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.
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
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 Serotoninsyndrome (muscle rigidity, fever, seizures) Pain medications and SSRIs must be avoided
THE RECEPTOR SENSITIVITYHYPOTHESIS 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 REUPTAKEINHIBITORS Most commonly prescribed class Current drugs Mechanism of action Side effects Serotonin
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/MM0066
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 Brainzaps Sexual dysfunction
SEROTONIN-NOREPINEPHRINEREUPTAKE INHIBITORS (SNRIS) Slightly greater efficacy than SSRIs Slightly fewer adverse effects than SSRIs Current drugs Venlafaxine (Effexor) Duloxetine (Cymbalta) Mechanism of Action Verysimilar to SSRIs Works on both neurotransmitters Venlafaxine 1:1 Side effects Duloxetine Similar to SSRIs Suicide
NOREPINEPHRINE-DOPAMINEREUPTAKE INHIBITORS (NDRIS) Current drugs Bupropion (Wellbutrin) Mechanims of Action Similar to SSRIs and SNRIs More potent in inhibiting dopamine Also anα3-β4 nicotinic antagonist Bupropion 1:1 Adverse effects Lowers seizure threshold Suicide Does not cause weight gain or sexual dysfunction (even used to treat the two)
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. CaseHistory: 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.