Psychopharmacology

Prianto Djatmiko

Main Psychotropic Drugs

Antipsychotics Antidepressants Mood-Stabilizers Anxiolytics Hypnotics Cognitive-Enhancers Psychostimulants

Prinsip mekanisme kerja obat psikofarmaka

Agonis artinya kerja obat menyerupai sifat neurotransmitter sasaran, berikatan dg reseptor dan memperkuat kerja neurotransmiter tsd di neuron Antagonis artinya kerja obat mem-blok reseptor neurotransmitter sasaran sehingga neurotransmitter tsb tdk dapat berikatan dg neuron.

Prinsip pemilihan obat psikofarmaka

1. 2. 3. 4. 5. 6. 7. Efek yang diharapkan berkaitan dengan gejala sasaran Start low go slow Implikasi dari efek samping obat Interaksi dengan obat-bat lain Fungsi hepar dan ginjal terkait dosis Tailoring-made Kehamilan? Menyusui?

Antipsikotik (Neuroleptik)
Golongan Tipikal (FGA) Golongan Atipikal (SGA/SDA)

Indikasi: Gangguan Psikotik (Termasuk Psikosis organik) Skizofrenia Depresi berat disertai gejala psikotik Agitasi (Gaduh-gelisah) Delirium Tic vokal (Sindrom Gilles de la tourrete)

Jalur dopaminergik saraf Teori Dopamine-Pathways

1. Jalur nigrostriatal: dari substantianigrakebasal ganglia fungsi gerakan, EPS 2. jalur mesolimbik: dari tegmental area menujukesistemlimbik memori, sikap, kesadaran, prosesstimulus 3. jalur mesocortical : dari tegmental area menujukefrontal cortex kognisi, fungsi sosial, komunikasi, responsterhadapstress

Antipsikotik Golongan Tipikal

Phenothiazine Chlorpromazine Thioridazine Perphenazine Fluphenazine Trifluoperazine Butyrophenone Haloperidol Diphenylbutylpiperidine Pimozide Benzamide Sulpiride

First Generation Antipsychotic (FGA) Dosage Guidelines

Drug Chlorpromazine Fluphenazine Starting Dose 50-100 mg/d 5 mg/d Dose Range 300-1000 mg/d 5-20 mg/d Usual Max. Ds 1000mg/d 20mg/d 100mgIM/

Fluphenazine Depot12.5-25 mgI M / 2-3weeks 6.25-50mgIM/2-4weeks

4weeks
Haloperidol 2-5 mg/d 2-20 mg/d 20 mg/d 300mg/ 3-4weeks 64mg/d 40 mg/d

Haloperidol Depot 25-50mgIM/2weeks 50-200mg/2-4weeks Perphenazine Trifluoperazine 4-8 mg/d 2 mg bid 16-64 mg/d 5-40 mg/d

Phenothiazines
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

Butyrophenones
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

Antipsikotik atipikal (SGA)

Clozapin Risperidon Olanzapin Quetiapin Ziprasidon Aripiprazol
Antagonis reseptor 5-HT, Blokade dopamin rendah

terdapat hubungan kuat antara system dopaminergik dan serotonergik serotonin memodulasi fungsi dopamine

(reductionsinserotoninactivityareassociatedw ith enhancem indopam activity) ents ine

Saat ini lebihbanyak digunakansebagai of choice drug karenarelatif lebihamandari efek sampingekstrapiramidal
1/2/2009 Zullies Ikawati's Lecture Notes 26

Second Generation Antipsychotic (SGA) Dosage Guidelines

SGA
Risperidone Olanzapine Quetiapine Clozapine

Starting Dose
1 2 mg/day 5 10 mg 25 mg bid 12.5 mg

Titration Range
1 mg/2-3 days 5 mg/week 50 mg/day

Max. Dose Schedule

2 6 mg/day (i) 10 20 mg/day 300 800 mg/day

Dose increased every 3 days

Day 2: 25 mg Day 3: 25 mg bid Day 6: 50 mg bid Day 9: 75 mg bid Day 12: 100 mg bid Day 15: 125 mg bid Day 18: 150 mg bid Day 21: 200 mg bid

300 900 mg/day

(i) The risk of EPS is significantly increased by using doses > 6 mg daily

Guideline for Schizophrenia

Second Generation Antipsychotic (SGA) #1
4 -12 WEEKS

No response

SGA #2
4 -12 WEEKS

No response

Conventional #1
4 12 WEEKS

No response

Clozapine
3 - 9 MONTHS

No response

Two Antipsychotics
(not 2 conventionals)

