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Page 1: Psikofarmakologi

Psikofarmakologi

Page 2: Psikofarmakologi

• Agonis artinya kerja obat menyerupai sifat neurotransmitter sasaran, berikatan dg reseptor dan memperkuat kerja neurotransmiter tsb di neuron

• Antagonis artinya kerja obat mem-blok reseptor neurotransmitter sasaran sehingga neurotransmitter tsb tdk dapat berikatan dg neuron.

Page 3: Psikofarmakologi
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PrinPrinssipip pemilihan obat psikofarmaka pemilihan obat psikofarmaka

1.1. EfEfek yang diharapkan berkaitan dengan gejala sasaranek yang diharapkan berkaitan dengan gejala sasaran2.2. Start low – go slowStart low – go slow

3.3. Implikasi dari efek samping obatImplikasi dari efek samping obat 4.4. InteraInteraksi dengan obat-ksi dengan obat-oobat lainbat lain5.5. Fungsi hepar dan ginjal terkait dosisFungsi hepar dan ginjal terkait dosis6.6. Tailoring-madeTailoring-made

7.7. Kehamilan? Menyusui?Kehamilan? Menyusui?

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Golongan Psikofarmaka

AntipsikotikAntidepresanAnxiolitik/AntianxietasHipnotik /SedatifCognitive EnhancerPsikostimulan

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Antipsikotik (Neuroleptik)Antipsikotik (Neuroleptik)

• Golongan Tipikal (Golongan Tipikal (FGAFGA))• Golongan Atipikal (Golongan Atipikal (SGA / SDASGA / SDA))

Indikasi:Indikasi:• Gangguan Psikotik (Termasuk Psikosis organik)Gangguan Psikotik (Termasuk Psikosis organik)• SkizofreniaSkizofrenia• Depresi berat disertai gejala psikotikDepresi berat disertai gejala psikotik• Agitasi (Gaduh-gelisah)Agitasi (Gaduh-gelisah)• DeliriumDelirium• Tic vokal (Sindrom Tic vokal (Sindrom Gilles de la tourreteGilles de la tourrete))

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Antipsikotik Golongan TipikalAntipsikotik Golongan Tipikal• PhenothiazinePhenothiazine

ChlorpromazineChlorpromazineThioridazineThioridazinePerphenazinePerphenazineFluphenazineFluphenazineTrifluoperazineTrifluoperazine

• ButyrophenoneButyrophenoneHaloperidolHaloperidol

• DiphenylbutylpiperidineDiphenylbutylpiperidinePimozidePimozide

• BenzamideBenzamideSulpirideSulpiride

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Antipsikotik Golongan TipikalAntipsikotik Golongan Tipikal

Nama GenerikNama Generik DosDosis Initialis Initial DosDosis Terapeutikis Terapeutik DDoossis Maxis Max

Chlorpromazine 50-100 mg/h 300-1000 mg/h 1000mg/h

Fluphenazine 5 mg/h 5-20 mg/h 20mg/h

Fluphenazine Decanoat 12.5-25 mg IM/bln 6.25-50 mg IM/bln 100 mg

Haloperidol 2-5 mg/h 2-20 mg/h 20 mg/h

Haloperidol Decanoat 25-50mgIM/bln 50-200mg/bln 200 mg

Perphenazine 4-8 mg/h 16-64 mg/h 64mg/h

Trifluoperazine 5 mg/h 5-40 mg/h 40 mg/h

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PhenothiazinesPhenothiazines• Antipsikotik pertama yg ditemukan & digunakan

– Chlorpromazine (Largactil®, 1952)– Thioridazine (Melleril®)

• Pharmacokinetics: – Waktu paruh 24-48 jam– Metabolisme di hepar

• Pharmacodynamics:– Memblok reseptor D2 – Jg mem-blok ACh, 5-HT, NE & Histamin

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ButyrophenonesButyrophenones• Haloperidol (Haldol®, 1967)• Longer half-life• Specific D2 blocker• Less sedation• Parkinsonian effects like those of high-potency

phenothiazines (Perphenazine, Fluphenazine Trifluoperazine)

• Acute extrapyrimidal effects:– Akathisia: anxious pacing– Acute Dystonia: spasm and posturing– Parkinsonism

