Psychopharmacology in

Psychiatry
Santun Bhekti Rahimah., dr., M.Kes

Definition
Drugs that

affect to behaviour.
Large scope from antidepresant alcohol
Drugs acting in the central nervous system
(CNS)
Mechanism not always been clearly
understood
it is a primary goal of neuropharmacologists
to identify the transmitters in CNS pathways

Basis for several major developments in

studies of the CNS
First, it is clear that nearly all drugs with

CNS effects act on specific receptors

modulate synaptic transmission
Second, drugs are among the most
important tools for studying all aspects of
CNS physiology,

agonists that mimic natural transmitters (and in many cases are

more selective than the endogenous substances)
antagonists are extremely useful in such studies.

Clasification
Antidepressants I
Mood stabilizers
Antipsychotics
Anxiolytic
Hypnotic - sedative

General Pharmacology strategies

Indication: Establish a diagnosis and identify
the target symptoms.
Choice of agent and dosage: Select an agent
with an acceptable side effect profile and
use the lowest effective dose.
Remember the delayed response for many
psych meds and drug-drug interactions.

Cont

Establish informed consent: The patient should

understand the benefits and risks of the
medication.
Management: Adjust dosage for optimum
benefit, safety and compliance.
Implement a monitoring program: Track and
document compliance, side effects, target
symptom response, blood levels and blood tests
as appropriate.

Basic Mechanism

Exicitatory and inhibitory post

synaps

Site of action

Neurotransmitter Pharmacology
in the Central Nervous System.

Cont

Antidepressants

Antidepressant Classifications
Tricyclics (TCAs)
Heterocyclic antidepresant
Monoamine Oxidase Inhibitors (MAOIs)
Selective Serotonin Reuptake Inhibitors

(SSRIs)

Antidepressants
Indications: Unipolar and bipolar

depression, organic mood disorders,

schizoaffective disorder, anxiety disorders
including OCD, panic, social phobia,
PTSD, premenstrual dysphoric disorder
and impulsivity associated with personality
disorders.

General guidelines for

antidepressant use

Antidepressant efficacy is similar so selection is

based on past history of a response, side effect
profile and coexisting medical conditions.
There is a delay typically of 3-6 weeks after a
therapeutic dose is achieved before symptoms
improve.
If no improvement is seen after a trial of
adequate length (at least 2 months) and
adequate dose, either switch to another
antidepressant or augment with another agent.

TCAs

Very effective but potentially

unacceptable side effect
profile i.e. antihistaminic,
anticholinergic,
antiadrenergic
Lethal in overdose (even a
one week supply can be
lethal!)
Can cause QT lengthening
even at a therapeutic serum
level

TCas
First generation: imipramine, amitriptyline,

doxepin, clomipramine
Have active metabolites including
desipramine and nortriptyline
Second generation: Amoxapine ,
maprotiline, trazodone and bupropion
Third generation: mirtazapine,
nefazodone. venlafaxine

First TCAs

Have tertiary amine side chains

Side chains are prone to cross react with other
types of receptors which leads to more side
effects including antihistaminic (sedation and
weight gain), anticholinergic (dry mouth, dry
eyes, constipation, memory deficits and
potentially delirium), antiadrenergic (orthostatic
hypotension, sedation, sexual dysfunction)
Act predominantly on serotonin receptors

Secondary TCAs/ Heterocyclics

Are often metabolites of tertiary amines
Primarily block norepinephrine
Side effects are the same as tertiary TCAs

but generally are less severe

Examples: Desipramine, notrtriptyline
PK similar wirh first gen., only nefazodone
and trazodone T1/2 short

TCas
Well absorbed orally

first pass

metabolism
High volume distribution
Hepatic metabolism
T1/2 8 36 h, once daily doses

Monoamine Oxidase Inhibitors

(MAOIs)

Bind irreversibly to monoamine oxidase thereby

preventing inactivation of biogenic amines such
as norepinephrine, dopamine and serotonin
leading to increased synaptic levels.
Are very effective for depression
Side effects include orthostatic hypotension,
weight gain, dry mouth, sedation, sexual
dysfunction and sleep disturbance
Hypertensive crisis can develop when MAOIs
are taken with tyramine-rich foods or
sympathomimetics.

