ANTI-PSYCHOTIC

DRUGS

Department of Pharmacology
College of Medicine
Our Lady of Fatima University
 SCHIZOPHRENIA
AFFECTIVE DISORDERS
(Depression/Mania)
ORGANIC PSYCHOSES
(Caused by Head Injury, Alcoholism,
others)
 A clinical syndrome characterized
by profound disruption in cognition
and emotion
affecting the most fundamental
attributes:
> language > affect
> thought > sense of self
> perception
clear sensorium but
marked thinking
disturbance.
 THE NATURE OF SCHIZOPHRENIA
1% population
begins at an early age
with strong hereditary factor
SEX: Equally prevalent in men
and women
AGE: Men- between 15 and 25
Women-between 25 and 35
 POSITIVE SYMPTOMS
- Delusions - Disorganized behavior
- Hallucinations - Disorganized speech/thinking
- Thought disorder - Catatonic behaviors

NEGATIVE SYMPTOMS
Withdrawal from social contacts
Flattening of emotional responses
Alogia, Avolition-Apathy, Anhedonia-Asociality
Attention deficit
 Diagnostic Criteria for Schizophrenia
DSM IV
A. Two or more of the following ( one-month period )
delusions, hallucinations, disorganized speech,
grossly disorganized or catatonic behavior and
negative symptoms.
B. Social/occupational dysfunction: one or major
areas of functioning such as work, interpersonal
relations, or self-care, are markedly below the level
achieved prior to the onset.
C. Continuous signs of the disturbance persist for at
least SIX months.
 THE DOPAMINE HYPOTHESIS
SCHIZOPHRENIA: WITH EXCESSIVE
DOPAMINERGIC ACTIVITY; NORe and GABA

DOPAMINE RECEPTOR-BLOCKING
ACTIVITY IN THE BRAIN

SEROTONIN RECEPTOR-BLOCKING
ACTIVITY IN THE BRAIN

BLOCK CHOLINERGIC, ADRENERGIC &

HISTAMINERGIC RECEPTORS
 OBSERVATIONS:
Anti- PSYCHOTIC drugs block postsynaptic
D2 receptors in the CNS

Drugs that increase DOPA aggravate

Schizophrenia
(levodopa, amphetamine, bromocriptine)

Dopamine Receptor Density: in schizophrenia

POSITRON EMISSION TOMOGRAPHY (PET):

Dopamine Receptor Density

HOMAVANILLIC ACID (HAV): change in amount

 5-HT2A RECEPTOR STIMULATION
basis for hallucinatory effects of
serotonin agonists LSD & mescaline
modulates release of dopamine from cortex,
limbic region, striatum
stabilizes NMDA glutamate receptors
can modulate the stability of a complex
consisting of 5-HT2A & NMDA receptors

5-HT2A BLOCKADE key factor in the mechanism

of action of atypical anti-psychotic drugs
 THE GLUTAMATE
HYPOTHESIS
The NMDA receptor (NMDAR), a glutamate
receptor, is the predominant molecular device
for controlling synaptic plasticity and memory
function.
The NMDAR is a specific type of ionotropic
glutamate receptor. NMDA (N-methyl-D-
aspartate) is the name of a selective agonist that
binds to NMDA receptors but not to other
glutamate receptors.
 Hypofunction of NMDA diminished
inhibitory influences on neuronal function
contributing to schizophrenia
Diminished GABAergic activity can induce
disinhibition of downstream glutamate
activity hyperstimulation of cortical
neurons through NMDA receptors
 CLASSIFICATION OF
ANTIPSYCHOTIC DRUGS:
1. TYPICAL ANTIPSYCHOTICS:
A. PHENOTHIAZENE DERIVATIVE
3 ring structure, 2 benzene rings are
linked by sulfur & nitrogen atom
N position 10 is replaced by carbon atom
with a double bond to the side chain
 ALIPHATIC DERIVATIVE:
CHLORPROMAZINE
TRIFLUPROMAZINE
PIPERIDINE DERIVATIVE:
THIORIDAZINE
MESORIDAZINE
PIPERACETAZINE
NOTE: Decrease incidence of EPS side
effects due to antimuscarinic
activity
 PIPERAZINE DERIVATIVE:

FLUPHENAZINE
PERPHENAZINE
TRIFLUOPERAZINE
Most potent phenothiazene &
thioxanthene antipsychotic
compound
NOTE: EPS but
tendency to produce sedation
or autonomic side effects.
B. THIOXANTHENE DERIVATIVES:

ALIPHATIC DERIVATIVE:
CHLORPROTHIXENE

PIPERAZINE DERIVATIVE:
CHLOPENTHIXOL
FLUPENTIXOL
THIOTHIXENE
 C. BUTYROPHENONE:

HALOPERIDOL
D. Miscellaneous structures
(newer typical anti-psychotics)
Pimozide
Molindone

