Antidepressants

Amine
Hypothesis

Depression is caused by a functional in activity of the CNS amine neurotransmitters NE, serotonin, and
DA.

Amine
Hypothesis
Problems
Neurotrophic
Hypothesis

Antidepressant drugs cause changes in amine activity within hours, but weeks may be required to achieve
clinical effects
At least one antidepressant, Bupropion, has minimal effects on brain NE or 5-HT
Brain-derived neurotrophic factor (BDNF)
Depression is associated with the loss of neurotrophic support.
Antidepressants increase neurogenesis and synaptic connectivity
Changes in trophic factors (especially brain-derived neurotrophic factor, BDNF) and
hormones appear to play a major role in the development of major depression
(A). Successful treatment results in changes in these factors
(B). CREB, cAMP response element-binding (protein).
BDNF, brain-derived neurotrophic factor.

Neuroendocrin
e
Factors

Cortisol levels
Corticotropin-releasing Hormone
Dexamethasone suppression test
25% depressed pts have abnormal thyroid function
Estrogen
Testosterone

Tricyclics
TCAs

Inhibit Reuptake of NE &

5HT
Potentiate NT Action at
Post-synaptic Rc
Chemically Related to
Phenothiazines
Triple Ring Nucleus
Some Form Active
Metabolites

Replaced by SSRIs &

Heterocyc
2/2 Better SE Profile
Depression w/
- Psychomotor
Retardation
- Sleep Disturbances
- Poor Appetite
- Weight Loss
Enureisis - Imipramine
Phobic Disorders
Chronic Pain -

Amitriptyline

Classification

Tricyclics
Heterocyclics
Selective serotonin reuptake inhibitors
Serotonin-norepinephrine reuptake inhibitors
5HT2 antagonists
Monoamine oxidase inhibitors

SE:
Sedation (Antihistamine
Actn)
Fatigue
Confusion
Muscarinic Rc Blockade
Orthostatic hTN (Alpha
Block)
Seizure Threshold
Sympathomimetic Effects
- Tachycardia
- Agitation
- Sweating
- Insomnia
Atropine-like Effects
Cardiomyopathy (EtOH)

Once Daily Dosing

Well Absorbed Orally
Volume of
Distribution
Not Readily
Dialyzable
Hepatic Metabolism
OVERDOSE:
Lethal on 2 Week
Supply
Agitation
Delirium
Convulsion
Coma

Peptic Ulcers Doxepin

Used 50 Years

Heterocyclics

Amoxapine

Tremor
Paresthesia
Weight Gain

Pharmacokinetics Like TCA

Varied Chemical Structures
Several w/ Diff Action Than
TCAs or SSRIs

Better Tolerated Than TCA

- Better SE Profile

NE & 5HT Reuptake

Inhibitors
DA Blocker
Metabolite of Loxapine
- Antipsychotic

Antipsychotic &
Antidepress
Properties

Dopamine Antagonism
Akathisia
Parkinsonism
AmenorrheaGalactorrhea Syndrome
Autonomic Effects

Nicotine Withdrawal

Dizziness
Seizures
Psychosis Aggravation
Low Incidence Sexual SE

Sometimes in Unrspnsve
TCA

SE:
Sedation
Less Antimuscaric Than
TCA
Less CV Effects

Cardiotoxicity
Conduction/Arrhythmi
a
Circulatory Collapse
Respiratory
Depression
Hyperpyrexia
Formerly Called
2nd/3rd
Generation
Antidepress

Like Phenothiazine

Buproprion

Unknown
Structurally Like
Amphetamine
CNS Activating Effects

Not Cause Weight Gain

Weight Loss w/ Naloxone

Maprotiline

Inhibit NE Reuptake

Seizure in Overdose
Autonomic Effects

Mirtazapine

Presynaptic Alpha 2 Rc
Antagonism

Sedative Effects
Autonomic Effects

5HT2
Antagonist
Trazadone

5HT2 Rc Antagonist

Nefazodone

Short HL = BID or TID

Added as Sleep Aid
- MOAIs Disturb Sleep

SE:
Priapism
Interactions:
Inhibits p450
Inhibit Metabolism of:
- Alprazolam

- Triazolam

SNRIs
Venlafaxine
Desvenlafaxine
Duloxetine
Milnacipran

Serotonin-Norepi Reuptake
Inhibitor

SSRIs

Selectively Inhibit
Serotonin
Transporters/ Reuptake of
the
Nerve-Ending Membrane

