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)
5. DIAGNOSIS
Extensive patient and family history
Blood test for hypothyroidism
Current medication
DSM-IV
One of the first two symptoms
Five other symptoms
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
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
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
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
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
http://www.mayoclinic.com/health/antidepressants/
MM00660
26. SSRIS SIDE EFFECTS
Anhedonia
Apathy
Nausea/vomiting
Drowsiness or
somnolence
Headache
Bruxism (involuntarily
grinding of the teeth)
Extremely vivid and
strange dreams
Dizziness
Fatigue
Changes in sexual
behavior
Suicidal thoughts
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
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 1:1
Duloxetine
29.
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
31. 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.
32. 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.
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.
MUST HAVE one of the top two
AT LEAST five of the other symptoms
Nearly DAILY
For at least TWO WEEKS
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
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
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
Both early drugs developed in sixties for anti tuberculosis but found to have antidepressant effects, got off market due to toxicity
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
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.
Bold ones are most common
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
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
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
Less selective in which cells they target, will prevent serotonin, norepinephrine, and dopamine reuptake
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
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
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.
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
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.
