ANTIDEPRESSANTSSamaiya MushtaqCHEM 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 Serotonin syndrome (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 Increased LDH 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) paroxetine (Paxil) sertraline (Zoloft) zimelidine (Zelmid) (discontinued) indalpine (Upstene) (discontinued)

Fluoxetine 1:1

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/antidepres

sants/MM00660

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

Brain zaps 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 Very similar to SSRIs Works on both neurotransmitters

Side effects Similar to SSRIs Suicide

Venlafaxine 1:1Duloxetine

NOREPINEPHRINE-DOPAMINE REUPTAKE INHIBITORS (NDRIS) Current drugs

Bupropion (Wellbutrin) Mechanims of Action

Similar to SSRIs and SNRIs More potent in inhibiting dopamine Also anα3-β4 nicotinic antagonist

Adverse effects Lowers seizure threshold Suicide Does not cause weight gain or sexual

dysfunction (even used to treat the two)

Bupropion 1:1

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 QUESTIONS1. 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?

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