diagnostic indicationsDiagnostic indications Classification of ADsClassification of ADs Relevant PharmacokineticsRelevant Pharmacokinetics Serious Adverse EffectsSerious Adverse Effects Drug InteractionsDrug Interactions

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Antianxiety/Sedative-Hypnotics:Antianxiety/Sedative-Hypnotics:Diagnostic IndicationsDiagnostic Indications

Generalized anxiety disorder (GAD)Generalized anxiety disorder (GAD) Phobic disordersPhobic disorders Anxiety disorder due to general medical conditionAnxiety disorder due to general medical condition

Panic disorderPanic disorder Obsessive-compulsive disorder (OCD)Obsessive-compulsive disorder (OCD) Posttraumatic stress disorder (PTSD)Posttraumatic stress disorder (PTSD)

Sleep disorders (dyssomnias; parasomnias)Sleep disorders (dyssomnias; parasomnias)

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Antianxiety AgentsAntianxiety AgentsClass/Trade NameClass/Trade Name Generic NameGeneric Name Usual Daily Dosage (mg/d)Usual Daily Dosage (mg/d)

BZDsBZDs

Librium, othersLibrium, others ChlordiazepoxideChlordiazepoxide 10-10010-100

Valium, othersValium, others DiazepamDiazepam 2-402-40

Serax, othersSerax, others OxazepamOxazepam 30-12030-120

Tranxene, othersTranxene, others ChlorazepateChlorazepate 15-6015-60

AtivanAtivan LorazepamLorazepam 1-101-10

CentraxCentrax PrazepamPrazepam 20-6020-60

PaxipamPaxipam HalazepamHalazepam 60-16060-160

XanaxXanax AlprazolamAlprazolam 0.75-40.75-4

Serotonergic agentsSerotonergic agents

Sertraline, othersSertraline, others SSRIsSSRIs 25-25025-250

BusparBuspar BuspironeBuspirone 15-6015-60

DesyrelDesyrel Trazodone*Trazodone* 50-10050-100

Noradrenergic agentsNoradrenergic agents

InderalInderal Propranolol*Propranolol* 30-12030-120

Catapres Catapres Clonidine*Clonidine* 0.1-0.50.1-0.5*Not approved by the FDA.

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Antianxiety AgentsAntianxiety AgentsClass/Trade NameClass/Trade Name Generic NameGeneric Name Usual Daily Dosage (mg/d)Usual Daily Dosage (mg/d)

Serotonergic/noradrenergic agentsSerotonergic/noradrenergic agents

Effexor XREffexor XR Venlafaxine XRVenlafaxine XR 75-37575-375

CymbaltaCymbalta DuloxetineDuloxetine 20-6020-60

AntihistaminesAntihistamines

BenedrylBenedryl Diphenhydramine*Diphenhydramine* 25-5025-50

AtaraxAtarax Hydroxyzine*Hydroxyzine* 25-5025-50

AnticonvulsantsAnticonvulsants

NeurontinNeurontin Gabapentin*Gabapentin* 300-5,000300-5,000

LyricaLyrica Pregabalin*Pregabalin* 150-600150-600

GabitrilGabitril Tiagabine*Tiagabine* 4-164-16

Depakote, othersDepakote, others Valproate*Valproate* 250-2,000250-2,000

Natural RemediesNatural Remedies

KavatrolKavatrol KavaKava 210-240 mg/kL210-240 mg/kL

Investigational TreatmentsInvestigational Treatments Partial BZD agonists (e.g., abecarnil)*, Neurosteroids*, Partial BZD agonists (e.g., abecarnil)*, Neurosteroids*, CRF antagonists*, Substance P antagonists*, NMDA CRF antagonists*, Substance P antagonists*, NMDA receptor antagonists*receptor antagonists*

*Not approved by the FDA.

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Sedative-HypnoticsSedative-HypnoticsClass/Trade NameClass/Trade Name Generic NameGeneric Name Daily Dosage (mg/d)Daily Dosage (mg/d)

Benzodiazepines

Long acting: Dalmane Flurazepam 15-45

Doral Quazepam 7.5-15

Intermediate acting: Prosom Estazolam 0.5-2

Restoril Temazepam 15-45

Short acting: Halcion Triazolam 0.125-0.25

Nonbenzodiazepines

Ambien Zolpidem 5-20

Sonata Zaleplon 5-20

Lunesta Eszopiclone 2-3

- Indiplon* 10-20

Melatonin Receptor Agonists

Rozerem Ramelteon 8-16

Sedating antidepressants

Desyrel Trazodone 25-100

Barbituate like agents

Notec Choral hydrate 500-1,500

Natural Remedies

- Melatonin* 0.3-2

- Valerian* 400-900*Not approved by the FDA.

