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PsychopharmacolPsychopharmacol
ogyogyPrianto DjatmikoPrianto Djatmiko
Main PsychoMain Psychotropictropic Drugs Drugs
AntipsychoticsAntipsychotics AntidepressantsAntidepressants Mood-StabilizersMood-Stabilizers AnxiolyticsAnxiolytics HypnoticsHypnotics CognitiveCognitive-Enhancers-Enhancers PsychostimulantsPsychostimulants
AgonisAgonis artinya kerja obat menyerupai artinya kerja obat menyerupai sifat sifat neurotransmitter neurotransmitter sasaran,sasaran, berikatan berikatan dg dg rereseptor dan memperkuat kerja septor dan memperkuat kerja neurotransmiter tsd di neuronneurotransmiter tsd di neuron
AntagonisAntagonis artinya kerja obat mem-blok artinya kerja obat mem-blok reseptor reseptor neurotransmitter neurotransmitter sasaran sasaran sehingga sehingga neurotransmitterneurotransmitter tsb tdk dapat tsb tdk dapat berikatan dg berikatan dg neuronneuron..
PrinPrinssipip mekanisme kerja obat mekanisme kerja obat psikofarmakapsikofarmaka
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-bat lainksi dengan obat-bat lain5.5. Fungsi hepar dan ginjal terkait dosisFungsi hepar dan ginjal terkait dosis6.6. Tailoring-madeTailoring-made
7.7. Kehamilan? Menyusui?Kehamilan? Menyusui?
Antipsikotik (Neuroleptik)Antipsikotik (Neuroleptik)
• Golongan Tipikal (Golongan Tipikal (FGAFGA))• Golongan Atipikal (Golongan Atipikal (SGA/SDASGA/SDA))
Indikasi:Indikasi:• Gangguan Psikotik (Termasuk Psikosis Gangguan Psikotik (Termasuk Psikosis
organik)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))
Teori Teori DopamineDopamine--PathwaysPathways
Antipsikotik Golongan Antipsikotik Golongan TipikalTipikal
• PhenothiazinePhenothiazineChlorpromazineChlorpromazineThioridazineThioridazinePerphenazinePerphenazineFluphenazineFluphenazineTrifluoperazineTrifluoperazine
• ButyrophenoneButyrophenoneHaloperidolHaloperidol
• DiphenylbutylpiperidineDiphenylbutylpiperidinePimozidePimozide
• BenzamideBenzamideSulpirideSulpiride
First Generation Antipsychotic (FGA) Dosage GuidelinesFirst Generation Antipsychotic (FGA) Dosage Guidelines
Drug Drug Starting Dose Starting Dose Dose RangeDose Range Usual Max. DsUsual Max. Ds
Chlorpromazine 50-100 mg/d 300-1000 mg/d 1000mg/d
Fluphenazine 5 mg/d 5-20 mg/d 20mg/d
Fluphenazine Depot 12.5-25 mgI M / 2-3weeks 6.25-50mgIM/2-4weeks
100mgIM/ 4weeks
Haloperidol 2-5 mg/d 2-20 mg/d 20 mg/d
Haloperidol Depot 25-50mgIM/2weeks 50-200mg/2-4weeks 300mg/ 3-4weeks
Perphenazine 4-8 mg/d 16-64 mg/d 64mg/d
Trifluoperazine 2 mg bid 5-40 mg/d 40 mg/d
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 & Histamine:
•Sedatif, sympathomimetic, anti-emetik
ButyrophenonesButyrophenones• Haloperidol (Haldol®, 1967)• Longer half-life: Drug holidays of 3 days• A more Specific D2 blocker• Little sedation• Parkinsonian effects like those of high-potency
phenothiazines (Perphenazine, Fluphenazine Trifluoperazine)
• Acute extrapyrimidal effects:– Akathisia: anxious pacing, rocking– Acute Dystonia: spasm and posturing– Parkinsonism
• Chronic extrapyrimidal effects: Tardive dyskinesia
Second Generation Antipsychotic (SGA) Dosage GuidelinesSecond Generation Antipsychotic (SGA) Dosage Guidelines
SGA SGA Starting Dose Starting Dose Titration Range Titration Range Max. Dose ScheduleMax. Dose Schedule
Risperidone 1 – 2 mg/day 1 mg/2-3 days 2 – 6 mg/day (i)
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
(i) The risk of EPS is significantly increased by using doses > 6 mg dailyi) The risk of EPS is significantly increased by using doses > 6 mg daily
Guideline 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
Summary of AntipsychoticsSummary of AntipsychoticsDrugDrug AdvantagesAdvantages DisadvantagesDisadvantages
Chlorpromazine Generic, inexpensive Many adverse effects, especially autonomic