Depression
Chronic Pain

Endogenous Depression
- DOC
Panic Attack
OCD
Bulimia
PMS
EtOH Dependence

Serotonin Syndrome When

Combo w/ Drugs
Serotonergic Function
- MOAIs
- Triptans
- TCAs
- Meperidine

Lack Potent
Antihisatmine,
-Adrenergic Blocking,
Anticholinergic Effects of
TCA
SE:
Withdrawal Reaction
Interactions:
Venlafaxamine Inhibits
Halperidol Metabolism
CNS Stimulating, Not
Sedating
Minimal Atropine-Like
Effects
Minimal CV Effects
SE:
HA
Nausea
Anxiety
Agitation
Insomnia
Libido
Retarded Ejaculation
Seizures from Overdose
Extrapyramidal Effect
Early Tx
- Akathisia
- Dyskinesia
- Dystonic Rxns
Withdrawal Syndrome
- Nausea
- Dizziness
- Anxiety
- Tremor
- Palpitations
Bleed Risk
- Platelet 5HT Uptake
Non-Vertebral Fracture
Risk
- Older Females

Hepatic Metabolism

Interactions:
Inhibit p450=
Potentiate:
- TCAs
- Warfarin
Less Interactions w/

Citalopram
Serotonin
Syndrome

When Combo
w/Drugs
Serotonergic
Function
- MOAIs
- Triptans
- TCAs
- Meperidine
Muscle Rigidity
Myoclonus
Hyperthermia
CV Instability
Seizures
Wet Dog Shakes

Tx:
Seizure Control
Muscle Relaxants
Cyproheptadine

Fluoxetine

Prototype 5-HT Reuptake

Inhbt

Only SSRI Approved for

Child

NOT Suicide Incidence

Bulimia

Paroxetine
Citalopram
Escitalopram
Fluvoxamine
MAOIs

5-HT Reuptake Inhibitor

Category D
- Fetal Cardiac
Malformations
Prolong QT
OCD ONLY

Inhibit MAO-A & MAO-B

Atypical Depression

Phenelzine

Vesicular Stores of NE &

5HT
By Inhibiting Metabolism

Tranylcypromin
e
Isocarboxazide

Significant:
- Anxiety
- Phobia
- Hypochondriasis

Structure Like
Amphetamine

Selegliline
Emsam

Active Metabolite w/
7-9 day Half-Life
Once Daily Dosing
No Need to Taper

MAO-B Inhibitor

Major Depressive Disorder

Parkinsons + Depression

SE:
BP First THEN BP
CNS Stimulation
Serotonin Syndrome
Interactions:
Many 2/2 P450 Inhibition
HTN Crisis w/ Indirect
Sympathomimetics
- Tyramine

Fastest Onset
Shortest HL

Transdermal Patch
- Once Daily

Antipsychotics & Lithium

Neuroleptic an antipsychotic drug that produces a high incidence of EPS.
Major Tranquilizer is an archaic term
Atypical Antipsychotics newer agents that are not potent Dopamine antagonists.

Serotonin
Schizophre
nia
Hypothesis

Dopamine

Hallucinogens such as LSD and

mescaline are serotonin
agonists
5-HT2A Rc blockade is a
mechanism of
action for the atypical
antipsychotics

Dopamine
Schizophre
nia
Hypothesis

Most neuroleptics strongly block D2 Rc in meso-limbic

frontal system
Dopaminergic drugs can aggravate schizophrenia or
induce psychosis de novo
DA Rc density in brains untreated schizophrenics
postmortem exam
PET scans show DA activity in schizophrenics compared
w/ control
Successful tx shown to alter homovanillic acid in CSF and
urine

Dopamine is a major CNS neurotransmitter that binds to five types of dopamine receptors.
D1 and D5 receptors activate adenylyl cyclase and thereby cAMP levels.
D2, D3, and D4 receptors inhibit adenylyl cyclase and cAMP levels
Plays a significant role in behavioral and drug reinforcement
Regulates emesis (vomiting), prolactin release, mood states, motor coordination, and olfaction.
Degradation results in the formation of homovanillic acid (HVA), a metabolite that is subsequently excreted
in the urine.

Hypofunction of NMDA Rc on GABA interneurons diminished inhibitory influences on neuronal function

schizophrenia.
PCP and Ketamine are NMDA receptor blockers and exacerbate schizophrenia
Glutamate is the primary excitatory neuro-transmitter in the brain.

Glutamate
Schizophrenia
Hypothesis

Positive Symptoms
Excessive DA activity in
mesolimbic neuronal
pathways

Agitation
Delusions
Disorganized Speech
Disorganized Thought
Hallucinations
Insomnia

Dopamine D2 receptor
blockers
alleviate the positive
symptoms

Phenothiazines
Chlorpromazi
ne
Thioridazine

Negative Symptoms
Insufficient DA activity in
cortical &
hippocampal neuronal
pathways.