• Chronic extrapyrimidal effects: Tardive dyskinesia

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AntipsAntipsikotik Atipikal/ Serotonin-Dopamine Antagonist (SDA)ikotik Atipikal/ Serotonin-Dopamine Antagonist (SDA)

SSDDA A Starting Dose Starting Dose Titration Range Titration Range Max. Dose Max. Dose

Risperidone 1 – 2 mg/day 1 mg/2-3 days 4 – 6 mg/day

Olanzapine 5 – 10 mg 5 mg/week 10 – 20 mg/day

Quetiapine 25 mg bid 50 mg/day 300 – 800 mg/day

Clozapine 12.5 mg Dose increased every 3 daysDay 2: 25 mg Day 3: 25 mg bidDay 6: 50 mg bidDay 9: 75 mg bidDay 12: 100 mg bidDay 15: 125 mg bidDay 18: 150 mg bidDay 21: 200 mg bid 300 – 900

mg/day

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Guideline for SchizophreniaGuideline for Schizophrenia

SGA #24 -12 WEEKS

Conventional #1

4 – 12 WEEKS

Clozapine3 - 9 MONTHS

•Two Antipsychotics (not 2 conventionals)

•ECT+/-Antipsychotic

•Different Antipsychotic (Atypical#3, Conventional#2)

No response

No response

No response

Second Generation Antipsychotic (SGA)

#14 -12 WEEKSNo response

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Neurological Side Effects of Antipsychotic DrugsNeurological Side Effects of Antipsychotic DrugsReactionReaction FeaturesFeatures Time of Time of

Maximal Maximal RiskRisk

Proposed Proposed MechanismMechanism

TreatmentTreatment

Acute dystonia Spasm of muscles of tongue, face, neck, back; may mimic seizures; not hysteria

1 to 5 days unknown Many treatments can alter, but effects of antimuscarinic agents are diagnostic and curative.*

Akathisia Motor restlessness: not anxiety or “agitation”

5 to 60 days unknown Reduce dose or change drug; antimuscarinic agents, dephenhydramine, benzodiazepines, or propranolol ++ may help

Parkinsonism Bradykinesia, rigidity, variable tremor, mask facies, shuffling gait

5 to 30 days antagonism of dopamine

Antimuscarinic agents helpful+

*Many drugs have been claimed to be helpful for acute dystonia. Among the most commonly employed treatments are dephenhydramine hydrochloride, 25 or 50 mg intramuscularly, or benztropine mesylate, 1 or 2 mg intramuscularly or slowly intravenously, followed by oral medication with the same agent for a period of days to perhaps several weeks thereafter.++ Propranolol is often effective in relatively low doses (2080 mg per day). Selective 1-adrenergic antagonists are less effective

C. Servy
acute dstonia: spasms of muscles, esp. facialakathisia: motor restlessness, can't be stillparkinsonism: slow movement, rigidity, odd facial expressions, shuffling
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Neurological Side Effects of Antipsychotic DrugsNeurological Side Effects of Antipsychotic Drugs

ReactionReaction FeaturesFeatures Time of Time of Maximal Maximal

RiskRisk

Proposed Proposed MechanismMechanism

TreatmentTreatment

Neuroleptic Malignant syndrome

catatonia, stupor, fever, unstable blood presure, myoglobinemia; can be fatal

weeks; can persist for days after stopping neuroleptic

antagonism of dopamine may contribute

stop antipsychotic immediately; dantrolene or bromocriptine may help§; antimuscarinic agents not effective

Perioral tremor (“rabbit” syndrome)

perioral tremor (may be a late variant of parkinsonism)

after months or years of treatment

unknown Antimuscarininic agents often help+

Tardive dyskinesia

oral-facial dyskinesia; widespread choreoathetosis or dystonia

after months or years of treatment (worse on withdrawal)

up regulation of striatal D2 receptors

prevention crucial; clozapine or olanzapine may help

§ Despite the response to dantrolene, there is no evidence of an abnormality of Ca+2 transport in skeletal muscle; with lingering antipsychotic effects, bromocriptine may be tolerated in large doses (10-40 mg per day).

