ANTIDEPRESSANTS

Samaiya Mushtaq
CHEM 5398
DEPRESSION
 Types
 Symptoms

 Diagnosis

 Causes

 Treatment
TYPES OF DEPRESSION
 Major depression
 Chronic depression (Dysthymia)

 Atypical depression

 Bipolar disorder/Manic depression

 Seasonal depression (SAD)

SYMPTOMS
 persistently sad, anxious, or empty moods
 loss of pleasure in usual activities (anhedonia)
 feelings of helplessness, guilt, or worthlessness
 crying, hopelessness, or persistent pessimism
 fatigue or decreased energy
 loss of memory, concentration, or decision-making capability
 restlessness, irritability
 sleep disturbances
 change in appetite or weight
 physical symptoms that defy diagnosis and do not respond to treatment
(especially pain and gastrointestinal complaints)
 thoughts of suicide or death, or suicide attempts
 poor self-image or self-esteem (as illustrated, for example, by verbal
self-reproach)
DIAGNOSIS
 Extensive patient and family history
 Blood test for hypothyroidism

 Current medication

 DSM-IV
 One of the first two symptoms
 Five other symptoms
CAUSES OF DEPRESSION
 Genetics
 Death/Abuse

 Medications
TREATMENT FOR DEPRESSION
 Psychotherapy
 Electroconvulsive therapy

 Natural alternatives

 Medication
 SSRIs
 MAOIs

 TCAs

 SNRIs

 NDRIs

 TeCAs
NEUROTRANSMITTERS AND THE
CATECHOLAMINE HYPOTHESIS
 Neurotransmitters pass along signal
 Smaller amount of neurotransmitters causes depression
MONOAMINE OXIDASE (MAO) AND
DEPRESSION
 MAO catalyze deamination of intracellular monoamines
 MAO-A oxidizes epinephrine, norepinephrine, serotonin
 MAO-B oxidizes phenylethylamine
 Both oxidize dopamine nonpreferentially

 MAO transporters reuptake extracellular monoamine

MONOAMINE OXIDASE INHIBITORS
(MAOIS)
 History
 Isoniazid
 Iproniazid

 Current Drugs
 Mechanism of Action

 Side Effects Isoniazid

Iproniazid
MAOIS ON THE MARKET
 MAO Inhibitors (nonselective)
 Phenelzine (Nardil)
 Tranylcypromine (Parnate)
 Isocarboxazid (Marplan)

 MAO-B Inhibitors (selective for MAO-B)

 Selegiline (Emsam)
MAOIS MECHANISM OF ACTION
 MAO contains a
cysteinyl-linked
flavin
 MAOIs covalently
bind to N-5 of the
flavin residue of the
enzyme
MAOIS SIDE EFFECTS
MAOIS SIDE EFFECTS
 Side effects have put MAOIs in the second or third line
of defense despite superior efficacy
 MAO-A inhibitors interfere with breakdown of tyramine
 High tyramine levels cause hypertensive crisis (the “cheese
effect”)
 Can be controlled with restricted diet

 MAOIs interact with certain drugs

 Serotoninsyndrome (muscle rigidity, fever, seizures)
 Pain medications and SSRIs must be avoided
THE RECEPTOR SENSITIVITY
HYPOTHESIS
 Supersensitivity and up-regulation of post-synaptic
receptors leads to depression
 Suicidal and depressed patients have increased 5HT-α2
receptors
TRICYCLIC ANTIDEPRESSANTS (TCAS)
 History
 Imipramine

 Current Drugs
 Mechanism of Action

 Side Effects

Imipramine
TCAS ON THE MARKET
 Amitriptyline
 Desipramine (Norpramin)

 Doxepin (Sinequan)

 Imipramine (Tofranil, Tofranil-PM)

 Nortriptyline (Pamelor)

 Protriptyline (Vivactil)

 Trimipramine (Surmontil)
TCAS MECHANISM OF ACTION
 TCAs inhibit serotonin,
norepinephrine, and dopamine
transporters, slowing reuptake
 TCAs also allow for the
downregulation of post-synaptic
receptors
 All TCAs and SSRIs contain an
essential amino group that appears
to interact with Asp-98 in hSERT
TCAS SIDE EFFECTS
 Muscarinic M1 receptor antagonism - anticholinergic effects
including dry mouth, blurred vision, constipation, urinary
retention and impotence
 Histamine H1 receptor antagonism - sedation and weight gain
 Adrenergic α receptor antagonism - postural hypotension
 Direct membrane effects - reduced seizure threshold,
arrhythmia
 Serotonin 5-HT2 receptor antagonism - weight gain (and
reduced anxiety)
TCAS SIDE EFFECTS
 Nonselectivity results in greater
side effects
 TCAs can also lead to
cardiotoxicity
 IncreasedLDH leakage
 Slow cardiac conduction

 High potency can lead to mania

 Contraindicated with persons
with bipolar disorder or manic
depression
TETRACYCLIC ANTIDEPRESSANTS
(TECAS)
 Current Drugs
 Mirtazapine (Remeron)
 Mechanism of Action
 Same as TCAs
 Side Effects
SELECTIVE SEROTONIN REUPTAKE
INHIBITORS
 Most commonly prescribed class
 Current drugs