ECT+/-Antipsychotic Different Antipsychotic

Conventional#2) (Atypical#3,

Summary of Antipsychotics
Drug Advantages Disadvantages

Chlorpromazine Thioridazine (Mellaril)

Generic, inexpensive Slight extrapyramidal syndrome; generic Depot form also available (enanthate, decanoate) generic, inexpensive Parenteral form also available; (?) decreased tardive dyskinesia Parenteral form also available; generic

Many adverse effects, especially autonomic 800 mg/d limit; no parenteral form; cardiotoxicity (?) Increased tardive dyskinesia moderate risk of EPS, sedation Uncertain

Fluphenazine (Modecate)

Perphenazine (Trilafon) Thiothixen (Navane)

Haloperidol

Severe extrapyramidal syndrome

Drug Loxapine (Loxitane) Clozapine (Clozaril)* (klo za peen)

Advantages (?) No weight gain May benefit treatmentresistant patients; little extrapyramidal toxicity

Disadvantages Uncertain 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) antipsychotics

Drug
Olanzapine (Zyprexa)*

Advantages
Effective against negative as well as positive symptoms; little or no extrapyramidal system dysfunction

Disadvantages
Weight gain, hyperglycemia, diabetes, dyslipidemia

Quetiapine (Seroquel)*

Little or no extrapyramidal system dysfunction

Weight gain, hyperglycemia, diabetes, dyslipidemia; cataracts (?)

*Atypical antipsychotics

Drug Ziprasidone (Geodon)*

Advantages less weight gain than other atypicals

Disadvantages prolongs Q-T interval, but no arrhythmias reported yet; somnolence, some EPS

Aripiperazole (Abilify)*

little or no EPS, less weight Akathesia, insomnia, gain, or Q-T changes anxiety. Caution in patients with epilepsy or Alzheimers

Neurological Side Effects of Antipsychotic Drugs

Reaction Features Time of Maximal Risk 1 to 5 days Proposed Mechanism unknown Treatment

Acute dystonia

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

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, 5 to 30 days rigidity, variable tremor, mask facies, shuffling gait

antagonism of dopamine

Antimuscarinic agents helpful+

Neurological Side Effects of Antipsychotic Drugs

Reaction Features Time of Maximal Risk weeks; can persist for days after stopping neuroleptic Proposed Mechanism Treatment

Neuroleptic Malignant syndrome

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

antagonism of stop antipsychotic dopamine may immediately; dantrolene contribute or bromocriptine may help; antimuscarinic agents not effective

Perioral tremor (rabbit syndrome) Tardive dyskinesia

perioral tremor (may after months be a late variant of or years of parkinsonism) treatment oral-facial dyskinesia; widespread choreoathetosis or dystonia after months or years of treatment (worse on withdrawal)

unknown

Antimuscarininic agents often help+

up regulation of striatal D2 receptors

prevention crucial; clozapine or olanzapine may help

Comparison of Some Antipsychotic Agents

Drug Relative Antipsychotic Potency
+ +

Sedation

Extrapyramidal
+++ +

Anticholinergic
+ +++

Hypotension

chlorpromazine (Thorazine) thioridazine (Mellaril)

+++ +++

+++ +++

fluphenazine (Prolixin)
haloperidol (Haldol)

+++
+++

+
+

+++
+++

+
+/-

++
+

loxapine (Loxitane)
molindone (Moban) clozapine (Clozaril) risperidone (Risperdal)

++
++ ++ +++

+
++ +++ +

++
+ +/+

+/+ +++ +

+
+ +++ ++

Some Adverse Effects of Second Generation Antipsychotics

Drug Diabetes Extrapyramid al Symptoms Elevated Prolactin QTc Weight Prolongation Gain

Aripiprazole Clozapine* Olanzapine Quetiapine Risperidone

+/++++ ++++ ++ ++

+ +/+ +/+++

+/+/+/+/+++

+/+ + +/+

+/++++ ++++ +++ ++

Ziprasidone

+/-

++

+/-

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

Long Acting Antipsychotic Drugs

Drug Fluphenazine Decanoate Modecate Fluphenazine Enanthate Prolixin Enanthate Haloperidol Decanoate Haldol Decanoate Classification Typical Route of Administration Intramuscular Subcutaneous Intramuscular Subcutaneous Intramuscular Duration of Action 2-3 weeks

Typical

2 weeks

Typical

3-4 weeks

Risperidone (Risperdal Consta)