* No significant difference in efficacy

with older typical anti-psychotics
 CLASSIFICATION OF ANTIPSYCHOTIC
DRUGS
1. TYPICAL ANTI-PSYCHOTICS
A. Phenothiazine Derivatives
Aliphatic Derivative: CHLORPROMAZINE
Piperidine Derivative: THIORIDAZINE
Piperazine Derivative: FLUPHENAZINE,
PERPHENAZINE, TRIFLUOPERAZINE
B. Thioxanthene Derivative:
THIOTHIXENE
C. Butyrophenone: HALOPERIDOL
D. Miscellaneous: PIMOZIDE, MOLINDONE
2. ATYPICAL ANTI-PSYCHOTICS
LOXAPINE RISPERIDONE
CLOZAPINE SERTINDOLE
ASENAPINE ZIPRASIDONE
OLANZAPINE ZOTEPINE
QUETIAPINE ARIPRIPAZOLE
PALIPERIDONE
 ATYPICAL ANTI-PSYCHOTICS

Greater ability to alter

5-HT2A-receptor activity
than interfere with
D2-receptor action
 ATYPICAL ANTI-PSYCHOTICS
- SULPRIDE
- SULPIRIDE
- Equivalent potency for D2 and D3 receptors
- Antagonists of 5-HT7
- Dissociate EPS & anti-psychotic efficacy
- Produce marked increase in prolactin levels
- May cause tardive dyskinesia
 PHARMACOKINETICS
READILY BUT INCOMPLETELY ABSORBED
FIRST PASS METABOLISM
HIGHLY LIPID SOLUBLE
HIGHLY PROTEIN BOUND (92-99%)
LARGE VOLUME OF DISTRIBUTION (>7L/kg)
COMPLETELY METABOLIZED
Except mesoridazine
(major metabolites of thioridazine)
LITTLE EXCRETED UNCHANGED
t is 10 -24 hours
 PHARMACODYNAMICS

Variety of EFFECTS in the following

CNS Endocrine
Autonomics

Blocks a wide range of receptors:

dopaminergic receptors histaminic receptors
alpha adrenoceptors 5-HT2 receptors
muscarinic receptors
 DOPAMINERGIC SYSTEM
1. MESOLIMBIC-MESOCORTICAL
substancia nigra>limbic system
BEHAVIOR and PSYCHOSIS
2. NIGROSTRIATAL
substancia nigra.>caudate & putamen
VOLUNTARY MOVEMENTS
3. TUBEROINFUNDIBULAR
arcuate nuclei & periventricular neurons,>
hypothalamus & post pituitary
INHIBITS PROLACTIN SECRETION
 DOPAMINERGIC SYSTEM
4. MEDULLARY-PERIVENTRICULAR
motor nuclei of the vagus
EATING BEHAVIOR

5. INCERTOHYPOTHALAMUS
from the medial zona incerta to the
hypothalamus and the amygdala
REGULATE THE ANTICIPATORY
MOTIVATIONAL PHASE OF
COPULATORY BEHAVIOR IN RATS
ANTI-PSYCHOTIC AGENTS
SIDE EFFECTS
PSYCHOLOGICAL EFFECTS
Mild to severe EPS
Akathisia, sleepiness, restlessness

impaired performance & judgment

NEUROPHYSIOLOGIC EFFECTS (EEG)

hypersynchrony: focal /unilateral
ANTI-PSYCHOTIC AGENTS
ENDOCRINE EFFECTS
Elevation of prolactin (typical antipsychotics,
risperidone & paliperidone)
Females:
Amenorrhea-galactorrhea syndrome

Increase libido, Infertility, Osteoporosis

Males:
Loss of libido

Impotence, Gynecomastia, Infertility

* Newer atypical drugs diminished D2 antagonism

 ANTI-PSYCHOTIC AGENTS
CARDIOVASCULAR EFFECTS
Orthostatic hypotension,Tachycardia
Decreased: mean arterial pressure,
peripheral resistance, stroke volume
ECG changes (esp. with Thioridazine):
prolongation of QT interval
Abnormal configurations of ST segment &
T waves
Torsade (Haloperidol)
 ANTI-PSYCHOTIC AGENTS
CARDIAC TOXICITY
Thioridazine minor T wave abnormalities
Overdosage: major ventricular arrhythmias
(Torsade de pointes, cardiac conduction block,
sudden death)
Atypical agents:
Ziprasidone greatest risk of QT prolongation
Clozapine -- myocarditis
ANTI-PSYCHOTIC AGENTS
BEHAVIORAL EFFECTS
Pseudodepression
due to drug-induced akinesia
Tx: antiparkinsonism drugs
Due to higher doses than needed
Tx: decrease dosage
Toxic-confusional states
due to anti-muscarinic action
ANTI-PSYCHOTIC AGENTS
METABOLIC EFFECTS