C. Servy
n.m.s.: innaprop. reg of Ca --> cat, stup, etc. Dantrolene can Tx itPerioral tremmortardive dyskinesia: face grimacing, stick tongue out, choreoath:snake like m. movement
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Adverse ReactionsAdverse Reactions

• NeurologicNeurologic – seizures with clozapine – seizures with clozapine

• Cardiovascular and cerbrovascular effectsCardiovascular and cerbrovascular effects Orthostatic Orthostatic hypotension – peripheral a blockadehypotension – peripheral a blockade– QT prolongation (thioridazine, ziprasidone, others)QT prolongation (thioridazine, ziprasidone, others)– Increased risk of stroke in elderly (risperidone, olanzapine)Increased risk of stroke in elderly (risperidone, olanzapine)

• Weight gain and metabolic effectsWeight gain and metabolic effects – Prominent with – Prominent with clozapine and olanzapine. Uncommon with ziprasidone and clozapine and olanzapine. Uncommon with ziprasidone and aripiprazole, others. Can increase risk of Type 2 diabetes.aripiprazole, others. Can increase risk of Type 2 diabetes.

C. Servy
QT prolongation: --> arrhythmias --> deaththiorid adn zip cause it more>ed stroke risk: risp and olan, are atypicals. chemically restrains elderlywt. gain : --> type 2 diab --> c.v. dz
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Adverse effects (cont.)Adverse effects (cont.)

• Blood disorders – mild leukocytosis, leukopenia, and eosinophilia. Bone marrow suppression or agranulocytosis with clozapine.

• Others– Skin reactions – dermatitis, photsensitivity, sun burn, pigmentary

retinopathy (typicals).– GI/metabolic – jaundice with CPZ; ileus and sialorrhea with

clozapine – Endocrine – hperprolactinemia– Sedation – due to H1 block– Anticholinergic effects – mainly typicals

C. Servy
agranulocytosis:clozapin: bone marrow suppressed --> <ed wbc.sso cloz is only taken if nothing else helpsdon't worry about others except anticholinergic: dry mouth and eyes greatly <es likelyhood of pt. compliance wih med.
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Comparison of Some Antipsychotic AgentsComparison of Some Antipsychotic AgentsDrugDrug Relative Relative

Antipsychotic Antipsychotic PotencyPotency

SedationSedation Extra-Extra-pyramidalpyramidal

Anti-Anti-cholinergiccholinergic

HypotensionHypotension

chlorpromazine(Thorazine)

+ +++ +++ + +++

thioridazine(Mellaril)

+ +++ + +++ +++

fluphenazine(Prolixin)

+++ + +++ + ++

haloperidol(Haldol)

+++ + +++ +/- +

loxapine(Loxitane)

++ + ++ +/- +

molindone(Moban)

++ ++ + + +

clozapine(Clozaril)

++ +++ +/- +++ +++

risperidone(Risperdal)

+++ + + + ++

C. Servy
comparing side effects is important.sedation: bc. histamine receptors are blocked --> sedation.
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Some Adverse Effects of Second Generation AntipsychoticsSome Adverse Effects of Second Generation Antipsychotics

DrugDrug DiabetesDiabetes ExtrapyramidExtrapyramidal Symptomsal Symptoms

Elevated Elevated ProlactinProlactin

QTc QTc ProlongationProlongation

Weight Weight GainGain

Aripiprazole +/- + +/- +/- +/-

Clozapine* ++++ +/- +/- + ++++

Olanzapine ++++ + +/- + ++++

Quetiapine ++ +/- +/- +/- +++

Risperidone ++ +++ +++ + ++

Ziprasidone +/- + + ++ +/-

*Clozapine is also associated with myocarditis and agranulocytosis; the other second-generation antipsychotics are not.