Atypical

Intramuscular

2 weeks

Antipsikotik yang beredar di Indonesia

Klorpromazin(generik, Meprosetil, Largactil, Largazine, Promactil) Haloperidol (Lodomer, Govotil, Halonace, Haldol, Seradol, Serenace) Flufenazin(Anatensol) Perfenazin(generik, T rilafon) Proklorperazin(Stemetil) T ioridazin(Melleril) T rifluoperazin(generik, Stelazine, T rizine) Levomepromazin(Nozinan) Flufenazindekanoat (Modecate) Haloperidol dekanoat (Haldol decanoas) Risperidon(Persidal, Rizodal, Zofredal) Klozapin(Clozaril) Quetiapin Olanzapin

Antidepresan

Antidepressan
Yang bersifat sedatif: Amitriptyline Imipramine Clomipramine Maproptiline Trazodone Mirtazapine Yang bersifat aktivasi/non-sedatif: Tianeptine Moclobemide SSRI (Fluoxetine,Sertraline,Citalopram,Fluvoxamine)

PHASES OF TREATMENT FOR DEPRESSION

Normalcy Relapse Severity

Relapse

Recurrence

Symptoms
Response

Disorder

Acute (6-12 weeks)

Continuation (4-9 months)

Maintenance (1 or more years)

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 TCAs
Block presynaptic receptors/transporters for serotonin, dopamine, and norepinephrine Block different numbers of postsynaptic receptors for acetylcholine and histamine. The main antihistamine effect is drowsiness. The multiple action of TCAs is sometimes an advantage,eg. promoting sleep

Overview of Serotonin
Serotonin (5-hydroxytryptamine, or 5-HT) is a monoamine neurotransmitter synthesized in serotonergic neurons in the central nervous system. The functions of serotonin are numerous and appear to involve control of appetite, sleep, memory and learning, temperature regulation, mood, behavior (including sexual), cardiovascular function, muscle contraction, endocrine regulation, and depression

Tricyclic side effects

TCAs have varying side effects. All TCAs are toxic to the heart at high doses, and are effective agents of suicide. This fact has fueled the search for other antidepressants.

Other 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 antidepressants
SSRIs: Selective Serotonine (5-HT) Re-uptake Inhibitors Method of Action: They act within the brain to increase the amount of serotonin in the synaptic gap by inhibiting reuptake. In contrast to other drugs, SSRIs are more potent inhibitors of serotonin reuptake, and they have less of an effect on 1, 2, histaminic, and muscarinic receptors

Measurement of drug action

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

Pre-synaptic terminal Serotonin transporters (SERT) Synapse

Serotonin

Serotonin reuptake inhibitor (SSRI)

SPECT tracer

Post-synaptic cell

Image available binding sites

SSRIs: Selective Serotonin Reuptake Inhibitors

Fluoxetine (Prozac, 1988): least selective Sertraline (Zoloft): quick action, less side effects Escitalopram (Cipralex) Fluvoxamine (Luvox, 1995): OCD, panic disorders & PTSD

Fluoxetine
Positive effects in one study on adults caused them to be much improved on the CGI scale (J Intellect Disabil Res 1998; 42: 3016)

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

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

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

Sertraline
Similar in effects to fluoxetine (Prozac) Improvement in some adults in aggression and selfinjurious behavior (J Clin Psychiarty 1996;57:333-6) Caused hyperactivity in children and agitation despite improvement in anxiety and irritability (J Child
Adolesc Psychopharmacol 1997;7:9-15)

SSRI-Common Side Effects

Insomnia, headache Nausea, anorexia
Diarrhea Constipation (Paxil)

Sexual dysfunction
Decreased libido Anorgasmia

Nervousness, tremor
Myoclonus Teeth-clenching

SSRI: Other Indications

Anxiety/Panic Bulimia Nervosa PMDD OCD-Spectrum Impulse Control

FDA Warning 3/22/2004

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

Serotonin syndrome
May occur if SSRIs are taken in high doses, especially combined with other serotonin-enhancing drugs, including herbs (valerian) Disorientation, agitation, shivering, diarrhea, increased reflexes, and more May be life-threatening Recover within 48 hours of abstinence

Nama Obat
Amitriptyline Imipramine Clomipramine Trazodone Mirtazapine Maprotiline Mianserin Amoxapine Tianeptine Moclobemide

Antikolinergik
+++ +++ ++ + + + + + +/+/-

Sedasi
+++ ++ ++ +++ +++ ++ ++ + +/+/-

Hipotensi Ortostatik
+++ ++ ++ + + + + ++ +/+

Sertraline
Paroxetine Fluvoxamine Fluoxetine Citalopram

+/+/+/+/+/-

+/+/+/+/+/-

+/+/+/+/+/-

Mood Stabilizer
Used for Bipolar or Manic-Depressive to regulate mood

Mood Stabilizer
Lithium carbonate Lithium is the classic mood stabilizer. 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, ataxia) Valproic Acid (Depakene) & Divalproex Sodium (Depakote) Can be very irritating to the stomach. Liver function and CBC should be monitored

Carbamazepine (Tegretol) Can lower white blood cell count. Therapeutic drug monitoring is required. Monitor for signs and symptoms of StevensJohnson syndrome. FDA approved for bipolar disorder
Lamotrigine (Lamictal) Particularly effective for Bipolar depression. Monitor for signs and symptoms of Stevens-Johnson syndrome. Oxcarbazepine (Trileptal) Not FDA approved for bipolar disorder.