Weight gain, hyperglycemia, hyperlipidemia

 ANTI-PSYCHOTIC AGENTS
AUTONOMIC NERVOUS SYSTEM EFFECTS
MUSCARINIC CHOLINERGIC BLOCKADE
urinary retention, dry mouth, loss of accomodation,
constipation
ALPHA ADRENORECEPTOR BLOCKADE
orthostatic hypotension, impotence, failure to
ejaculate

Rx: switch to drugs with less or no antimuscarinic

or adrenoceptor blocking actions
ANTI-PSYCHOTIC AGENTS
TOXIC OR ALLERGIC REACTIONS
Agranulocytosis (clozapine)
Develops rapidly 6th and 18th weeks of therapy
Cholestatic jaundice
Skin eruptions

OCULAR COMPLICATIONS
Deposits in anterior portion of the eye (cornea &
iris) browning of vision (chlorpromazine)
Limit dosage to max. daily dose of 800 mg/d
ANTI-PSYCHOTIC AGENTS
DYSMORPHOGENESIS
WHEN USE IN PREGNANCY:
Teratogenic risk (small): Effect on
neurotransmitters involved in neurodevelopment
 ADVERSE PHARMACOLOGIC EFFECTS
OF ANTIPSYCHOTIC DRUGS
TYPE MANIFESTATIONS
Autonomic Loss of accomodation, dry
Nervous System mouth, difficulty urinating,
constipation
Orthostatic hypotension,
impotence, failure to ejaculate blockade
Central Nervous Parkinsons disease,
System Akathisia, dystonias
Tardive dyskinesia
Toxic-confusional state
Endocrine Amenorrhea-galactorrhea,
System infertility, impotence
Other Weight gain
MECHANISM
Muscarinic
cholinoceptor blockade
-adrenoceptor
Dopamine-receptor
blockade
Supersensitivity of
dopamine receptors
Muscarinic blockade
Dopamine-receptor
blockade resulting in
hyperprolactinemia
Possibly combined H1
& 5-HT2 blockade
 CLINICAL INDICATIONS
A. PSYCHIATRIC INDICATIONS
SCHIZOPHRENIA
Psychotic Bipolar Disorder (BPI)
Psychotic Depression
Treatment Resistant Depression
SCHIZO-AFFECTIVE DISORDERS
MANIC EPISODES IN BIPOLAR DISORDERS
GILLES DE LA TOURETTE SYNDROME
SENILE DEMENTIA
Disturbed behavior in ALZHEIMERS DISEASE
 CLINICAL INDICATIONS
B. NON-PSYCHIATRIC INDICATIONS
ANTI-EMETIC EFFECT
dopamine receptor blockade
Prochlorperazine
ANTI-PRURITIC EFFECT
Histamine-1 receptor blockade
Phenothiazines (promethazine)
PREOPERATIVE SEDATION (Promethazine)
NEUROLEPTANESTHESIA (Droperidol)
 ADVERSE REACTIONS
NEUROLOGIC EFFECTS
1. PARKINSONS SYNDROME:
bradykinesia, rigidity, tremor, mask
facies, shuffling gait seen in 5-30 days
Mechanism: antagonism of dopamine
Rx: anti-parkinsons agents, amantadine
Contraindicated: Levodopa
 ADVERSE REACTIONS

2. AKATHISIA:
Uncontrollable restlessness
motor restlessness
5 -60 days
Mechanism unknown
Rx: sedative antihistamine with
anticholinergic property ( eg.
Diphenhydramine)
 ADVERSE REACTIONS

3. ACUTE DYSTONIC REACTION:

Spastic retrocollis or torticollis
Spasm of muscles tongue, face, neck,
back, may mimic seizures
During the first 1 -5 days of Rx
Mechanism unknown
Rx: anti-parkinsons agents,
diphenhydramine
 ADVERSE REACTIONS

4. PERIODIC TREMOR RABBIT SYNDROME

After months or years of treatment

Mechanism : unknown
Rx: Anti-parkinsons Drugs
 ADVERSE REACTIONS

5. NEUROLEPTIC MALIGNANT SYNDROME

Catatonia, stupor, fever, unstable BP,
myoglobulinemia after weeks of treatment
Mechanism: antagonism of dopamine
Rx: Stop neuroleptic immediately; Dantrolene
Not effective: bromocriptine, Anti-parkinsons
 ADVERSE REACTIONS
6. TARDIVE DYSKINESIA:
Supersensivity of D receptors
(cholinergic deficiency)
Late occuring syndrome of abnormal choreo-
athetoid movements
Most important unwanted effects (20-40% of
chronically treated patients)
oral-facial dyskinesia,choreoathetosis,dystonia
 ADVERSE REACTIONS
TARDIVE DYSKINESIA:
Early recognition is important advanced
cases difficult to reverse
Mechanism: excess function of dopamine
Rx: worse on withdrawal
First step: discontinue , reduce dosage or
switch to newer atypical agents (quetiapine or
clozapine )
Second step: Eliminate all drugs with central
anti-cholinergic action (anti-parkinsons & TCA)
 ADVERSE REACTIONS

