1. ANTIDEPRESSANTS
Samaiya Mushtaq
CHEM 5398

2. DEPRESSION
Types
Symptoms
Diagnosis
Causes
Treatment

3. TYPES OF DEPRESSION Major depression Chronic depression (Dysthymia)
Atypical depression
Bipolar disorder/Manic depression
Seasonal depression (SAD)
Major depression – recurring and disabling. Symptoms must last for at least two weeks and impair one’s ability to interfere with a person's ability to work, sleep, study, eat, and enjoy once-pleasurable activities.
Chronic depression – less disabling than major depression, but symptoms can last longer, sometimes being unhappy for two years. More common in women, affects 10.9 million people.
Atypical depression, rather than the other two, is characterized less by pervasive sadness and more by overeating, oversleeping, sensitivty to rejection
Bipolar/manic depression oscillates between major depression and epsidoes of mania (extreme elation), Bipolar I – episode of mania with or without depression. Bipolar II – episode of depression with episode of hypomania or mania.
Seasonal depression (SAD) – often occurs wehre winters are short or there is a big change in the amount of sunlgiht, and often treated with light therapy.

4. 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)
MUST HAVE one of the top two
AT LEAST five of the other symptoms
Nearly DAILY
For at least TWO WEEKS

5. DIAGNOSIS Extensive patient and family history
Blood test for hypothyroidism
Current medication
DSM-IV
One of the first two symptoms
Five other symptoms
Doctor will ask many questions about personal mood, new behaviors, changes in routine
Check blood and current drugs to rule out other factors (hypothyroidism, drug side effects)
Drugs like antihypertensives, oral contraceptives, and Accutane for acne can cause depression
BIG THING IS DISRUPTION IN FUNCTIONING

6. CAUSES OF DEPRESSION
Genetics
Death/Abuse
Medications

7. TREATMENT FOR DEPRESSION
Psychotherapy
Electroconvulsive therapy
Natural alternatives
Medication
SSRIs
MAOIs
TCAs
SNRIs
NDRIs
TeCAs
Psycotherapy/talk therapy – especially useful when combined with meds. Goal is to teach good coping skills for every day stressors
ECT – electric shock is applied to scalp through electrodes, results in seizure in the brain. Fast and effecitve in patients with depression or suicidal thoughts (good for suicide bc doesn’t have the same delayed onset as meds). Usually given up to three times a week for two to four weeks
Natural alternatives – St. John’s wort (sold in teas and tablets, and in diet pills) not good for severe depression but can help mild depression

8. NEUROTRANSMITTERS AND THE CATECHOLAMINE HYPOTHESIS
Neurotransmitters pass along signal
Smaller amount of neurotransmitters causes depression
SYNAPSE:
Neurotransmitter passes along synapse from inside storage vesicles through transporters in the presynaptic cell to receptors in the post synaptic cell.
Monoamine hypohtesis suggests that small amount of neurotransmitter causes depression

9. 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

10. MONOAMINE OXIDASE INHIBITORS (MAOIS)
History
Isoniazid
Iproniazid
Current Drugs
Mechanism of Action
Side Effects
Isoniazid
Both early drugs developed in sixties for anti tuberculosis but found to have antidepressant effects, got off market due to toxicity
Iproniazid

11. MAOIS ON THE MARKET MAO Inhibitors (nonselective)
Phenelzine (Nardil)
Tranylcypromine (Parnate)
Isocarboxazid (Marplan)
MAO-B Inhibitors (selective for MAO-B)
Selegiline (Emsam)
Phenelzine – major depression
Tranylcypromine – major depression
Isocarboxazid – major depression
Selegiline – comeback of MAOI (MAO-B inhibitor, more selective, loses selectivity at high doses) because no side effects from diet.
Used primarily for treatment for Parkinson’s disease (also approved for major depression) – shows significant improvenemnt when taken with L-DOPA

12. MAOIS MECHANISM OF ACTION
MAO contains a cysteinyl-linked flavin
MAOIs covalently bind to N-5 of the flavin residue of the enzyme
MAOIs bind to the N-5 of the flavin residue if MAO, which prevents MAO from catalyzing the oxidative deamination of the monoamine, increasing their intracellular concentration so more can be released.