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AntidepresanAntidepresan

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Pro

gre

ssio

nAcute

(6-12 weeks)

Severi

ty

Continuation(4-9 months)

Maintenance(1 or more years)

“Normalcy”

Response

Relapse

Relapse Recurrence

PHASES OF TREATMENT FOR DEPRESSIONPHASES OF TREATMENT FOR DEPRESSION

to

diso

rder

Symptoms

Disorder

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AntidepressanAntidepressan• Yang bersifat sedatif:

– Amitriptyline– Imipramine– Clomipramine– Maproptiline– Trazodone– Mirtazapine

• Yang bersifat aktivasi/non-sedatif:– Tianeptine– Moclobemide– SSRI (Fluoxetine,Sertraline,Citalopram,Fluvoxamine)

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Tricyclic antidepressants (TCAs):Tricyclic antidepressants (TCAs):– Amitriptyline has higher sedative and Amitriptyline has higher sedative and

anticholinergic effects and affects serotonin more anticholinergic effects and affects serotonin more than imipramine does.than imipramine does.

– Imipramine (Tofranil®) discovered as a Imipramine (Tofranil®) discovered as a modification of a phenothiazine (antipsychotic)modification of a phenothiazine (antipsychotic)

– Clomipramine (Anafranil®) has the highest Clomipramine (Anafranil®) has the highest serotonin effect of the TCAs, with little serotonin effect of the TCAs, with little anticholinergic or sedative action. Also for OCD.anticholinergic or sedative action. Also for OCD.

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Pharmacodynamics of TCAsPharmacodynamics of TCAs

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Tricyclic side effectsTricyclic side effects

• TCAs have varying side effects.TCAs have varying side effects.• All TCAs are toxic to the heart at high All TCAs are toxic to the heart at high

doses, and are effective agents of suicide. doses, and are effective agents of suicide. This fact has fueled the search for other This fact has fueled the search for other antidepressants.antidepressants.

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Other antidepressantsOther antidepressants

– Maprotiline (Ludiomil®) is based on the TCA molecule. May cause seizures, and accumulates to toxic levels. More lethal than TCAs. Blocks reuptake of NE.

– Reversible MAOIs or RIMA: moclebemide (Aurorix®)

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SSRI antidepressantsSSRI antidepressants

• SSRIs: Selective Serotonine (5-HT) Re-uptake InhibitorsSSRIs: Selective Serotonine (5-HT) Re-uptake Inhibitors• Method of Action: They act within the brain to increase the Method of Action: They act within the brain to increase the

amount of serotonin in the synaptic gap by inhibiting re-amount of serotonin in the synaptic gap by inhibiting re-uptake. uptake.

• In contrast to other drugs, SSRIs are more potent inhibitors In contrast to other drugs, SSRIs are more potent inhibitors of serotonin reuptake, and they have less of an effect on of serotonin reuptake, and they have less of an effect on 1, 1, 2, histaminic, and muscarinic receptors 2, histaminic, and muscarinic receptors

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Measurement of drug action

Pre-synaptic terminal

Post-synaptic cell

Serotonin transporters (SERT)

SynapseSerotonin reuptake inhibitor (SSRI)

SPECT tracer

Image available binding sites

Serotonin

Modern antidepressant drugs (SSRIs) block the serotonin transporter (SERT)

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SSRIs: Selective Serotonin Reuptake SSRIs: Selective Serotonin Reuptake InhibitorsInhibitors

– Fluoxetine (Prozac®, 1988): least selectiveFluoxetine (Prozac®, 1988): least selective– Sertraline (Zoloft®): quick action, less side Sertraline (Zoloft®): quick action, less side

effectseffects– Escitalopram (CipralexEscitalopram (Cipralex®®))– Fluvoxamine (Luvox®, 1995): OCD, panic Fluvoxamine (Luvox®, 1995): OCD, panic

disorders & PTSDdisorders & PTSD

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FluoxetineFluoxetine

• Positive effects in one study on adults caused them to be Positive effects in one study on adults caused them to be “much improved” on the CGI scale “much improved” on the CGI scale (J Intellect Disabil Res 1998; 42: 301-(J Intellect Disabil Res 1998; 42: 301-6)6)

• Children have negative effects that cause discontinuation of Children have negative effects that cause discontinuation of the drug such as hyperactivity and agitation the drug such as hyperactivity and agitation (Dev Med Child Neurol (Dev Med Child Neurol 1998; 40: 551-62)1998; 40: 551-62)

• Also reports of producing mania in people with PDDs Also reports of producing mania in people with PDDs (J Am (J Am

Acad Child Adolesc Psychiatry 1998;37:248-9).Acad Child Adolesc Psychiatry 1998;37:248-9).

