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. Efek yang diharapkan berkaitan dengan gejala sasaran

2. Start low – go slow
3. Implikasi dari efek samping obat
4. Interaksi dengan obat-bat lain
5. Fungsi hepar dan ginjal terkait dosis
6. Tailoring-made
7. 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 substantia nigra ke basal ganglia fungsi gerakan, EPS
2. jalur mesolimbik: dari tegmental area menuju ke sistemlimbik memori, sikap,
kesadaran, proses stimulus
3. jalur mesocortical : dari tegmental area menuju ke frontal cortex kognisi, fungsi
sosial, komunikasi, respons terhadap stress
 Antipsikotik Golongan Tipikal
• Phenothiazine
 Chlorpromazine
 Thioridazine
 Perphenazine
 Fluphenazine
 Trifluoperazine
• Butyrophenone
 Haloperidol
• Diphenylbutylpiperidine
 Pimozide
• Benzamide
 Sulpiride
First Generation Antipsychotic (FGA) Dosage Guidelines

Drug Starting Dose Dose Range Usual 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

 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)
• Clo zapin
• Ris peridon
• Olanzapin Antagonis reseptor 5-HT,
• Quetiapin Blokade dopamin rendah

• Zipras idon
• Aripiprazol

• terdapat hubungan kuat antara system dopaminergik dan

serotonergik serotonin memodulasi fungsi dopamine

• Saat ini lebih banyak digunakan sebagai “drug of choice”

karena relatiflebih aman dari efek samping ekstrapiramidal
1/2/2009 Zullies Ikawati's Lecture Notes 26
Second Generation Antipsychotic (SGA) Dosage Guidelines

SGA Starting Dose Titration Range Max. 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 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 (Atypical#3,
Conventional#2)
 Summary of Antipsychotics
Drug Advantages Disadvantages
Chlorpromazine Generic, inexpensive Many adverse effects,
especially autonomic
Thioridazine (Mellaril) Slight extrapyramidal 800 mg/d limit; no
syndrome; generic parenteral form;
cardiotoxicity
Fluphenazine (Modecate) Depot form also available (?) Increased tardive
(enanthate, decanoate) dyskinesia

Perphenazine (Trilafon) generic, inexpensive moderate risk of EPS,

sedation
Thiothixen (Navane) Parenteral form also Uncertain
available; (?) decreased
tardive dyskinesia

Haloperidol Parenteral form also Severe extrapyramidal

available; generic syndrome
 Drug Advantages Disadvantages
Loxapine (Loxitane) (?) No weight gain Uncertain
Clozapine (Clozaril)* (klo’ May benefit treatment- May cause agranulocytosis
za peen) resistant patients; little in up to 2% of patients;
extrapyramidal toxicity weight gain,
hyperglycemia, diabetes,
dyslipidemia

Risperidone (Risperdal)* Broad efficacy; little or no May cause extrapyramidal

extrapyramidal system syndrome or hypotension
dysfunction at low doses with higher doses; weight
gain, hyperglycemia,
diabetes, dyslipidemia

*Atypical (or second generation) antipsychotics

 Drug Advantages Disadvantages
Olanzapine (Zyprexa)* Effective against negative Weight gain,
as well as positive hyperglycemia, diabetes,
symptoms; little or no dyslipidemia
extrapyramidal system
dysfunction

Quetiapine (Seroquel)* Little or no extrapyramidal Weight gain,

system dysfunction hyperglycemia, diabetes,
dyslipidemia; cataracts (?)