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Pharmacokinetics: BenzodiazepinesPharmacokinetics: Benzodiazepines

Absorption:Absorption: Variable speedVariable speed

Onset of action:Onset of action: Lipid solubility Lipid solubility →→ faster onset faster onset

Duration of action:Duration of action: Single dose:Single dose: the greater the lipid solubility the greater the lipid solubility →→ faster redistribution to fat tissues faster redistribution to fat tissues →→ shorter shorter duration of actionduration of action

Chronic use:Chronic use: in equilibrium with fat tissues in equilibrium with fat tissues

Protein binding:Protein binding: HIGH for all agentsHIGH for all agents

Metabolism:Metabolism:

Elimination half life:Elimination half life:

Lorazepam, oxazepam, temazepam not Lorazepam, oxazepam, temazepam not metabolized by liver CYP 450metabolized by liver CYP 450

In part, determines duration of actionIn part, determines duration of action

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Pharmacokinetics: BenzodiazepinesPharmacokinetics: Benzodiazepines

Dosing adjustmentsDosing adjustments ElderlyElderly Hepatic impairmentHepatic impairment Cytochrome P450 isoenzymesCytochrome P450 isoenzymes

Route of AdministrationRoute of Administration Oral routeOral route

Faster absorption = greater “rush”Faster absorption = greater “rush”

Acute parenteral (IM)Acute parenteral (IM) Lorazepam – Lorazepam – drug of choicedrug of choice, rapid and reliable absorption, rapid and reliable absorption Chlordiazepoxide and diazepam – may precipitate locally Chlordiazepoxide and diazepam – may precipitate locally

and are poorly absorbed, painfuland are poorly absorbed, painful

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Pharmacokinetics: BuspironePharmacokinetics: Buspirone

TT½½ – 2-3 hrs – 2-3 hrs

Slow onset of actionSlow onset of action Weeks vs. daysWeeks vs. days

CYP 3A4 substrateCYP 3A4 substrate Inducers Inducers → ? Loss of efficacy→ ? Loss of efficacy Inhibitors → ? Toxicity or increased side effectsInhibitors → ? Toxicity or increased side effects

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Pharmacokinetics:Pharmacokinetics:Nonbenzodiazepine HypnoticsNonbenzodiazepine Hypnotics

(Selectively bind to the BZD(Selectively bind to the BZD11 receptors) receptors)

ZaleplonZaleplon ZolpidemZolpidem EszopicloneEszopiclone

MetabolismMetabolism Aldehyde Aldehyde oxidase,oxidase,

CYP 3A4CYP 3A4

Various CYP Various CYP isoenzymesisoenzymes

CYP 3A4, CYP 3A4, 2E12E1

Tmax (Hr)Tmax (Hr) 1.41.4 1.41.4 11

T1/2 (Hr)T1/2 (Hr) 1.041.04†† 2.1*2.1*†† 6*6*††

* Prolonged in elderly; * Prolonged in elderly; †† prolonged in severe hepatic impairment prolonged in severe hepatic impairment

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Adverse Effects: Adverse Effects: BenzodiazepinesBenzodiazepines

SedationSedation and impairment of performance and impairment of performance Psychomotor skillsPsychomotor skills

Driving; engaging in dangerous physical activities; using Driving; engaging in dangerous physical activities; using hazardous machineryhazardous machinery

Especially during initial phase of treatmentEspecially during initial phase of treatment MemoryMemory impairment impairment

Anterograde amnesia (desired before surgery, Anterograde amnesia (desired before surgery, other procedures)other procedures)

Dose-related, and tolerance may not developDose-related, and tolerance may not develop Most likely with triazolamMost likely with triazolam

DisinhibitionDisinhibition Possible risk factors: History of aggression, Possible risk factors: History of aggression,

impulsivity, borderline or antisocial personalityimpulsivity, borderline or antisocial personality

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Adverse Effects:Adverse Effects:BenzodiazepinesBenzodiazepines

Abuse potentialAbuse potential decreases when properly prescribed and decreases when properly prescribed and supervised.supervised.