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SertralineSertraline

• Similar in effects to fluoxetine (Prozac)Similar in effects to fluoxetine (Prozac)• Improvement in some adults in aggression and self-Improvement in some adults in aggression and self-

injurious behavior injurious behavior (J Clin Psychiarty 1996;57:333-6)(J Clin Psychiarty 1996;57:333-6)

• Caused hyperactivity in children and agitation Caused hyperactivity in children and agitation despite improvement in anxiety and irritability despite improvement in anxiety and irritability (J Child (J Child Adolesc Psychopharmacol 1997;7:9-15)Adolesc Psychopharmacol 1997;7:9-15)

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SSRI-Common Side EffectsSSRI-Common Side Effects

• Insomnia, headacheInsomnia, headache• Nausea, anorexiaNausea, anorexia

– Diarrhea Diarrhea – Constipation Constipation

• Sexual dysfunctionSexual dysfunction– Decreased libidoDecreased libido– AnorgasmiaAnorgasmia

• Nervousness, tremorNervousness, tremor– MyoclonusMyoclonus

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SSRI: Other IndicationsSSRI: Other Indications

• Anxiety/PanicAnxiety/Panic• Bulimia NervosaBulimia Nervosa• MDDMDD• OCD-SpectrumOCD-Spectrum• Impulse ControlImpulse Control

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FDA Warning 3/22/2004FDA Warning 3/22/2004

The Food and Drug Administration (FDA) requests a The Food and Drug Administration (FDA) requests a Warning Statement in the labeling for certain Warning Statement in the labeling for certain antidepressants to encourage close observation of adult antidepressants to encourage close observation of adult and pediatric patients treated with these agents for and pediatric patients treated with these agents for worsening depression or the emergence of suicidality. The worsening depression or the emergence of suicidality. The drugs that are the focus of this new Warning Statement drugs that are the focus of this new Warning Statement include: Prozac (fluoxetine); Zoloft (sertraline); Paxil include: Prozac (fluoxetine); Zoloft (sertraline); Paxil (paroxetine); Luvox (fluvoxamine); Celexa (citalopram); (paroxetine); Luvox (fluvoxamine); Celexa (citalopram); Effexor (venlafaxine) and Remeron (mirtazapine). Effexor (venlafaxine) and Remeron (mirtazapine).

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Serotonin syndromeSerotonin syndrome

• May occur if SSRIs are taken in high doses, especially May occur if SSRIs are taken in high doses, especially combined with other serotonin-enhancing drugs, including combined with other serotonin-enhancing drugs, including herbs (valerian)herbs (valerian)

• Disorientation, agitation, shivering, diarrhea, increased Disorientation, agitation, shivering, diarrhea, increased reflexes, and morereflexes, and more

• May be life-threateningMay be life-threatening• Recover within 48 hours of abstinenceRecover within 48 hours of abstinence

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Mood StabilizerMood Stabilizer

Used for “Bipolar” or “Manic-Depressive” Used for “Bipolar” or “Manic-Depressive” to regulate moodto regulate mood

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• Lithium carbonate – Lithium is the classic mood stabilizer. Lithium carbonate – Lithium is the classic mood stabilizer. Monitoring blood lithium levels (therapeutic range: 0.8 – 1.2 mEq/L) and look Monitoring blood lithium levels (therapeutic range: 0.8 – 1.2 mEq/L) and look for signs and symptoms of toxicity (such as nausea, vomiting, diarrhea, for signs and symptoms of toxicity (such as nausea, vomiting, diarrhea, ataxia)ataxia)

• Valproic Acid (Depakene) & Divalproex Sodium (Depakote®) – Can be very Valproic Acid (Depakene) & Divalproex Sodium (Depakote®) – Can be very irritating to the stomach. Liver function and CBC should be monitoredirritating to the stomach. Liver function and CBC should be monitored

• Carbamazepine (Tegretol®) – Can lower white blood cell count. Therapeutic Carbamazepine (Tegretol®) – Can lower white blood cell count. Therapeutic drug monitoring is required. Monitor for signs and symptoms of Stevens-drug monitoring is required. Monitor for signs and symptoms of Stevens-Johnson syndrome. FDA – approved for bipolar disorderJohnson syndrome. FDA – approved for bipolar disorder

• Lamotrigine (Lamictal®) – Particularly effective for Bipolar depression. Lamotrigine (Lamictal®) – Particularly effective for Bipolar depression. Monitor for signs and symptoms of Stevens-Johnson syndrome.Monitor for signs and symptoms of Stevens-Johnson syndrome.