7. SEIZURES:

Complication of chlorpromazine
2-5% of patients treated with clozapine
Rx: anticonvulsant
 DRUG INTERACTIONS

ADDITIVE EFFECTS when combined with

drugs that have:
Sedative effects
Alpha-adrenoceptor blocking action
Anti-cholinergic action
Quinidine-like action (thioridazine &
ziprasidone)
 OVERDOSES
- rarely fatal
- drowsiness agitation COMA
- neuromuscular excitability convulsions
- pupils--miosis,
- decreased Deep Tendon Reflex (DTR)
- HYPOTENSION & HYPOTHERMIA
- Mesoridazine & Thioridazine
Ventricular arrhythmias
 MANIA
STATE OF ELEVATED MOOD
& PSYCHOMOTOR ACCELERATION,
WITH EXCESS CATECHOLAMINES ACTIVITY
IN WHICH CATHECOLAMINES ARE RELEASE
FROM ADRENERGIC NERVE TERMINALS.
 ANTI-MANIC AGENTS

Bipolar Affective Disorder:

Manic-Depressive
 BIPOLAR DISORDER
Nature of Bipolar Disorder:
High risk for suicide
Strong familial component genetic

Manic phase - catecholamine activity

excitement disinhibition psychotic symptoms
hyperactivity aggression cognitive impairment
impulsivity diminished need for sleep

Depression phase - catecholamine activity

depressed mood sleep disturbance psychotic symptoms
diurnal variation anxiety
 ANTI-MANIA
MOOD STABILIZING DRUG
LITHIUM CARBONATE
 LITHIUM
OTHER INDICATIONS:
GOUT(mid-19th century)
THYROTOXICOSIS
INAPPROPRIATE ADH SECRETION
 BIPOLAR AFFECTIVE DISORDER
LITHIUM CARBONATE is the universally preferred
treatment esp. in manic phase
80% overall success rate for achieving remission
60% effective as maintenance treatment & in
severely ill
Usecombined treatment with anti-psychotics or
benzodiazepines
Other drugs: valproate, aripiprazole, olanzapine,
quetiapine, risperidone, ziprasidone
 OTHER DRUGS FOR BIPOLAR DISORDERS
A. Valproic acid
- appropriate first-line treatment but not for
maintenance
- adverse effects: GI distress, possible weight
gain, alopecia
- dose: 750 mg/d 1500-2000 mg
- max. dose: 60 mg/kg/day
B. Carbamazepine
- effective for acute mania & prophylaxis
- initial dose: 200 mg BID
- maintenance dose: 800-1200 mg/day
- adverse effects: diplopia, ataxia
OTHER DRUGS FOR BIPOLAR DISORDERS

C. Lamotrigine prevents depression that

follows manic phase
adverse effects: nausea, dizziness, headache
D. Riluzole a neuro-protective agent used
also for Amyotrophic Lateral Sclerosis
E. Ketamine non competetive NMDA antagonist
that enhance AMPA receptor
F. AMPA receptor potentiators
 AMPA -amino-3-hydroxy-5-methyl-4-
isoxazolepropionic acid receptor (also known as
AMPA receptor, AMPAR, or quisqualate
receptor) is a non-NMDA-type ionotropic
trans-membrane receptor for glutamate that
mediates fast synaptic transmission in the central
nervous system (CNS). Its name is derived from
its ability to be activated by the artificial glutamate
analog AMPA.
 OTHER PSYCHIATRIC APPLICATIONS:

RECURRENT ENDOGENOUS DEPRESSION

SCHIZOAFFECTIVE DISORDER

SCHIZOPHRENIA

UNIPOLAR DEPRESSION
ABSORPTION Virtually complete within 6 -8 hrs; peak
plasma levels in 30 min to 2 hrs
DISTRIBUTION In total body water; slow entry into
intracellular compartment. Initial Vd is 0.5
L/kg, rising to 0.7-0.9 L/kg; some
sequestration in bone. No protein binding.
METABOLISM None
EXCRETION Virtually entirely in urine; Clearance about
20% of creatinine. Plasma half life about 20
hours
TARGET PLASMA 0.6-1.4 mEq/L
CONCENTRATION
DOSAGE 0.5 mEq/kg/d in divided doses
 Inhibits 2 signal transduction pathways:
1. Suppresses inositol signaling
By depletion of intracellular inositol
2. Inhibits glycogen synthase kinase-3 (GSK-3)
It has now been shown that LITHIUM, which has been
used as a treatment for bi-polar disorder, acts as a mood
stabilizer by selectively inhibiting GSK-3. The mechanism
through which GSK-3 inhibition stabilizes mood is not
known, though it is suspected that the inhibition of GSK-
3s ability to promote inflammation contributes to the
therapeutic effect. (NEWER DISCOVERY)
LITHIUM PHARMACODYNAMICS
EFFECTS ON ELECTROLYTES & IONS TRANSPORT:
Substitute for sodium in generating action potentials.
Na+-Na+ exchange across the membrane is inhibited
because Li+-Na+ exchange gradually slowed after Lithium
is introduced.
EFFECTS ON NEUROTRANSMITTERS
Enhance effects of serotonin?
Decrease norepinephrine & dopamine turnover
Block dopamine receptor supersensitivity
Augment synthesis of acetylcholine?
EFFECTS ON SECOND MESSENGERS
effect on Inositol 1,4,5 triphospate (IP3 )/
Diacylglycerol (DAG)-needed in alpha a and
muscarinic transmission
LITHIUM PHARMACODYNAMICS
MOST POPULAR HYPOTHESIS