DependenceDependence may occur at usual doses taken beyond several may occur at usual doses taken beyond several weeks.weeks.

Withdrawal Withdrawal may occur even when discontinuation is not abrupt may occur even when discontinuation is not abrupt (e.g., by 10% every 3 days). Symptoms include: tachycardia, (e.g., by 10% every 3 days). Symptoms include: tachycardia, increased blood pressure, muscle cramps, anxiety, insomnia, increased blood pressure, muscle cramps, anxiety, insomnia, panic attacks, impairment of memory and concentration, panic attacks, impairment of memory and concentration, perceptual disturbances, derealization, hallucinations, perceptual disturbances, derealization, hallucinations, hyperpyrexia, seizures. May continue for months.hyperpyrexia, seizures. May continue for months.

Rebound anxietyRebound anxiety: : return of target symptoms, with increased return of target symptoms, with increased intensity.intensity.

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Adverse Effects: BuspironeAdverse Effects: Buspirone

AdvantagesAdvantages No sedation or impairment of performanceNo sedation or impairment of performance No cross-tolerance with BZDsNo cross-tolerance with BZDs No tolerance or withdrawalNo tolerance or withdrawal No abuse potentialNo abuse potential

DisadvantagesDisadvantages NauseaNausea HeadacheHeadache Insomnia, nervousnessInsomnia, nervousness RestlessnessRestlessness Dizziness, lightheadednessDizziness, lightheadedness

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Drug Interactions: Drug Interactions: BenzodiazepinesBenzodiazepines

Additive Additive pharmacodynamicpharmacodynamic effects effects(e.g., alcohol) (e.g., alcohol)

BZD BZD withdrawalwithdrawal when other drugs that when other drugs that increase seizure risk are also takenincrease seizure risk are also taken

Diazepam may increase levels of Diazepam may increase levels of digoxin digoxin and phenytoinand phenytoin

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Drug Interactions: Drug Interactions: Anxiolytic/HypnoticsAnxiolytic/Hypnotics

Drugs that affect CYP 3A4Drugs that affect CYP 3A4 Inhibit BZD metabolismInhibit BZD metabolism

(e.g., fluoxetine/norfluoxetine via P450 3A3/4 (e.g., fluoxetine/norfluoxetine via P450 3A3/4 inhibits metabolism of triazolam)inhibits metabolism of triazolam)

Effect on zolpidem > zaleplonEffect on zolpidem > zaleplon May be clinically nonsignificantMay be clinically nonsignificant

Clinically relevant increased exposure for Clinically relevant increased exposure for eszopiclone and inhibitorseszopiclone and inhibitors

Additive CNS depressionAdditive CNS depression Alcohol, antipsychotics, mood stabilizersAlcohol, antipsychotics, mood stabilizers

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Antidepressants: Antidepressants: Diagnostic Indications Diagnostic Indications

Mood disordersMood disorders Major depressive disorderMajor depressive disorder

Single or recurrentSingle or recurrent With or without melancholiaWith or without melancholia Seasonal patternSeasonal pattern

Bipolar disorderBipolar disorder DepressedDepressed MixedMixed

Cyclothymic disorderCyclothymic disorder Dysthymic disorderDysthymic disorder

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Other psychiatric Other psychiatric disorders (e.g., disorders (e.g., schizoaffective disorder, depressive type)schizoaffective disorder, depressive type)

Mood disorder Mood disorder due to a general medical due to a general medical condition condition (e.g., dementia with depression; (e.g., dementia with depression; Alzheimer’s type)Alzheimer’s type)

Substance-induced Substance-induced mood disorder (e.g., mood disorder (e.g., amphetamine or similarly acting amphetamine or similarly acting sympathomimetic intoxication or withdrawal)sympathomimetic intoxication or withdrawal)

Antidepressants: Antidepressants: Diagnostic Indications Diagnostic Indications

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Antidepressant AgentsAntidepressant AgentsClass/Generic NameClass/Generic Name Trade NameTrade Name Usual Daily Dosage (mg/d)Usual Daily Dosage (mg/d)