*Atypical antipsychotics
 Drug Advantages Disadvantages

Ziprasidone (Geodon)* less weight gain than other prolongs Q-T interval, but
atypicals 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
Alzheimer’s
 Neurological Side Effects of Antipsychotic Drugs
Reaction Features Time of Proposed Treatment
Maximal Mechanism
Risk
Acute dystonia Spasm of muscles 1 to 5 days unknown Many treatments can alter,
of tongue, face, but effects of
neck, back; may antimuscarinic agents are
mimic seizures; not diagnostic and curative.*
hysteria

Akathisia Motor restlessness: 5 to 60 days unknown Reduce dose or change

not anxiety or drug; antimuscarinic
“agitation” agents, dephenhydramine,
benzodiazepines, or
propranolol ++ may help

Parkinsonism Bradykinesia, 5 to 30 days antagonism of Antimuscarinic agents

rigidity, variable dopamine helpful+
tremor, mask
facies, shuffling gait
 Neurological Side Effects of Antipsychotic Drugs
Reaction Features Time of Proposed Treatment
Maximal Mechanism
Risk
Neuroleptic catatonia, stupor, weeks; can antagonism of stop antipsychotic
Malignant fever, unstable persist for dopamine may immediately; dantrolene
syndrome blood presure, days after contribute or bromocriptine may
myoglobinemia; can stopping help§; antimuscarinic
be fatal neuroleptic agents not effective

Perioral perioral tremor (may after months unknown Antimuscarininic agents

tremor be a late variant of or years of often help+
(“rabbit” parkinsonism) treatment
syndrome)
Tardive oral-facial after months up regulation prevention crucial;
dyskinesia dyskinesia; or years of of striatal D2 clozapine or olanzapine
widespread treatment receptors may help
choreoathetosis or (worse on
dystonia withdrawal)
 Comparison of Some Antipsychotic Agents
Drug Relative Sedation Extra- Anti- Hypotension
Antipsychotic pyramidal cholinergic
Potency
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 Extrapyramidal Elevated QTc Weight

Symptoms Prolactin Prolongation Gain

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

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

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

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

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

Ziprasidone +/- + + ++ +/-

*Clozapine is also associated with myocarditis and agranulocytosis; the other second-
generation antipsychotics are not.
 Long Acting Antipsychotic Drugs
Drug Classification Route of Duration of Action
Administration

Fluphenazine Typical Intramuscular 2-3 weeks

Decanoate Subcutaneous
Modecate

Fluphenazine Typical Intramuscular 2 weeks

Enanthate Subcutaneous
Prolixin Enanthate

Haloperidol Typical Intramuscular 3-4 weeks

Decanoate
Haldol Decanoate

Risperidone Atypical Intramuscular 2 weeks

(Risperdal Consta)
 Antipsikotik yang beredar di Indonesia
• Klorpromazin (generik,
Meprosetil, Largactil,
Largazine, Promactil)
• Haloperidol (Lodomer,
Govotil, Halonace, Haldol,
Seradol, Serenace)
• Flufenazin (Anatensol)
• Perfenazin (generik, Trilafon)
• Proklorperazin (Stemetil)
• Tioridazin (Melleril)
• Trifluoperazin (generik,
Stelazine, Trizine)
• Levomepromazin (Nozinan)
• Flufenazin dekanoat
(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 Recurrence

Relapse
Severity

Symptoms Prog
Response
to d i

ressi
sord

on
er

Disorder

Acute Continuation Maintenance

(6-12 weeks) (4-9 months) (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 re-
uptake.
• 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)
Serotonin reuptake
Synapse Serotonin 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: 301-
6)
• 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 self-
injurious 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 Antikolinergik Sedasi Hipotensi Ortostatik
Amitriptyline +++ +++ +++
Imipramine +++ ++ ++
Clomipramine ++ ++ ++
Trazodone + +++ +
Mirtazapine + +++ +
Maprotiline + ++ +
Mianserin + ++ +
Amoxapine + + ++
Tianeptine +/- +/- +/-
Moclobemide +/- +/- +
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 Stevens-
Johnson 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 rate¹‚²
• 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 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:
Divalproex
• 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:
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
Buspirone
• -Blockers
Propranolol
• 2-AR partial agonist
Clonidine
• 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.
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 positive-
incentive 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