EFFECTS ON PHOSPHOINOSITOL
TURNOVER..> EARLY RELATIVE
REDUCTION OF MYOINOSITOL
IN HUMAN BRAIN
LITHIUM inhibits inositol monophosphatase
& several important enzymes in the normal
recycling of membrane phosphoinositides.
(-) IP2----IP1
(-) IP1----inositol
It will lead to a depletion of
PIP2(phosphotidylinositol-4,5-bis-phosphate)
which is the membrane precursor of IP3 and DAG

LITHIUM could cause a selective

depression of the overactive circuits.
 Persistent activation of muscarinic receptors
can prevent the normal inhibitory action of
adenosine on certain hippocampal neurons.
These excitatory cholinergic action can be
prevented by LITHIUM.
It can also inhibit norepinephrine-sensitive adenylyl
cyclase. (related to its anti-depressant & anti-manic
effects)
May uncouple receptors from their G proteins which
can give untoward side effects.
 LITHIUM ADVERSE EFFECTS
1. CNS EFFECTS: dizziness, mild ataxia
2. NEUROMUSCULAR EFECTS: fine tremors
3. CVS EFFECTS: ventricular arrythmias
4. GIT EFFECTS: nausea, vomiting, diarrhea
5. GUT EFFECTS: polyuria
6. ENDOCRINE EFFECTS: hypothyroidism
7. ALLERGIC REACTION: pruritus, rash
8. OVERDOSE TOXICITY: vomiting, drowsiness,
decrease consciousness and seizures
Rx: dialysis
The TWO most common side effects

UNCOUPLING OF THE
VASOPRESSIN and TSH RECEPTORS

FROM THEIR G PROTEINS

 Decrease Renal Clearance by 25% with:
Diuretics (eq. thiazide)
Newer NSAIDs
Severe EPS if combined with:
Neuroleptics
Increased toxicity:
Antipsychotic agents
A. Neurologic & Psychiatric
Neurologic:
Tremors most common;

TREATMENT: propranolol, atenolol
Choreoathetosis, motor hyperactivity, ataxia,
dysarthria, aphasia
Psychiatric: mental confusion & withdrawal

B. Decreased Thyroid Function

SUBCLINICAL HYPOTHYROIDISM due to uncoupling
of TSH receptors from G proteins
Serum TSH concentration every 6-12 mos.
C. Nephrogenic Diabetes Insipidus & other Renal
problems
Polydipsia and POLYURIA (due to uncoupling of the
vasopressin from G proteins)
Due to loss of responsiveness to ADH (nephrogenic
Diabetes Insipidus) responds to amiloride
D. Edema
Sodium retention
E. Cardiac Adverse Effects
Depresses sinus node
ECG: T-wave flattening
Contraindication: Sick Sinus Syndrome
F. Use during Pregnancy
Increased renal clearance
Passes through breast milk: infants manifest
lethargy, cyanosis, poor suck & Moro reflexes,
hepatomegaly
Lithium-induced dysmorphogenesis: Ebsteins
anomaly
G. Miscellaneous
Transient acneiform eruptions
Folliculitis
Leukocytosis
- Dose indicative of toxicity: > 2 mEq/L
- Manifestations: vomiting, drowsiness,
decrease consciousness and seizures

- Tx: Dialysis, peritoneal or hemodialysis

 LITHIUM
CONTRAINDICATIONS
A. MARKED DEHYDRATION OR SODIUM
DEPLETION
B. SIGNIFICANT RENAL OR CARDIAC
DISEASES
C. PREGNANCY
D. RENAL CONCENTRATION ABILITY
Nephrogenic diabetes insipidus with polyuria
 ANTIDEPRESSANTS
American Psychiatric Association: Diagnostic
& Statistical Manual of Mental Disorders
( DSM-IV)
MAJOR DEPRESSION & DYSTHYMIA(minor)
pure depressive symptoms
BIPOLAR DISORDER
& CYCLOTHYMIC DISORDER
--depression associated with mania
 DEPRESSION
I. REACTIVE OR SECONDARY DEPRESSION
Core Depression Syndrome: depression, anxiety, tension,
bodily complaints, guilt (> 60%)
II. ENDOGENOUS DEPRESSION
Occurs at any age, Core Depression Syndrome plus
ABNORMAL vital signs rhythm of sleep, motor activity,
libido, decrease appetite ( 25%). Responds well to anti-
depressants and ECT. Tends to recur throughout life.
III. DEPRESSION ASSOCIATED WITH
BIPOLAR AFFECTIVE DISORDER
(10-15%) manic depressionusual
Can be misdiagnosed in hypomanic stage
Can be treated with lithium and anti-psychotics
 Pathogenesis of Major Depression