SSRISSRI

CitalopramCitalopram CelexaCelexa 20-4020-40

EscitalopramEscitalopram LexaproLexapro 1-201-20

FluoxetineFluoxetine ProzacProzac 10-6010-60

FluvoxamineFluvoxamineaa LuvoxLuvox 100-300100-300

ParoxetineParoxetine PaxilPaxil 10-5010-50

SertralineSertraline ZoloftZoloft 50-20050-200

SNRISNRI

AtomoxetineAtomoxetineaa StratteraStrattera 60-12060-120

DSNRIDSNRI

DuloxetineDuloxetine CymbaltaCymbalta 30-6030-60

MilnacipranMilnacipranbb 100-200100-200

VenlafaxineVenlafaxine EffexorEffexor 75-37575-375

AminoketoneAminoketone

BupropionBupropion WellbutrinWellbutrin 150-450150-450

TriazolopyridineTriazolopyridine

NefazodoneNefazodone SerzoneSerzonecc 100-600100-600

TrazodoneTrazodone DesyrelDesyrel 150-600150-600

SSRI, Selective serotonin reputake inhibitor; SSRI, selective norepinephrine, DSNI, dual norepinphrine reputae inhibitor; TCA, Tricyclic antidepressant; MAOI, monoamine oxidase inhibitor.

aNot approved by the FDA for depression. bNot available in the United States. cSerzone no longer available. dTransdermal system approved for depression.

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Antidepressant AgentsAntidepressant AgentsClass/Generic NameClass/Generic Name Trade NameTrade Name Usual Daily Dosage (mg/d)Usual Daily Dosage (mg/d)

TetracyclicTetracyclic

AmoxapineAmoxapine AscendinAscendin 200-600200-600

MaprotilineMaprotiline LudiomilLudiomil 75-22575-225

MirtazapineMirtazapine RemeronRemeron 15-4515-45

TCATCA

AmitriptylineAmitriptyline ElavilElavil 75-30075-300

ClomipramineClomipramine AnafranilAnafranil 100-250100-250

DesipramineDesipramine Norpramine Norpramine 75-30075-300

Doxepin Doxepin SinequanSinequan 75-30075-300

ImipramineImipramine TofranilTofranil 75-30075-300

NortriptylineNortriptyline PamelorPamelor 75-30075-300

ProtriptylineProtriptyline VivactilVivactil 20-6020-60

TrimipramineTrimipramine SurmontilSurmontil 75-30075-300

MAOIMAOI

IsocarboxazidIsocarboxazid MarplanMarplan 40-6040-60

PhenelzinePhenelzine NardilNardil 30-9030-90

TranylcypromineTranylcypromine ParnateParnate 30-6030-60

SelegilineSelegilinedd EmsamEmsam 20mg/20 cm20mg/20 cm22 patch patch

SSRI, Selective serotonin reputake inhibitor; SSRI, selective norepinephrine, DSNI, dual norepinphrine reputae inhibitor; TCA, Tricyclic antidepressant; MAOI, monoamine oxidase inhibitor.

aNot approved by the FDA for depression. bNot available in the United States. cSerzone no longer available. dTransdermal system approved for depression.

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Pharmacokinetics: ADsPharmacokinetics: ADsDrugDrug AbsorptionAbsorption DistributionDistribution MetabolismMetabolism Elimin tElimin t

1/21/2

SSRIsSSRIs complete High PB hepaticfluoxetineactive met.

24 hoursfluox. days

VenlafaxineVenlafaxine complete widelyLow PB

hepaticactive metabolites

5 hours

NefazodoneNefazodone complete1st pass effect

loose PB hepatic active metabolites

2-4 hours

MirtazapineMirtazapine complete high PB hepatic active metabolites

20-40 hours> in women

TCAsTCAs complete1st pass effect

High PB hepaticCYP 2D6

24 hours

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Pharmacokinetics: SSRIsPharmacokinetics: SSRIs

CitalopramCitalopram FluoxetineFluoxetine SertralineSertraline ParoxetineParoxetine FluvoxamineFluvoxamine

% protein-bound% protein-bound 8080 9494 9999 9595 7777

Peak plasma level Peak plasma level (hour)(hour)

3-43-4 6-86-8 6-86-8 2-82-8 2-82-8

Half-life (hours)Half-life (hours) 3535 24-7224-72 2525 2020 1515

Dose range (mg/d)Dose range (mg/d) 20-6020-60 20-8020-80 50-20050-200 10-5010-50 50-30050-300

Absorption altered Absorption altered by fast or fed statusby fast or fed status

NoNo NoNo YesYes NoNo NoNo

Linear Linear pharmacokineticspharmacokinetics

YesYes NoNo YesYes NoNo NoNo

GI absorption (%)GI absorption (%) ~100~100 8080 4444 6464 9494

Van Harten. Van Harten. Clin PharmacokinetClin Pharmacokinet, 1993. Preskorn. , 1993. Preskorn. Clin PharmacokinetClin Pharmacokinet. 1997. Data on file. Forest Laboratories, Inc. Preskorn. . 1997. Data on file. Forest Laboratories, Inc. Preskorn. J Clin PsychiatryJ Clin Psychiatry. 1993.. 1993.