 Mechanism of action

 Side effects

Serotonin
SSRIS ON THE MARKET
 citalopram (Celexa)
 dapoxetine (Priligy)

 escitalopram (Lexapro)

 fluoxetine (Prozac)

 fluvoxamine (Luvox) Fluoxetine 1:1

 paroxetine (Paxil)

 sertraline (Zoloft)

 zimelidine (Zelmid) (discontinued)

 indalpine (Upstene) (discontinued)

Sertraline
SSRIS MECHANISM OF ACTION
 Exact mechanism remains uncertain
 Ser-438 residue in the human serotonin transporter
(hSERT) appears to be a determining factor in SSRI
potency
 Antidepressants interact directly with hSERT

 http://www.mayoclinic.com/health/antidepressants/MM0
0660
SSRIS SIDE EFFECTS
SSRIS SIDE EFFECTS
 Many disappear within 4 weeks (adaption phase)
 Side effects more manageable compared to MAOIs and
TCAs
 Sexual side effects are common

 SSRI cessation syndrome

 Brainzaps
 Sexual dysfunction
SEROTONIN-NOREPINEPHRINE
REUPTAKE INHIBITORS (SNRIS)
 Slightly greater efficacy than SSRIs
 Slightly fewer adverse effects than SSRIs

 Current drugs
 Venlafaxine (Effexor)
 Duloxetine (Cymbalta)

 Mechanism of Action
 Verysimilar to SSRIs
 Works on both neurotransmitters
Venlafaxine 1:1
 Side effects Duloxetine
 Similar to SSRIs
 Suicide
NOREPINEPHRINE-DOPAMINE
REUPTAKE INHIBITORS (NDRIS)
 Current drugs
 Bupropion (Wellbutrin)
 Mechanims of Action
 Similarto SSRIs and SNRIs
 More potent in inhibiting dopamine
 Also anα3-β4 nicotinic antagonist
Bupropion 1:1
 Adverse effects
 Lowers seizure threshold
 Suicide
 Does not cause weight gain or sexual dysfunction (even used
to treat the two)
ASSIGNED READING
 An Introduction to Medicinal Chemistry, by Graham L.
Patrick, Chapter 20, pp. 593-8.
 Kelly, John. Novel therapeutic targets for the treatment
of depression. Current Medicinal Chemistry: Central
Nervous System Agents (2003), 3(4), 311-322.

Optional Reading:

Wong, David T.; Perry, Kenneth W.; Bymaster, Frank P. Case

History: The Discovery of Fluoxetine Hydrochloride (Prozac).
Nature Reviews Drug Discovery (2005), 4(9), 764-774.

Krishnan, K. Ranga. Revisiting monoamine oxidase inhibitors.

Journal of Clinical Psychiatry (Memphis, TN, United States)
(2007), 68(Suppl. 8), 35-41.
 HOMEWORK QUESTIONS
1. Many of the medications to treat depression are thought to involve systems utilizing
the monoamine neurotransmitters, noradrenaline, dopamine, and serotonin (5-HT).
Draw the structures of these neurotransmitters. Why are they called monoamines?
Illustrate their structural resemblance to one another.
2. Monoamine oxidase inhibitors (MAOIs) increase CNS synaptic concentrations of
these monoamines by inhibiting an enzyme responsible for their degradation. Draw
the reaction scheme for the biological degradation of noradrenaline by monoamine
oxidase.
3. Illustrate how the TCAs and SSRIs might resemble the monoamine neurotransmitters,
providing one example of each class of antidepressant.
REFERENCES
 http://ajp.psychiatryonline.org/cgi/reprint/157/11/1901
 http://www.webmd.com/depression/
 http://pn.psychiatryonline.org/content/41/24/21.full
 http://www.mayoclinic.com/health/maois/MH00072
 http://www.springerlink.com/content/b9b8668ff59f89d7/fulltext.pdf
 http://www.emsam.com/pi_emsam.pdf
 http://www.nevdgp.org.au/info/topics/depression_theory.htm
 http://www.uspharmacist.com/content/t/psychotropic_disorders/c/11467/
 http://www.jbc.org/content/284/15/10276.full.pdf+html
 http://www.aafp.org/afp/981200ap/cadieux.html
 http://www.mayoclinic.com/health/antidepressants/MH00071
 http://books.google.com/books?
id=R0W1ErpsQpkC&pg=PA565&lpg=PA565&dq=tcas+mechanism+of+action&source=bl&ots=oASle2Z-
pr&sig=36CB_3JY4uD3LIYvqXWmAb3nliY&hl=en&ei=HzfFS9OrB4Tu9gTD6_ixDg&sa=X&oi=book_result&
ct=result&resnum=8&ved=0CCoQ6AEwBw#v=onepage&q=tcas%20mechanism%20of%20action&f=false
 http://www.informaworld.com/smpp/content~content=a916036122&db=all