ANTIDEPRESSANTS Samaiya Mushtaq CHEM 5398. DEPRESSION Types Symptoms Diagnosis Causes Treatment.
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Transcript of 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