• Oxcarbazepine (Trileptal®) – Not FDA approved for bipolar disorder. Oxcarbazepine (Trileptal®) – Not FDA approved for bipolar disorder.

Mood StabilizerMood Stabilizer

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Treatment:Treatment:APA Practice Guidelines 2002APA Practice Guidelines 2002

• Acute mania/mixed mania:Acute mania/mixed mania:– 11stst line: lithium line: lithium oror valproate valproate oror antipsychotic* antipsychotic*– 11stst line severe: lithium line severe: lithium oror valproate + antipsychotic* valproate + antipsychotic*

• Acute depression:Acute depression:– 11stst line: lithium line: lithium oror lamotrigine lamotrigine– 11stst line severe: lithium + antidepressant line severe: lithium + antidepressant

• MaintenanceMaintenance– lithium lithium oror valproate: valproate:– Alternatives: lamotrigine, carbamazepine, oxycarbazepineAlternatives: lamotrigine, carbamazepine, oxycarbazepine– Atypical antipsychotics “may be considered”Atypical antipsychotics “may be considered”

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Mood Stabilizers:Mood Stabilizers:LithiumLithium

• Advantages:Advantages:– 50+ years worldwide experience (FDA-approved 1970)50+ years worldwide experience (FDA-approved 1970)– effective in euphoric mania and hypomaniaeffective in euphoric mania and hypomania– inexpensiveinexpensive– reduces suicide rate¹‚²reduces suicide rate¹‚²

• Disadvantages:Disadvantages:– slow onset ~ 14 daysslow onset ~ 14 days– narrow therapeutic indexnarrow therapeutic index– non-response in > 50% (usually bipolar subtypes)non-response in > 50% (usually bipolar subtypes)– frequent side effects (polyuria, tremor, GI symptoms) and non-compliancefrequent side effects (polyuria, tremor, GI symptoms) and non-compliance– discontinuation associated with high relapse rate³ discontinuation associated with high relapse rate³

¹Baldessarini RJ, et al. J Clin Psychiatry. 2003;64 Suppl 5:44-52.

²Goodwin FK, et al. JAMA. 2003 Sep 17;290(11):1467-73.

³Cavanagh J, et al. Acta Psychiatr Scand. 2004 Feb;109(2):91-5.

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Mood Stabilizers:Mood Stabilizers:DivalproexDivalproex

• Advantages:Advantages:– extensive experience (FDA-approved for epilepsy 1983; for

bipolar mania 1995)– rapid onset (1-4 days)– loading dose strategy¹ well-tolerated:

•20 mgs/kg•77% moderate to marked response

– effective in Bipolar subtypes– effective for psychotic symptoms²– plasma levels (50-125 mcg/ml)– less cognitive impairment than lithium³

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Mood Stabilizers:Mood Stabilizers:DivalproexDivalproex

• Disadvantages:Disadvantages:– sedation– transient hair loss– weight gain– tremor– GI upset– dose-related thrombocytopenia– rare hepatotoxicity, pancreatitis– possible Polycystic Ovarian Syndrome– plasma level monitoring

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Mood Stabilizers:Mood Stabilizers:LamictalLamictal

• FDA-approved for FDA-approved for maintenancemaintenance treatment treatment of of Bipolar I DisorderBipolar I Disorder

• Black box warning for serious rash Black box warning for serious rash (includes (includes Stevens-Johnson Syndrome and toxic epidermal Stevens-Johnson Syndrome and toxic epidermal necrolysis)necrolysis)

• Slow titrationSlow titration necessary necessary• Interaction with other AEDs Interaction with other AEDs (especially valproic acid (especially valproic acid

and carbamazepine)and carbamazepine)