MAOI Drugs

Phenelzine
isocarboxacid
Tranylcypromine

Structure related
amphetamine

MAOIs

Inhibitots of hepatic drug metabolizing enzyme

Drugs interaction
Trannytcypromine is the fastest one shorter
duratio

SSRIs

Selective Serotonin Reuptake

Inhibitors (SSRIs)

Block the presynaptic serotonin reuptake

Treat both anxiety and depressive sx
Most common side effects include GI upset,
sexual dysfunction (30%+!), anxiety,
restlessness, nervousness, insomnia, fatigue or
sedation, dizziness
Very little risk of cardiotoxicity in overdose

SSRI
Fluxetin (first SSRI)
Paroxetin
Xentraline
Escitalopram
citalopram

Fluoxetine

the SSRIs have not been shown to be more effective ,

they lack many of the toxicities of the tricyclic and
heterocyclic antidepressants.
Thus, patient acceptance has been high despite adverse
effects such as nausea, decreased libido, and even
decreased sexual function.
A dangerous pharmacodynamic interaction :may occur
when fluoxetine or one of the n
a serotonin syndrome. This sometimes fatal syndrome
includes hyperthermia, muscle rigidity, myoclonus,
and rapid changes in mental status and vital signs.

Mood Stabilizers

Bipolar Drugs/ Mood Stabilize

Classic
Lithium

Newer
Carbamazepin
Clonazepam
Olanzapine
Valproic acid

Mood stabilizers
Indications: Bipolar,

schizoaffective,
impulse control and intermittent explosive
disorders.
Classes: Lithium, anticonvulsants,
antipsychotics
Which you select depends on what you
are treating and again the side effect
profile.

Lithium
Mechanism

Not well defined.

Inhibitit inositol monophosphatase IP3
and DAG

Lithium

Only medication to reduce suicide rate.

Rate of completed suicide in BAD ~15%

Effective in long-term prophylaxis of both mania

and depressive episodes in 70+% of BAD I pts
Factors predicting positive response to lithium

Prior long-term response or family member with good

response
Classic pure mania
Mania is followed by depression

Lithium side effects

Most common are GI distress including reduced

appetite, nausea/vomiting, diarrhea
Thyroid abnormalities
Nonsignificant leukocytosis
Polyuria/polydypsia secondary to ADH
antagonism. In a small number of patients can
cause interstitial renal fibrosis.
Hair loss, acne
Reduces seizure threshold, cognitive slowing,
intention tremor

Lithium toxicity
Mild- levels 1.5-2.0 see vomiting, diarrhea,

ataxia, dizziness, slurred speech,

nystagmus.
Moderate-2.0-2.5 nausea, vomiting,
anorexia, blurred vision, clonic limb
movements, convulsions, delirium,
syncope
Severe- >2.5 generalized convulsions,
oliguria and renal failure

Antipsychotics as mood
stabilizers

FDA approved indications in Bipolar disorder

Generic name

Trade name

Manic

Mixed

Maintenance

Aripiprazole

Abilify

Ziprasidone

Geodon

X*

Risperdone

Risperdal

Asenapine

Saphris

Quetiapine

Seroquel

X*

Quetiapine XR

Seroquel XR

X*

Chlorpromazine

Thorazine

Olanzapine

Zyprexa

Olanzapine
fluoxetine comb

Symbyax

Depressed

*denotes FDA approval for adjunct therapy not

mono-therapy

Antipsychotics
Indications for use: schizophrenia,

schizoaffective disorder, bipolar disorderfor mood stabilization and/or when

psychotic features are present, delirium,
psychotic depression, dementia,
trichotillomania, augmenting agent in
treatment resistant anxiety disorders.