Apathy (avolition)
Affective flattening
Lack of motivation
Lack of pleasure
(anhedonia)
Poverty of speech (alogia)
Social isolation

Serotonin 5-HT2A Rc
blockers
alleviate the negative
symptoms

Thioxanthenes
Aliphatic Derivative

Thiothixene

Prototypical

Butyrophenon
es
Haloperidol

Protoypical

Piperidine
Slightly Less Potent Than Phenothiazines
These Agents More Potent & Fewer SE but
Derivative
More Extrapyramidal SE
- Retinal Deposit SE
Perphenazine Piperazine
Derivative
- Most Potent
Highly lipid soluble
Highly protein
Pharmacokinetics Significant first pass metabolism
Metabolized in the liver to inactive metabolites
bound
Renal excretion of inactive polar metabolites
Large volume of distribution
Long duration of action when compared to plasma HL
Antipsychotic activity produced (at least in part) by dopaminergic blockade in the mesolimbic and
Pharmacological
mesofrontal systems
Effects
Parkinsonian effects are produced by dopamine antagonism in the nigro-striatal system
Hyperprolactinemia caused by blockade of dopamines tonic inhibitory effect on prolactin release from the
pituitary
Changes in eating behavior caused by dopamine blockade in the medullary-periventricular pathway
Psychologic effects Nonpsychotic pts, neuroleptics cause combo of sleepiness, restlessness, and
autonomic effects
May precipitate seizures
Amenorrhea-galactorrhea, decreased libido, gynecomastia,

Orthostatic hTN more likely with low potency drugs such as Chlorpromazine

Atypical Antipsychotics
2nd Generation

More Effective Than

Typical for
Negative
Schizophrenia Sx

Clozapine

Tx Failure ONLY

Clozaril

Olanzapine
Zyprexa

Less Toxic but More

Expensive
Less Extrapyramidal Sx
than
Typical Anitpsychotics
Life Threat
Agranulocytoss 2%
Myocarditis
Hyperglycemia
Hyperlipidemia
Weight Gain

Low Affinity for D2 Rc

- Not Correlate w/
Clinical Effective
Dose

Risperidone
Risperdal

Asenapine
Saphris

Quetiapine
Seroquel
Sig QT Prolongation

Ziprasidone
Geodon

Lower Hyperlipidemia &

Hyperglycemia of 2nd
Gens

Aripiprazole
Abilify

Lurasidone
Latuda

Paliperidone
Invega

Iloperidone
Fanapt

Indications:
Typical & Atypical
Sedation
Toxicity

Schizophrenia
Schizoaffective disorder

Mania
Tourettes

Extrapyramidal
Dose Dependent
Tardive Dyskinesia
- Choreoathetoid Movements of Lips and Buccal Cavity
- Late Onset

Alzheimer's
Psychotic depression

Poikilothermy
Neuroleptic Malignant Syndrome:
- Hyper-thermia
- Muscle rigidity
- Impairment of sweating
- Autonomic instability
- Leukocytosis

Antiemetic

- Worse w/ Antimuscarinics

From excessively rapid blockade of post-synaptic DA Rc

Tx w/ antiparkinson drugs (bromocriptine) or diazepam

Acute Dystonic Reactions

- Spastic Torticollis

Muscarinic Blockade
- Atropine-like Effect

Akathisia (Uncontrolled Restlessness)

Alpha Rc Blockade
Akinesia (Pseudo-depression)
Hyperprolactinemia

Lithium

Not Well Defined

Causes Synaptic
Transmission by
Depletion 2nd Messenger IP3 &
DAG

Bipolar Affective Disorder

- Mania
- Frequency &
Amplitude
of Mood Swings

Inhibit Glycogen Synthase

Kinase-3
GSK3
- Component of Diverse
Intracellular
Signaling Pathways

Add-on for Tx of Unipolar

Depression

Alternative
Bipolar
Drugs

Carbamazepine
Clonazepam
Olanzapine

SE:
Tremor
Sedation
Ataxia
Aphasia
Thyroid Enlargement
Nephrogenic DI
Edema
Acne
Leukocytosis
Congenital Cardiac
Anomolies
Contra:
Nursing Mothers
Interactions:
Thiazides Renal Clearance
25%
- Dose Needs Reduction
NSAIDs Also Clearance
Extrapyramidal Sx w/
Antipsychotics

Rapid & Completely

Absorbed From Gut
Volume of Distribution
is
Total Body Water
- Change TBW Affect
Plasma Levels
Renally Excreted
Unchanged

Valproic Acid
Aripiprazole Abilify
Lamotrigine - Lamictal