14. MAOIS SIDE EFFECTS Drowsiness/Fatigue Muscle twitching Constipation
Weight gain
Nausea
Blurred vision
Diarrhea
Headache
Dizziness
Increased appetite
Low blood pressure
Restlessness
Lightheadedness,
Shakiness
Decreased urine output
Weakness
Decreased sexual function
Increased sweating
Sleep disturbances
Bold ones are most common

15. 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
Major side effects have kept MAOI use limitied
HUGE PITFALL IS DIETARY RESTRICTION
Must avoid foods with high levels of tyramine like avocados, bananas, aged cheese, certain meats and wines
This is however not seen with selegiline because that is a MAO-B inhibitor, and since tyramine displaces NOREPINEPHRINE from storage vesicles, it effects MAO-A more
Serotonin syndrome is caused by drug interactions with herbal weight loss supplement (St John’s wort) and SSRIs and Pain meds like tramadol and meperidine

16. THE RECEPTOR SENSITIVITY HYPOTHESIS
Supersensitivity and up-regulation of post- synaptic receptors leads to depression
Suicidal and depressed patients have increased 5HT-α2 receptors

17. TRICYCLIC ANTIDEPRESSANTS (TCAS)
History
Imipramine
Current Drugs
Mechanism of Action
Side Effects
Imipramine was first tried as an antipsychoti drug for schizophrenia, proved to be insufficient but proved to have antidepressant qualities, in the 50s around the same time as MAOIs.
Imipramine is very good for severe depression, but it’s almost too good – also causes hypomania and mania
Imipramine

18. TCAS ON THE MARKET Amitriptyline Desipramine (Norpramin)
Doxepin (Sinequan)
Imipramine (Tofranil, Tofranil-PM)
Nortriptyline (Pamelor)
Protriptyline (Vivactil)
Trimipramine (Surmontil)
Side effects have made them second line of defense to SSRIs but they are good for treatment resistant depression bc they are so strong.
Amitriptyline – most widely used, most effectve
Desipramine – active metabolite of imipramine, used for neuropathic pain
Doxepin – used for depression and insomnia
Imipramine – used for major depression and enuresis
Nortriptyline – same thing
Protriptyline – depression UNIQUE BECAUSE IT IS ENERGIZING rather than sedating
Trimipramine – depression, insomnia, and pain

19. 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
Less selective in which cells they target, will prevent serotonin, norepinephrine, and dopamine reuptake

20. 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)

21. 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

22. TETRACYCLIC ANTIDEPRESSANTS (TECAS)
Current Drugs
Mirtazapine (Remeron)
Mechanism of Action
Same as TCAs
Side Effects

23. SELECTIVE SEROTONIN REUPTAKE INHIBITORS
Most commonly prescribed class
Current drugs
Mechanism of action
Side effects
Serotonin
Also first rationally designed drug class, up until the 70s the antidepressants were sort of found by accident
Serotonin is also referred to as 5-hydroxytryptamine

24. 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
More trade names once patent is over but I kept original trade names
Citalopram: Major depression
Dapoxetine: Premature Ejaculation
Escitalopram: Major depression and various other anxiety disorders
Fluxoetine: Major depression, OCD, bulimia, etc
Fluvoxamine: OCD
Paroxetine: Major depression or anxiety
Sertraline: Major depression or anxiety
Zimelidine had neurological problems like Guillan Barre
Indalpine had problems with fetal low WBC
Sertraline

25. 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
s/MM00660
The drug binds in the residue to prevent the presynaptic serotonin transporter from reuptaking the serotonin neurotransmitter.
This increases extracellular concentration of serotonin, allowing more messages to be passed along.
Over time, this also leads to the downregulation of the postsynaptic receptors so they are fewer and less sensitive, so they more transmittance.

26. SSRIS SIDE EFFECTS Anhedonia Fatigue Apathy Changes in sexual behavior
Nausea/vomiting
Suicidal thoughts
Drowsiness or somnolence
Headache
Bruxism (involuntarily grinding of the teeth)
Extremely vivid and strange dreams
Dizziness

27. 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
Many side effects go away onec the body gets used to the drug because the drug takes sometime tos tart working
Sexual side effects are common (ED, low libido) due to stimuatlion of 5-HT2 receptors leading to less release of dopamine

28. 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 is a racemix mixture
While SSRIs are less potent than the other classes of drugs, they have more manageable side effects so they’re considered better
The mechanism is similar to SSRIs, as are the side effects. However, the rate of suicide for SNRIs has been debateable, especially venlafaxine.
Finnish study showed Ven increased suicide risk 1.6 times compared to no treatment while Fluoxetine halved it.
FDA study showed 5-fold increase in <25 so it is contraindicated in adolescents.
Venlafaxine 1:1
Duloxetine

30. 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
Bupropion is a racemic mixture

31. ASSIGNED READING
An Introduction to Medicinal Chemistry, by Graham L. Patrick, Chapter 20, pp
Kelly, John. Novel therapeutic targets for the treatment of depression. Current Medicinal Chemistry: Central Nervous System Agents (2003), 3(4),
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),
Krishnan, K. Ranga. Revisiting monoamine oxidase inhibitors. Journal of Clinical Psychiatry (Memphis, TN, United States) (2007), 68(Suppl. 8),

32. HOMEWORK QUESTIONS
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.
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.
Illustrate how the TCAs and SSRIs might resemble the monoamine neurotransmitters, providing one example of each class of antidepressant.

33. REFERENCES http://ajp.psychiatryonline.org/cgi/reprint/157/11/1901
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