Key pathways affected by

dopamine in the Brain

MESOCORTICAL- projects from the

ventral tegmentum (brain stem) to the
cerebral cortex. This pathway is felt to
be where the negative symptoms and
cognitive disorders (lack of executive
function) arise. Problem here for a
psychotic patient, is too little dopamine.

MESOLIMBIC-projects from the

dopaminergic cell bodies in the ventral
tegmentum to the limbic system. This
pathway is where the positive symptoms
come from (hallucinations, delusions,
and thought disorders). Problem here in
a psychotic patient is there is too much
dopamine.

NIGROSTRIATAL- projects from the

dopaminergic cell bodies in the
substantia nigra to the basal ganglia.
This pathway is involved in movement
regulation. Remember that dopamine
suppresses acetylcholine activity.
Dopamine hypoactivity can cause
Parkinsonian movements i.e. rigidity,
bradykinesia, tremors), akathisia and
dystonia.

TUBEROINFUNDIBULAR-projects from
the hypothalamus to the anterior
pituitary. Remember that dopamine
release inhibits/regulates prolactin
release. Blocking dopamine in this
pathway will predispose your patient to
hyperprolactinemia
(gynecomastia/galactorrhea/decreased
libido/menstrual dysfunction).

Antipsychotics
Classic drugs (D2)
Chlorpomazine
Fluphenqazine
Haloperidol
Thioridazone
Trifluoperazine

Newer agents (5HT2)

Clozapine
Olanzapine
Quetiapine
Risperidone
Ziprasidone

Class. By chemical structure

Phenothiazines: chlorpomazine,

thioridazone, fluphenazone
Thioxanthenes: Thiothiene
Butyrophenones: haloperidol
Heterocyclics: newer agents

Antipsychotics: Typicals
Are D2 dopamine receptor antagonists
High potency typical antipsychotics bind to

the D2 receptor with high affinity. As a

result they have higher risk of
extrapyramidal side effects. Examples
include Fluphenazine, Haloperidol,
Pimozide.

 Low potency typical antipsychotics have

less affinity for the D2 receptors but tend

to interact with nondopaminergic receptors
resulting in more cardiotoxic and
anticholinergic adverse effects including
sedation, hypotension. Examples include
chlorpromazine and Thioridazine.

Antipsychotics: Atypicals
The Atypical Antipsychotics -

atypical
agents are serotonin-dopamine 2
antagonists (SDAs)
They are considered atypical in the way
they affect dopamine and serotonin
neurotransmission in the four key
dopamine pathways in the brain.

Risperidone

Available in regular tabs, IM depot forms and

rapidly dissolving tablet
Functions more like a typical antipsychotic at
doses greater than 6mg
Increased extrapyramidal side effects (dose
dependent)
Most likely atypical to induce hyperprolactinemia
Weight gain and sedation (dosage dependent)

Clozapine

Available in 1 form- a regular tablet

Is reserved for treatment resistant patients because of side
effect profile but this stuff works!
Associated with agranulocytosis (0.5-2%) and therefore
requires weekly blood draws x 6 months, then Q- 2weeks
x 6 months)
Increased risk of seizures (especially if lithium is also on
board)
Associated with the most sedation, weight gain and
transaminitis
Increased risk of hypertriglyceridemia,
hypercholesterolemia, hyperglycemia, including nonketotic
hyperosmolar coma and death with and/or without weight
gain

Haloperidone

Comes in regular tabs

Needs BID dosing
Titrate over 4 days to 12mg/day in order to minimize
risk of orthostatic hypotension
Low EPS, akathisia, wt gain and metabolic disturbances
Inhibitors of 3A4 (ketoconazole) or 2D6 (fluoxetine,
paroxetine)-Can increase blood levels two-fold!
QT Prolongation- mean increase of 19msec at 12mg BID
Not recommended for patients with hepatic impairment