Treatment: APA Practice Guidelines 2002

Acute mania/mixed mania:
1st line: lithium or valproate or antipsychotic* 1st line severe: lithium or valproate + antipsychotic*

Acute depression:
1st line: lithium or lamotrigine 1st line severe: lithium + antidepressant

Maintenance
lithium or valproate: Alternatives: lamotrigine, carbamazepine, oxycarbazepine Atypical antipsychotics may be considered

Neuroleptics in bipolar disorders

All neuroleptics have effect on acute manic episodes and delay occurrence of new manic episodes Effect on depressive episodes (not triggered by a manic episode) is inconclusive Neuroleptics may be useful in bipolar I disorders No convincing evidence in bipolar II and III disorders

Mood Stabilizers: Lithium

Advantages: 50+ years worldwide experience (FDA-approved 1970) effective in euphoric mania and hypomania inexpensive reduces suicide rate Disadvantages:
slow onset ~ 14 days narrow therapeutic index non-response in > 50% (usually bipolar subtypes) frequent side effects (polyuria, tremor, GI symptoms) and non-compliance discontinuation associated with high relapse rate
Baldessarini RJ, et al. J Clin Psychiatry. 2003;64 Suppl 5:44-52. Goodwin FK, et al. JAMA. 2003 Sep 17;290(11):1467-73. Cavanagh J, et al. Acta Psychiatr Scand. 2004 Feb;109(2):91-5.

Mood Stabilizers: Divalproex

Advantages:
extensive experience (FDA-approved for epilepsy 1983; for bipolar mania 1995) rapid onset (1-4 days) loading dose strategy well-tolerated: 20 mgs/kg 77% moderate to marked response effective in Bipolar subtypes effective for psychotic symptoms plasma levels (50-125 mcg/ml) less cognitive impairment than lithium

Mood Stabilizers: Divalproex

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: Lamictal

FDA-approved for maintenance treatment of Bipolar I Disorder Black box warning for serious rash (includes
Stevens-Johnson Syndrome and toxic epidermal necrolysis)

Slow titration necessary Interaction with other AEDs (especially valproic acid
and carbamazepine)

ANXIOLYTICS

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

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

Anxiolytics
Benzodiazepines (BZDs) Barbiturates (BARBs) 5-HT1A receptor agonists: Azaspirodecanedione -Blockers
Buspirone Propranolol Clonidine

2-AR partial agonist

Antidepressants
TCAs, SSRIs

Antihistaminic drugs
Diphenhydramine

Mechanisms of Action
1) Enhance GABAergic Transmission
frequency of openings of GABAergic channels. Benzodiazepines opening time of GABAergic channels. Barbiturates receptor affinity for GABA. BDZs and BARBS

2) Stimulation of 5-HT1A receptors. 3) Inhibit 5-HT2A, 5-HT2C, and 5-HT3 receptors

Pharmacodynamics of Benzodiazepines

Side 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 Benzodiazepines

Drug overdose is treated with flumazenil (a BDZ receptor antagonist, short half-life), but respiratory function should be adequately supported and carefully monitored. Seizures and cardiac arrhythmias may occur following flumazenil administration when BDZ are taken with TCAs. Flumazenil is not effective against BARBs overdose.

Tolerance & Dependence

Tolerance state of decreased sensitivity to the drug as a result of exposure to it. Functional tolerance (number of binding sites is reduced also called down regulation of receptors) Note: opposite phenomenon: up-regulation Physical Dependence caused by withdrawal symptoms (not the reason that people continue to take most drugs) Psycholological Dependence (now called positiveincentive theory of addiction)

BUSPIRONE
Buspirone is an antianxiety agent that acts as a partial agonist at the 5-HT1A receptor presynaptically inhibiting serotonin release and it has an affinity for brain D2 dopamine receptors, where it acts as an antagonist and agonist. Short-term symptomatic relief of excessive anxiety in patients with generalized anxiety disorder.

BUSPIRONE
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

BUSPIRONE
Side effects: Tachycardia, palpitations, nervousness, GI distress and paresthesias may occur. Causes a dose-dependent pupillary constriction.

Thank you for your attention