Thioridazine (Mellaril) Slight extrapyramidal syndrome; generic
800 mg/d limit; no parenteral form; cardiotoxicity
Fluphenazine (Modecate) Depot form also available (enanthate, decanoate)
(?) Increased tardive dyskinesia
Perphenazine (Trilafon) generic, inexpensive moderate risk of EPS, sedation
Thiothixen (Navane) Parenteral form also available; (?) decreased tardive dyskinesia
Uncertain
Haloperidol Parenteral form also available; generic
Severe extrapyramidal syndrome
DrugDrug AdvantagesAdvantages DisadvantagesDisadvantages
Loxapine (Loxitane) (?) No weight gain Uncertain
Clozapine (Clozaril)* (klo’ za peen)
May benefit treatment-resistant patients; little extrapyramidal toxicity
May cause agranulocytosis in up to 2% of patients; weight gain, hyperglycemia, diabetes, dyslipidemia
Risperidone (Risperdal)* Broad efficacy; little or no extrapyramidal system dysfunction at low doses
May cause extrapyramidal syndrome or hypotension with higher doses; weight gain, hyperglycemia, diabetes, dyslipidemia
*Atypical (or second generation) antipsychoticsAtypical (or second generation) antipsychotics
DrugDrug AdvantagesAdvantages DisadvantagesDisadvantages
Olanzapine (Zyprexa)* Effective against negative as well as positive symptoms; little or no extrapyramidal system dysfunction
Weight gain, hyperglycemia, diabetes, dyslipidemia
Quetiapine (Seroquel)* Little or no extrapyramidal system dysfunction
Weight gain, hyperglycemia, diabetes, dyslipidemia; cataracts (?)
*Atypical antipsychotics*Atypical antipsychotics
DrugDrug AdvantagesAdvantages DisadvantagesDisadvantages
Ziprasidone (Geodon)* less weight gain than other atypicals
prolongs Q-T interval, but no arrhythmias reported yet; somnolence, some EPS
Aripiperazole (Abilify)* little or no EPS, less weight gain, or Q-T changes
Akathesia, insomnia, anxiety. Caution in patients with epilepsy or Alzheimer’s
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
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).
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)
+++ + + + ++
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.
Long Acting Antipsychotic DrugsLong Acting Antipsychotic Drugs
DrugDrug ClassificationClassification Route of Route of AdministrationAdministration
Duration of ActionDuration of Action
Fluphenazine DecanoateModecate
Typical Intramuscular Subcutaneous
2-3 weeks
Fluphenazine Enanthate
Prolixin Enanthate
Typical Intramuscular Subcutaneous
2 weeks
Haloperidol Decanoate
Haldol Decanoate
Typical Intramuscular 3-4 weeks
Risperidone (Risperdal Consta)
Atypical Intramuscular 2 weeks
AntidepresanAntidepresan
AntidepressanAntidepressan• Yang bersifat sedatif:
– Amitriptyline– Imipramine– Clomipramine– Maproptiline– Trazodone– Mirtazapine
• Yang bersifat aktivasi/non-sedatif:– Tianeptine– Moclobemide– SSRI (Fluoxetine,Sertraline,Citalopram,Fluvoxamine)
Pro
gre
ssion
Acute(6-12 weeks)
Seve
rity
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
Tricyclic antidepressants (TCAs):Tricyclic antidepressants (TCAs):– Amitriptyline has higher sedative and
anticholinergic effects and affects serotonin more than imipramine does.
– Imipramine (Tofranil®) discovered as a modification of a phenothiazine (antipsychotic)
– Clomipramine (Anafranil®) has the highest serotonin effect of the TCAs, with little anticholinergic or sedative action. Also for OCD..
Pharmacodynamics of TCAsPharmacodynamics of TCAs
• Block presynaptic receptors/transporters Block presynaptic receptors/transporters for serotonin, dopamine, and for serotonin, dopamine, and norepinephrinenorepinephrine
• Block different numbers of postsynaptic Block different numbers of postsynaptic receptors for acetylcholine and histamine. receptors for acetylcholine and histamine. The main antihistamine effect is The main antihistamine effect is drowsiness.drowsiness.