MONOAMINE HYPOTHESIS
1950s RESERPINE introduced produced depression
Mechanism of action was to inhibit storage of amine and
norepinephrine in the vesicles of presynaptic nerve ending
Depression must be associated with decrease functional
amine dependent synaptic transmission.
Depression is also related to a deficiency in the amount
or functions of cortical and limbic Serotonin (5-HT),
norepinephrine (NE), and dopamine (DA)
Pathogenesis of Major Depression
NEUROTROPHIC HYPOTHESIS
Depression is associated with the loss of
neurotrophic support and that effective
anti-depressant therapies increase neurogenesis and
synaptic connectivity in cortical areas such as the
hippocampus. BDNF(brain-derived neurotrophic
factor) are critical in the regulation of neural
plasticity, resilience, and neurogenesis.. It exerts its
influence on neuronal survival and growth effects by
activating the tyrosine kinase receptor B in both
neurons and glia.
 NEUROENDOCRINE FACTORS
Depression associated with hormonal abnormalities
A. Abnormalities in the HPA
(hypothalamic pituitary adrenal) axis:
- Elevated cortisol levels

- Non-suppression of ACTH
- Release in the dexamethasone suppression test
- Chronically elevated CRH (Corticotropin-
releasing hormone), a polypeptide hormone and
neurotransmitter involved in the stress response

* Dysregulation of the stress hormone axis

 NEUROENDOCRINE FACTORS
B. Thyroid dysregulation
- Blunt response of thyrotropin to TRH(Thyrotropin-
releasing hormone) also called thyrotropin-releasing factor (TRF), is a tropic,
tripeptidal hormone that stimulates the release of TSH (thyroid-stimulating
hormone) and prolactin from the anterior pituitary. TRH has been used clinically
for the treatment of spinocerebellar degeneration and disturbance of
consciousness in humans
- Elevation of circulating thyroxine during depressed state
C. Sex steroids
- Estrogen deficiency
- Severe testosterone deficiency
Treatment: Hormonal Replacement Therapy
 INTEGRATION OF HYPOTHESES:
HPA & steroid abnormalities suppress
transcription of BDNF gene
Binding of hippocampal glucocorticoid by
cortisol in chronic stress
 Other indications:
GENERALIZED ANXIETY DISORDER (GAD)
POST-TRAUMATIC STRESS DISORDER (PTSD)
OBSESSIVE-COMPULSIVE DISORDER (OCD)
NEUROPATHIC PAIN & FIBROMYALGIA-ASSOCIATED PAIN
PRE-MENSTRUAL DYSPHORIC DISORDER (PMDD)
STRESS URINARY INCONTINENCE
A. SELECTIVE SEROTONIN REUPTAKE INHIBITORS
(SSRI)
B. SEROTONIN - NOREPINEPHRINE REUPTAKE
INHIBITORS (SNRI)

C. 5-HT2 ANTAGONISTS
D. TETRACYCLIC & UNICYCLIC ANTIDEPRESSANTS
E. MONOAMINE OXIDASE INHIBITORS (MAOI)
 (SSRI)
FLUOXETINE CITALOPRAM FLUVOXAMINE
SERTRALINE PAROXETINE ESCITALOPRAM
(SNRI)
VENLAFAXINE DULOXETINE DESVENLAFAXINE MILNACIPRAN