Citrome L, Postgraduate Medicine

2011

Antipsychotic adverse effects

Tardive Dyskinesia (TD)-involuntary muscle movements

that may not resolve with drug discontinuation- risk
approx. 5% per year
Neuroleptic Malignant Syndrome (NMS): Characterized
by severe muscle rigidity, fever, altered mental status,
autonomic instability, elevated WBC, CPK and lfts.
Potentially fatal.
Extrapyramidal side effects (EPS): Acute dystonia,
Parkinson syndrome, Akathisia
Autonomics effect: atropin like effect
Endocrin effect

Anxiolytics
Used to treat many diagnoses including

panic disorder, generalized Anxiety

disorder, substance-related disorders and
their withdrawal, insomnias and
parasomnias. In anxiety disorders often
use anxiolytics in combination with SSRIS
or SNRIs for treatment.

Introduction

Anxiety is a state characterized by psychological

symptoms, often accompanied by physical symptoms of
autonomic arousal (palpitations, light headedness,
perspirations, butterflies, restlessness)

Benzodiazepines and/or selective serotonin reuptake

inhibitor (SSRI) antidepressant used for generalized anxiety
disorders (GAD) and panic disorders

Trycyclic antidepressant (TCAs) & Monoamine Oxidase

(MAO) Inhibitors for long term management of anxiety

Introduction (contd)

SSRI have receive FDA approval for the

treatment of GAD, panic disorders, Obsessive
Compulsive Disorders (OCD), Post traumatic
stress disorders (PTSD) & Social phobia

SSRI most be used start low, go slow

For acute relief of anxiety or panic attacks,

benzodiazepines are useful

Introduction (contd)

All Benzodiazepines currently available & are

qualitatively similar in terms of their efficacy & safety
profiles

Clonazepam & Alprazolam are most commonly to treat

anxiety disorders

The benefit of Buspirone (for GAD) are virtual absence

of dependence & abuse liability

Buspirone indicated for patients with a history of alcohol

abuse

Benzodiazepines

Prototypic agent Diazepam (D)

Other agents :
Clonazepam (C)
Alprazolam (A)
Lorazepam (L)

MOA:
Bind to components of GABA A Receptors facilitate
inhibitory actions of GABA in CNS

Indications:
Anxiety disorders (especially A & C for panic & phobic disorders)
Sedation, seizures, muscle relaxants (D)
Management of alcohol withdrawal

Benzodiazepines (contd)
Pharmacokinetics:
-

Potency C > A > L > D

T L=A< C < D
Hepatic metabolism

ADRS:
-

Cognitive impairments
Sedation, amnesia
Diminished motor skill

Warnings/Precautions:

- Additive sedative effects with other CNS depressant

(ethanol)
- Tolerance & Dependence (prolonged use)

SSRI

Prototypic agent : Fluoxetine (F)

Other agents :
Paroxetine (P)
Sertraline (S)
Citalopram (C)

MOA: Inhibit reuptake of Serotonin

Indications:
Depression
Anxiety disorders (OCD, pannic attacks, social phobias, etc)

Pharmacokinetics:
per oral only
hepatic metabolism

SSRI (contd)
ADRS:
-

Sedations or insomnia
Headache, nausea, appetite & weight changes
Sexual dysfunctions

Warning/Precautions:
-

Serotonin syndrome may occur with other

serotoninergic drugs (i.e. MAO inhibitors)
SSRI inhibit Cy-P450 liver enzymes

Buspirone
MOA:

Partial agonist AT 5 HT1A brain receptors

Anxyolitic action unknown
Indications:

Generalized anxiety disorders (GAD)

Pharmacokinetics:

Per oral only

Hepatic metabolism
ADRS:

Diziness
Headache
Nausea

Sedative- hypnotics
Bbenzodiazepins:

Short action, intermediate, long

Barbiturats:

Ultra short, short, long

Miscelaneous agent: buspirones, choral

hydrate, eszopiclone, ramelteon, zaleplon,

zolpidem

Benzodiazapines

Used to treat insomnia, parasomnias and

anxiety disorders.
Often useepressant withdrawal protocols
Side effects/cons

Somnolence
Cognitive deficits
Amnesia
Disinhibition
Tolerance
Dependence

Drug
Alprazolam
(Xanax)