• The multiple action of TCAs is sometimes The multiple action of TCAs is sometimes an advantage,eg. promoting sleepan advantage,eg. promoting sleep
Overview of SerotoninOverview of Serotonin• Serotonin (5-hydroxytryptamine, or Serotonin (5-hydroxytryptamine, or
5-HT) is a monoamine 5-HT) is a monoamine neurotransmitter synthesized in neurotransmitter synthesized in serotonergic neurons in the central serotonergic neurons in the central nervous system.nervous system.
• The functions of serotonin are The functions of serotonin are numerous and appear to involve numerous and appear to involve control of appetite, sleep, memory control of appetite, sleep, memory and learning, temperature and learning, temperature regulation, mood, behavior regulation, mood, behavior (including sexual), cardiovascular (including sexual), cardiovascular function, muscle contraction, function, muscle contraction, endocrine regulation, and endocrine regulation, and depressiondepression
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.
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®)
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 amount of serotonin in the synaptic gap by inhibiting re-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
Measurement of drug actionMeasurement 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)
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
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).
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)
SSRI-Common Side EffectsSSRI-Common Side Effects
• Insomnia, headacheInsomnia, headache• Nausea, anorexiaNausea, anorexia
– Diarrhea Diarrhea – Constipation (Paxil)Constipation (Paxil)
• Sexual dysfunctionSexual dysfunction– Decreased libidoDecreased libido– AnorgasmiaAnorgasmia
• Nervousness, tremorNervousness, tremor– MyoclonusMyoclonus– Teeth-clenchingTeeth-clenching
SSRI: Other IndicationsSSRI: Other Indications
• Anxiety/PanicAnxiety/Panic• Bulimia NervosaBulimia Nervosa• PMDDPMDD• OCD-SpectrumOCD-Spectrum• Impulse ControlImpulse Control
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).
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
Nama Obat Antikolinergik Sedasi Hipotensi Ortostatik
Amitriptyline +++ +++ +++
Imipramine +++ ++ ++
Clomipramine ++ ++ ++
Trazodone + +++ +
Mirtazapine + +++ +
Maprotiline + ++ +
Mianserin + ++ +
Amoxapine + + ++
Tianeptine +/- +/- +/-
Moclobemide +/- +/- +
Sertraline +/- +/- +/-
Paroxetine +/- +/- +/-
Fluvoxamine +/- +/- +/-
Fluoxetine +/- +/- +/-
Citalopram +/- +/- +/-
Mood StabilizerMood Stabilizer
Used for “Bipolar” or “Manic-Depressive” Used for “Bipolar” or “Manic-Depressive” to regulate moodto regulate mood
• 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
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”
Neuroleptics in bipolar disordersNeuroleptics in bipolar disorders
• All neuroleptics have effect on acute manic All neuroleptics have effect on acute manic episodes and delay occurrence of new manic episodes and delay occurrence of new manic episodesepisodes
• Effect on depressive episodes (not triggered by a Effect on depressive episodes (not triggered by a manic episode) is inconclusivemanic episode) is inconclusive
• Neuroleptics may be useful in bipolar I disordersNeuroleptics may be useful in bipolar I disorders• No convincing evidence in bipolar II and III disordersNo convincing evidence in bipolar II and III disorders
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.
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
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
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)
ANXIOLYTICSANXIOLYTICS
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
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
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
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
PharmacoPharmacodynamdynamics of Benzodiazepinesics of Benzodiazepines
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.
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.
Tolerance & DependenceTolerance & Dependence
• Tolerance – state of decreased sensitivity Tolerance – state of decreased sensitivity to the drug as a result of exposure to it.to the drug as a result of exposure to it.
• Functional tolerance (number of binding Functional tolerance (number of binding sites is reduced – also called “down sites is reduced – also called “down regulation” of receptors) regulation” of receptors)
Note: opposite phenomenon: up-Note: opposite phenomenon: up-regulationregulation
• Physical Dependence – caused by Physical Dependence – caused by withdrawal symptoms (not the reason that withdrawal symptoms (not the reason that people continue to take most drugs)people continue to take most drugs)
• Psycholological Dependence (now called Psycholological Dependence (now called positive-incentive theory of addiction)positive-incentive theory of addiction)
• Buspirone is an antianxiety agent Buspirone is an antianxiety agent that acts as a 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
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
BUSPIRONEBUSPIRONE
Side effects:Side effects:• Tachycardia, palpitations, nervousness, GI distress and
paresthesias may occur.• Causes a dose-dependent pupillary constriction.
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