IMIPRAMINE AMITRIPTYLINE DESPIRAMINE

NORTRIPTYLINE CLOMIPRAMINE DOXEPIN
TRIMIPRAMINE PROTRIPTYLINE
 5-HT2 ANTAGONISTS
TRAZODONE
NEFAZODONE
TETRACYCLIC & UNICYCLIC ANTIDEPRESSANTS
UNICYCLIC: BUPROPION
TETRACYCLIC:MIRTAZAPINE
AMOXAPINE
MAPROTILINE
MONOAMINE OXIDASE INHIBITORS(MAOI)
1. Hydrazine derivatives
A. PHENELZINE
B. ISOCARBOXAZID
2. Non-hydrazine derivatives
A. TRANYLCYPROMINE
B. SELEGILINE
C. MOCLOBEMIDE
A. SELECTIVE SEROTONIN REUPTAKE INHIBITORS
(SSRI)
- Inhibits Serotonin Transporter (SERT)
- High affinity for monoamine receptors
- Lack affinity for Histamine, Acetylcholine,
alpha-adrenoceptors
- Highly lipophilic
- Broad spectrum
 MEMBERS OF (SSRI)
FLUOXETINE CITALOPRAM FLUVOXAMINE
SERTRALINE PAROXETINE ESCITALOPRAM
CLINICAL USES:
MAJOR DEPRESSIVE DISORDER (MDD)
GENERALIZED ANXIETY DISORDER (GAD)
POST-TRAUMATIC STRESS DISORDER (PTSD)
OBSESSIVE-COMPULSIVE DISORDER (OCD)
PANIC DISORDER
PREMENSTRUAL DYSPHORIC DISORDER (PMDD)
BULIMIA
 SELECTIVE SEROTONIN REUPTAKE INHIBITORS
(SSRI)
KINETICS:
FLUOXETINE metabolite: norfluoxetine longest t
at 180 hrs
- discontinue 4 wks or longer before MAOI to
prevent SEROTONIN SYNDROME
DYNAMICS:
- Inhibits transporter for serotonin (SERT) by
binding the receptor inhibition of dopamine
system
SELECTIVE SEROTONIN REUPTAKE INHIBITORS
(SSRI)
ADVERSE EFFECTS
GIT nausea, GI upset, diarrhea
Headache, insomnia, hypersomnia
Weight gain (Paroxetine)
Discontinuance syndrome (Paroxetine &
Sertraline): dizziness, paresthesias 1-2 days
after discontinuation, persists 1 week or
longer
B. SEROTONIN-NOREPINEPHRINE REUPTAKE INHIBITORS
(SNRI)
bind the Serotonin (SERT)
and
Norepinephrine (NET) transporters

2 CLASSES:
 MEMBERS OF (SNRI)

VENLAFAXINE DULOXETINE
DESVENLAFAXINE MILNACIPRAN

IMIPRAMINE AMITRIPTYLINE
DESPIRAMINE NORTRIPTYLINE
CLOMIPRAMINE DOXEPIN
TRIMIPRAMINE PROTRIPTYLINE
 CLINICAL USAGES
(SNRI)

VENLAFAXINE DULOXETINE
DESVENLAFAXINE MILNACIPRAN

MDD Neuropathies Stress Urinary Incontinence

GAD Fibromyalgia Menopausal Vasomotor Symptoms

 CLINICAL USAGES
(SNRI)

IMIPRAMINE AMITRIPTYLINE
DESPIRAMINE NORTRIPTYLINE
CLOMIPRAMINE DOXEPIN
TRIMIPRAMINE PROTRIPTYLINE
 SNRI

(-) SNR pump---OFF-SWITCHES of the amine transmission

SELECTIVE SNRI
SNRI TCA
 5-HT2 ANTAGONISTS

TRAZODONE
NEFAZODONE hepatotoxic
Hypnotic
Major Depressive Disorder(MDD)
General Anxiety Disorder(GAD)
 5-HT2 ANTAGONISTS
antianxiety, antipsychotic, antidepressant effect
KINETICS and DYNAMICS:
TRAZODONE
- weak but selective inhibitor of SERT
with little effect on NET
- weak to modest pre-synaptic alpha adrenergic blocker
- modest histamine 1 antagonist
NEFAZODONE
- weak inhibitor of both SERT & NET
- potent antagonist of postsynaptic 5-HT2A receptor
- hepatotoxic
 5-HT2 ANTAGONISTS
Adverse Effects:
- Sedation & GI disturbances most common
- Priapism (Trazodone)
- Orthostatic hypotension 0 alpha-blocking effect
- Hepatotoxicity including rare fatalities &
fulminant hepatic failure that requires
transplantation (Nefazodone)
D. TETRACYCLIC & UNICYCLIC ANTIDEPRESSANTS

UNICYCLIC: BUPROPION

TETRACYCLIC: MIRTAZAPINE
AMOXAPINE
MAPROTILINE
 UNICYCLIC ANTIDEPRESSANTS
BUPROPION
- CNS activating property
- Modest to moderate inhibition of NE & dopamine
reuptake
- Pre-synaptic release of catecholamines - NE *
dopamine availability
-used in smoking cessation.
 TETRACYCLIC ANTIDEPRESSANTS
MIRTAZAPINE
- antagonist of pre-synaptic alpha 2 auto-receptor
- enhances release of NE & 5-HT
- antagonist of 5-HT2 & 5-HT3 receptors
- potent H1 antagonist sedating effect
AMOXAPINE
- action resemble TCA like Desipamine
AMOXAPINE & MAPROTILINE
- moderate inhibition of post-synaptic
Dopamine 2 receptors
- MDD unresponsive to other drugs
 TETRACYCLIC & UNICYCLIC ANTIDEPRESSANTS

