antidepressants samaiya mushtaq chem 5398. depression types symptoms diagnosis causes treatment

ANTIDEPRESSANTSSamaiya 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 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 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