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CardiacCardiacOrthostasis,

hypertension,heart block,tachycardia

UrogenitalUrogenitalErectile dysfunction,ejaculation disorder,

anorgasmia, priapism

Central Nervous SystemCentral Nervous SystemDizziness, cognitive impairment,

sedation, light-headedness,somnolence, nervousness,

insomnia, headache, tremor,changes in satiety and appetite

GastrointestinalGastrointestinalNausea, constipation,vomiting, dyspepsia,

diarrhea

Autonomic Nervous SystemAutonomic Nervous SystemDry mouth, urinary retention,

blurred vision, sweating

Adverse Effects: AntidepressantsAdverse Effects: Antidepressants

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Adverse Effects: SSRIsAdverse Effects: SSRIs

AdvantagesAdvantages Improved safety and tolerability (e.g., cardiac Improved safety and tolerability (e.g., cardiac

toxicity)toxicity) Better long-term compliance (?)Better long-term compliance (?)

DisadvantagesDisadvantages Sexual dysfunctionSexual dysfunction Increased risk of suicide (?)Increased risk of suicide (?) Drug interactionsDrug interactions

Pharmacodynamic (serotonin syndrome)Pharmacodynamic (serotonin syndrome) Pharmacokinetic (CYP 450 inhibition)Pharmacokinetic (CYP 450 inhibition)

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Adverse Effects of AntidepressantsAdverse Effects of AntidepressantsDrugsDrugs SedationSedation AnticholinergicsAnticholinergics Orthostatic HypotensionOrthostatic Hypotension Cardiac EffectsCardiac Effects

SSRIsSSRIs

CitalopramCitalopram LowLow NoneNone NoneNone NoneNone

EscitalopramEscitalopram LowLow NoneNone NoneNone NoneNone

FluoxetineFluoxetine LowLow NoneNone NoneNone NoneNone

FluvoxamineFluvoxamine LowLow NoneNone NoneNone NoneNone

ParoxetineParoxetine LowLow LowLow NoneNone NoneNone

SertralineSertraline LowLow NoneNone NoneNone NoneNone

SNRIsSNRIs

Atomoxetine*Atomoxetine* LowLow LowLow LowLow LowLow

DSNRIsDSNRIs

DuloxetineDuloxetine LowLow LowLow LowLow LowLow

MilnacipranMilnacipran LowLow LowLow LowLow LowLow

VenlafaxineVenlafaxine LowLow LowLow LowLow LowLow

AminoketonesAminoketones

BupropionBupropion LowLow Very lowVery low Very low - noneVery low - none LowLow

TriazolopyridinesTriazolopyridines

NefazodoneNefazodone LowLow LowLow LowLow LowLow

TrazodoneTrazodone HighHigh LowLow ModerateModerate LowLow

SSRI, Selective serotonin reputake inhibitor; SSRI, selective norepinephrine, DSNI, dual norepinphrine reputae inhibitor; TCA, Tricyclic antidepressant; MAOI, monoamine oxidase inhibitor. Adapted from Ward M. Appendix B. In: Flaherty J, Davis JM, Janicak PG, eds. Psychiatry: Diagnosis and Therapy. 2nd ed. Norwalk, Conn: Appleton & Lange, 1995:493-494. aAmoxapine is the only antidepressant with a clinically meaningful potency for blocking D2 receptors with the potential to cause acute and tardive extrapyramidal effects. * Not FDA approved for depression.