ADVERSE EFFECTS:
- Parkinsonian syndrome - AMOXAPINE
due to D2-blocking effect
- Significant sedative effect MIRTAZAPINE
- TCA-like adverse effect, seizures
MAPROTILINE due to its high NET affinity
- Agitation, insomnia, anorexia - BUPROPION
 E. MONOAMINE OXIDASE INHIBITORS(MAOI)
1. Hydrazine derivatives
- binds irreversibly & non-selectively to MAO-A and
MAO-B
A. PHENELZINE
B. ISOCARBOXAZID
2. Non-hydrazine derivatives
A. TRANYLCYPROMINE - irreversible & non-selective
to MAO-A and MAO-B
B. SELEGILINE - irreversible MAO-B specific
C. MOCLOBEMIDE- reversible & selective inhibitor of
MAO-A
 MONOAMINE OXIDASE INHIBITORS
MONOAMINE OXIDASE
metabolizes Tryptamine & Dopamine
2 Forms of MAO:
MAO-A
- Present in Dopamine and NE neurons
- Found in the brain, gut, placenta, liver
- 1O substrates are: NE, Epinephrine, Serotonin
MAO-B
- Found on serotonergic & histaminergic neurons
- Distributed in brain, liver, platelets
- Acts primarily on Tyramine, phenylethylamine &
benzylamine
 MONOAMINE OXIDASE INHIBITORS
- Rarely used potentially lethal--with food &
drug interactions
- Primary use: depression unresponsive to
other antidepressants
- Other uses: Anxiety states (social & panic)
Parkinsons disease- SELEGILINE
- Substantial CNS effects
NOTE: MAO-A amine oxidase responsible for NORe,
serotonin and tyramine
MAO-B selective for dopamine(SELEGILINE)
 MONOAMINE OXIDASE INHIBITORS
ADVERSE EFFECTS:
- Orthostatic hypotension & weight gain most
common
- Sexual effects highest rate among antidepressants
- Sedation more with Phenelzine than Selegiline
& Tranylcypromine
- Confusion at higher doses
- Interaction with food & serotogenic drugs due to
blockade of tyramine metabolism
- Sudden discontinuation syndrome psychosis,
excitement, confusion
 Muscarinic NE 5HT
Sedation
Drugs Block Reuptake Reuptake
Block Block

Amitryptyline +++ +++ ++ +++

Imipramine ++ + + ++
Amoxapine ++ + ++ +
Bupropion U - - - -
Trazodone Tetra +++ - - ++
Mirtazepine +++ - - -
Venlafaxine - - +++ ++
Fluoxetine - + - +++
SSRI
1. MAJOR DEPRESSION TCAs, SNRIs, SSRIs
2. ANXIETY DISORDER - SNRIs, SSRIs
Major Anxiety Disorders:
PTSD OCD (SSRI-Fluoxetine)
GAD Panic disorder (TCA-Imipramine)
Social anxiety disorder
3. PAIN DISORDER - TCAs, SNRIs, Phenothiazine
4. PMDD - SSRIs
5. SMOKING CESSATION Bupropion, Nortriptyline
6. OTHER USAGES:
a. ENURESIS - TCAs, SNRIs (duloxetine)
b. VASOMOTOR SYMPTOMS OF MENOPAUSE-
SSRI, SNRI (desvenlafaxine,venlafaxine)
5-HT2A antagonist (nefazodone)
c. SEXUAL DISORDER SSRI
d. EATING DISORDER (BULIMIA) SSRI
Cataplexy associated with narcolepsy,
school phobia(SSRI) Attention deficit syndrome
(imipramine and desipramine)
Generalized anxiety disorder
(combined serotonin and NE uptake inhibitors)
NOTE: Serotonin Syndrome - hyperthermia, muscle rigidity
and myoclonus, rapid changes in mental states & vital signs
 Foods that interact with MAOI
High in tyramine content :
BEER
BROAD BEANS, LAVA BEANS

CHEESE

CHICKEN LIVER

SAUSAGES

RED WINE

YEAST
 OVERDOSE TOXICITY
- Coma with shock
- metabolic acidosis
- respiratory depression
- sudden apnea
- Agitation
- Delirium
- Hypertensive crisis
- Cardiac conduction defects such as
arrhythmias
 DRUG INTERACTIONS

MAO Inhibitors and sympathomimetics and

opiates

Anti-hypertensive drugs exaggerated

hypotension

TCA increase concentration with cimetidine

and phenothiazines
 DRUGS WITH SPECIAL
IMPORTANCE
Desipramineless sedating, low anti-
muscarinic effects
Amitryptyline-more sedating and marked
anti-muscarinic effects
Maprotiline-seizures
Trazodoneprolonged penile erection
Fluoxetineminimal sedative effects, very
low anti-muscarinic effects
Nefazodone-less sedating, no SSRI