Dose
Equiva
lency
(mg)
0.5

Peak Blood
Level
(hours)

Elimination
HalfLife1
(hours)

1-2

12-15

Rapid oral absorption

2-4

15-40

Active metabolites;
erratic
bioavailability
from IM
injection

1-4

18-50

Can have layering

effect

1-2

20-80

Active metabolites;
erratic
bioavailability
from IM
injection

1-2

40-100

Active metabolites
with long halflives

1-6

10-20

No active metabolites

2-4

10-20

No active metabolites

2-3

10-40

Slow oral absorption

2-3

Rapid onset; short

duration of action

10.0
Chlordiaze
poxide
(Librium)
Clonazepam
(Klonopin)

0.25
5.0

Diazepam
(Valium)

Flurazepam
(Dalmane)

30.0

Lorazepam
(Ativan)

1.0

Oxazepam
(Serax)

15.0

Temazepam
(Restoril)

30.0

Triazolam
(Halcion)

0.25
1

Comments

AGENTS USED FOR

SLEEP DISORDERS
(SEDATIVE-HYPTONIC)
Hypnotic -sedative

Sedative agent
GRADED DOSE DEPENDENT

INTRODUCTION
Insomnia is a common & non specific

disorder at 40-50% peoples

Causes of insomnia are medical illness,

alcohol/drugs, periodic limb movement

disorders, sleep apnea, psychiatric illness

Without an obvious underlying cause, it is

known as primary or psycho-physiological

Hypnotic are drug used to treat psycho-

physiological (primary) insomnia

Sedatif Hipnotic agent

Benzodiazepin
Barbiturat
Glutethimide (a piperidinedione) and

meprobamate (a carbamate)
Etanol
chloral hydrate
Trichloroethanol
paraldehyde

BARBITURATES:
- Currently not recommended, due to abuse potential & lethal
potential
- Pentobarbital, Secobarbital, Amobarbital
NON-BARBITURATES:
- Similar mechanism with barbiturates
- Chloralhydrate is still commonly used to day, due to its
efficacy as a shortterm sedative hypnotic & low cost
BENZODIAZEPINES:
- Widely used as sedative hypnotics
- Quick onset: Triazolam, Flurazepam, Quazepam
- Longer acting: Temazepam, Flurazepam
NEWLY AGENTS:
- Zaleplon (Pyrazolopyridine), Zolpidem (Imidaropyridine)

BENZODIAZEPIN
Most widely uses for hipnotic sedatif

Mechanism of action
No single mechanism

has been idendified.

Facilitate neuronal membrane inhibition by
actions at specific receptors
Facilitating and prolonging the inhibitory
effefs of GABA and gycine

Brief Pharmacology of Newer Agents

ZOLPIDEM:
-

Drugs Of Choice for insomnia

Act on benzodiazepine-Omega-1-receptor,
selectively (sedation)
Rapid onset & short duration of action
Less potential for abuse, fatal overdose,
withdrawal reactions

ZALEPLON:

- Short acting, faster onset than zolpidem

DRUG

ADVANTAGES

DISADVANTAGES

Chlorpromazine

inexpensive

ADR >> (esp. autonomic)

Thioridazine

Extrapyr. Synd. <<

Cardiotoxic

Thiothixene

Decreased tardive
dyskinesia

Haloperidol

Potent; p.e (+)

Extrapyr. Synd severe

Clozapine

May benefit: resistant

patient
Extrapyr. Synd. <<

Agranulocytosis

Risperidone

Broad efficacy
Extrapyr. Synd. << (low
dose)

Higher dose: extrapyr.

dysfunc. & hypotension

Olanzapine
Quentiapine

Neg. & pos. symptoms

Extrapyr. Synd. <<

Weight gain (less for

quentiapine)
Quentiapine: short T

Efficacy as antipsychotic are similar; SE differ

significantly