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ANXIOLANXIOLITIKITIK

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An anxiolytic is a An anxiolytic is a drug drug prescribed for the prescribed for the treatment of treatment of symptoms symptoms of of anxietyanxiety

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Types of anxiolyticsTypes of anxiolytics

Anxiolytics are generally divided into two Anxiolytics are generally divided into two groups of medication:groups of medication:Benzodiazepines and Benzodiazepines and Non-benzodiazepinesNon-benzodiazepines

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AnxiolyticsAnxiolytics

• Benzodiazepines (BZDs)Benzodiazepines (BZDs)• Barbiturates (BARBs)Barbiturates (BARBs)• 5-HT5-HT1A 1A receptor agonists: Azaspirodecanedionereceptor agonists: Azaspirodecanedione

BuspironeBuspirone• -Blockers-Blockers

PropranololPropranolol• 2-AR partial agonist2-AR partial agonist

ClonidineClonidine• AntidepressantsAntidepressants

TCAs, SSRIsTCAs, SSRIs• Antihistaminic drugsAntihistaminic drugs

DDiiphenhydraminephenhydramine

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Mechanisms of ActionMechanisms of Action

1)1) Enhance GABAergic TransmissionEnhance GABAergic Transmission frequency of openings of GABAergic channels. frequency of openings of GABAergic channels.

BenzodiazepinesBenzodiazepines opening time of GABAergic channels. Barbituratesopening time of GABAergic channels. Barbiturates receptor affinity for GABA. BDZs and BARBSreceptor affinity for GABA. BDZs and BARBS

2) Stimulation of 5-HT2) Stimulation of 5-HT1A 1A receptors.receptors.

3) Inhibit 5-HT3) Inhibit 5-HT2A2A, 5-HT, 5-HT2C2C, and 5-HT, and 5-HT33 receptors receptors

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Pharmacokinetics of BenzodiazepinesPharmacokinetics of Benzodiazepines

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Side Effects of BenzodiazepinesSide Effects of Benzodiazepines

• Related primarily to the CNS depression and include: drowsiness, excess sedation, impaired coordination, nausea, vomiting, confusion and memory loss. Tolerance develops to most of these effects.

• Dependence with these drugs may develop.• Serious withdrawal syndrome can include

convulsions.

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Toxicity/Overdose with BenzodiazepinesToxicity/Overdose with Benzodiazepines

• Drug overdose is treated with flumazenil (a BDZ Drug overdose is treated with flumazenil (a BDZ receptor antagonist, short half-life), but respiratory receptor antagonist, short half-life), but respiratory function should be adequately supported and carefully function should be adequately supported and carefully monitored.monitored.

• Seizures and cardiac arrhythmias may occur following Seizures and cardiac arrhythmias may occur following flumazenil administration when BDZ are taken with flumazenil administration when BDZ are taken with TCAs. TCAs.

• Flumazenil is not effective against BARBs overdoseFlumazenil is not effective against BARBs overdose.

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• Buspirone is an antianxiety agent that acts as a Buspirone is an antianxiety agent that acts as a partial agonist at the 5-HTpartial agonist at the 5-HT1A 1A receptor presynaptically receptor presynaptically inhibiting serotonin release and it has an affinity for inhibiting serotonin release and it has an affinity for brain D2 dopamine receptors, where it acts as an brain D2 dopamine receptors, where it acts as an antagonist and agonist. antagonist and agonist.

• Short-term symptomatic relief of excessive anxiety Short-term symptomatic relief of excessive anxiety in patients with generalized anxiety disorder. in patients with generalized anxiety disorder.

BUSPIRONEBUSPIRONE

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BUSPIRONEBUSPIRONE

• Buspirone does not have sedative effects and does not potentiate CNS depressants.

• Has a relatively high margin of safety, few side effects and does not appear to be associated with drug dependence.

• No rebound anxiety or signs of withdrawal when discontinued

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BUSPIRONEBUSPIRONE

Side effects:Side effects:• Tachycardia, palpitations, nervousness, GI distress and

paresthesias may occur.• Causes a dose-dependent pupillary constriction.

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Thank you for your attention