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DrugsDrugs SedationSedation AnticholinergicsAnticholinergics Orthostatic HypotensionOrthostatic Hypotension Cardiac EffectsCardiac Effects

TetracyclicsTetracyclics

AmoxapineAmoxapineaa LowLow ModerateModerate LowLow NoneNone

MaprotilineMaprotiline ModerateModerate ModerateModerate LowLow ModerateModerate

MirtazapineMirtazapine ModerateModerate LowLow LowLow LowLow

TCAsTCAs

AmitriptylineAmitriptyline HighHigh HighHigh ModerateModerate HighHigh

ClomipramineClomipramine HighHigh HighHigh LowLow ModerateModerate

DesipramineDesipramine LowLow LowLow LowLow ModerateModerate

Doxepin Doxepin HighHigh ModerateModerate ModerateModerate ModerateModerate

ImipramineImipramine ModerateModerate ModerateModerate HighHigh HighHigh

NortriptylineNortriptyline ModerateModerate ModerateModerate LowLow ModerateModerate

ProtriptylineProtriptyline LowLow ModerateModerate LowLow ModerateModerate

TrimipramineTrimipramine HighHigh HighHigh ModerateModerate HighHigh

MAOIsMAOIs

IsocarboxazidIsocarboxazid LowLow NoneNone HighHigh NoneNone

PhenelzinePhenelzine LowLow LowLow HighHigh NoneNone

TranylcypromineTranylcypromine HighHigh Very lowVery low Very lowVery low NoneNone

Selegiline TSSelegiline TS LowLow LowLow HighHigh High (high doses)High (high doses)

Adverse Effects of AntidepressantsAdverse Effects of Antidepressants

SSRI, Selective serotonin reputake inhibitor; SSRI, selective norepinephrine, DSNI, dual norepinphrine reputae inhibitor; TCA, Tricyclic antidepressant; MAOI, monoamine oxidase inhibitor. Adapted from Ward M. Appendix B. In: Flaherty J, Davis JM, Janicak PG, eds. Psychiatry: Diagnosis and Therapy. 2nd ed. Norwalk, Conn: Appleton & Lange, 1995:493-494. aAmoxapine is the only antidepressant with a clinically meaningful potency for blocking D2 receptors with the potential to cause acute and tardive extrapyramidal effects.

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Antidepressants: Antidepressants: Drug Interactions Drug Interactions

Antidepressants and mood stabilizers may be Antidepressants and mood stabilizers may be inhibitors, inducers, or substratesinhibitors, inducers, or substrates of one or more of one or more cytochrome P450 isoenzymescytochrome P450 isoenzymes

Knowledge of their Knowledge of their P450 profileP450 profile is useful in is useful in predicting drug-drug interactionspredicting drug-drug interactions

When some isoenzymes are absent or inhibited, When some isoenzymes are absent or inhibited, others may offer a others may offer a secondary metabolic pathwaysecondary metabolic pathway

P450 P450 1A2, 2C (subfamily), 2D6, and 3A41A2, 2C (subfamily), 2D6, and 3A4 are are especially important to antidepressant metabolism especially important to antidepressant metabolism and drug-drug interactionsand drug-drug interactions

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Minimizing the Risk of Drug Minimizing the Risk of Drug Interactions Associated with Interactions Associated with

AntidepressantsAntidepressants When adding an antidepressant with a potential

for pharmacokinetic interaction to another drug, clinicians could: Reduce the dose Reduce the dose of the current drug Begin with a low dose Begin with a low dose of the antidepressant Use therapeutic drug monitoring therapeutic drug monitoring where

appropriate MonitorMonitor therapeutic and adverse effects Choose an antidepressantChoose an antidepressant with a favorable profile

for that interaction

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Indications forIndications forTherapeutic Drug MonitoringTherapeutic Drug Monitoring

Nonresponders Nonresponders for dosage adjustmentfor dosage adjustment

Suspicion of Suspicion of noncompliancenoncompliance

To avoid To avoid toxicitytoxicity (especially in the elderly) (especially in the elderly)

OverdoseOverdose

If If adverse effects adverse effects limit further dosage increaseslimit further dosage increases

Patients with Patients with absorption abnormalitiesabsorption abnormalities

DocumentDocument response response

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GoalsGoals

Anxiolytic-Sedative-Hypnotics (ASHs)Anxiolytic-Sedative-Hypnotics (ASHs) Diagnostic indicationsDiagnostic indications Classification of ASHsClassification of ASHs Relevant PharmacokineticsRelevant Pharmacokinetics Serious Adverse EffectsSerious Adverse Effects Drug InteractionsDrug Interactions

Antidepressants (ADs)Antidepressants (ADs) Diagnostic indicationsDiagnostic indications Classification of ADsClassification of ADs Relevant PharmacokineticsRelevant Pharmacokinetics Serious Adverse EffectsSerious Adverse Effects Drug InteractionsDrug Interactions