MDD and Clinical Pharmacology of Antidepressants

major depression = ___

unipolar depression

Manic Depression= _____

bipolar depression

what is a major depressive episode?

1. depressed mood or loss of interest or pleasure

2. sleep disturbances

3. changes in appetite and weight

4. decreased energy or fatigue

5. difficulty concentrating, making decisions

6. psychomotor agitation or retardation

7. thoughts of suicide, attempt or plan 

what are the DSM-5 criteria for MDD?

** 5 (or more) of the following symptoms must have been present during the same 2 week period and represent a change from previous functioning; at least 1 of the symptoms is either

1. depressed mood

2. loss of interest or pleasure 

3. weight/appetite changes

4. insomnia or hypersomnia

5. psychomotor agitation/retardation

6. fatigue/loss of energy

7. feelings of guilt/worthlessness

8. diminished concentration or indecisiveness

9. suicidal ideation/attempt 

what are chronic diseases associated with major depressive disorder?

1. heart disease

2. cancer

3. chronic lung disease

4. stroke

5. alzheimer’s disease

6. diabetes

7. CKD

what are major causes of depression?

1. HPA axis dysfunction - dysregulation of hypothalamic pituitary adrenal axis leads to elevated levels of cortisol and suppression of neurogenesis

2. Neurotrophic hypothesis - decreased levels of nerve growth factors (BDNF) leads to diminished neurogenesis and cortical atrophy

3. Monoamine hypothesis - depression is caused by functional deficit in monoamine neurotransmission (mania is the result of functional effects)

4. inflammation

5. decrease neuroplasticity

6. decrease neurogenesis

7. increase in oxidative stress

8. atrophy of the hippocampus

9. decrease in BDNF

10. decrease serotonin, noradrenaline, dopamine

what are evidence for monoamine hypothesis of depression?

1. reserpine (an old anti-hypertensive that blocks vesicular storage of monoamines) precipitates depression

2. Iproniazid (an old anti-tuberculosis drug that inhibits MAOs) has antidepressant properties. Isoniazid is the new anti-TB agent

3. Tryptophan - (the precursor for serotonin) deprivation precipitates depressive episodes in patients with h/o depression 

5-HT is implicated in?

1. mood

2. memory

3. sleep

4. cognition

Noradrenaline is implicated in?

1. arousal/alertness/sleep

2. memory

3. mood

4. attention

5. fight/flight

dopamine is indicated in?

1. decision making

2. planning

3. abstract reasoning

4. fine motor control

5. reward/motivation

6. prolactin serotonin 

SSRIs drugs for antidepressants

1. citalopram (celexa)

2. escitalopram (lexapro)

3. fluoxetine (prozac)

4. paroxetine (paxil)

5. sertraline (zoloft)

SNRIs drugs for antidepressant

1. desvenlafaxine (pristiq)

2. duloxetine (cymbalta)

3. levomilnacipran (fetzima)

4. venlafaxine (effexor)

atypical drugs for antidepressant

1. bupropion (wellbutrin)

2. mirtazapine (remeron)

serotonin modulators as an antidepressant?

1. trazodone

2. vilazodone (vilbryd)

3. vortioxetine (trintellix)

TCAs as antidepressant drugs?

1. amitriptyline

2. dexepin (silenor)

3. desipramine (norpramine)

4. impiramine

5. nortriptyline (pamelor)

MAOIs as an antidepressant?

1. isocarboxazid (marplan)

2. selegiline patch (emsam)

3. tranylcypromine (parnate)

4. phenelzine (nardil)

antidepressant drugs carry a boxed warning of?

increased suicidal thoughts and attempted suicides in children and adolescents 

what are the clinical uses and ADRs for SSRIs?

clinical uses: MDD, GAD, OCD, PD, PTSD, PMDD

ADRs: N/V, diarrhea, insomnia, loss of libido, anorgasmia's, diaphoresis

• less dangerous than TCAs in OD

• as effective as TCAs for mild-moderate depression and MOAi’s but

• less than TCAs for severe depression

what is serotonin syndrome?

1. restlessness

2. hallucinations

3. loss of coordination

4. fast heartbeat

5. increased body temperature

6. overactive reflexes

7. n/v

8. diarrhea

9. rapid changes in BP

clinical uses and ADRs for SNRIs?

clinical uses: MDD, GAD, SAD, PD

ADRs: fatigue, n/v, constipation, xerostomia, decreased libido, ED (male); anorgasmia (female); sustained, elevated BP and pulse rate

clinical pharmacology of trazodone (MOA, clinical uses, ADRs)?

• MOA - potent 5-HT2R block, weaker block of 5-HT reuptake; partial agonist at 5-HT1A Rs

• Uses - antidepressant, anxiolytic, and antipsychotic actions

• ADRs - orthostatic hypotension and reflex tachycardia (alpha 1 receptor block); sedation (H1 R block); priapism

clinical pharmacology of bupropion (MOA, clinical uses, ADRs)

• MOA - weak block of DA and NE reuptake; antagonist of nAChRs

• clinical uses - antidepressant and smoking cessation

• ADRs - lowers seizure threshold with higher doses, agitation (not associated with sexual side effects)

clinical uses of Mirtazapine (MOA, clinical uses, ADRs)?

• MOA - 5-HT2, 5-HT3, and alpha-2 receptor antagonist (results in enhanced NA and 5HT transmission)

• clinical uses - antidepressant; anxiolytic

• ADR - somnolence (probably H1 R block), increase appetite and weight gain

clinical pharmacology of vilazodone and vortioxetine (MOA, clinical uses, ADRs)

• MOA - 5-HT reuptake blk; 5HT1A R partial agonists 

• clinical uses - MDD

• ADR - n/v, diarrhea, sexual dysfunction (vortioxetine, less with vilazodone) 

Tricyclic and Polycyclic (1st generation Thymoleptics) - pharmacology?

1. Amitriptyline (elavil)

2. desipramine (norpramin)

3. doxepin (sinequan)

4. imipramine (tofranil)

5. nortriptyline (pamelor)

6. protriptyline (vivactil)

7. trimipramine (surmontil)

• non selective inhibitors of monoamine reuptake

• lead to increased levels of monoamine synapse

• synthesis, storage and release are not affected

• require 2-4 weeks for antidepressant action

clinical pharmacology of TCAs?

ADRs:

• confusion and sedation (H1-R block)

• dry mouth, blurred vision, constipation, cardiac dysrhythmias, urinary retention (mAChR block)

• postural hypotension (alpha1-R block) - a serious problem in elderly patients

• cardiac arrhythmias (inhibition of Na+ channels and Na/K-ATPase

• some of these unwanted effects can wear off in 1-2 weeks 

clinical pharmacology of MAOi

1. phenalzine

2. tranylcpromine

3. isocarboxazid

4. selegiline

clinical use - pts refractory to SSRI and TCAs

pharmacology - inhibit MAOa and MAOb leads to potentiation of aminergic transmission

ADRs - elevated BP and in combination with certain other drugs or foods leads to hypertensive crisis

foods to avoid with MAOIs?

High Tyramine foods and beverages:

1. meat - Beef liver, chicken liver, fermented sausages (pepperoni and salami) bacon, hot dogs, corned

beef, and luncheon meats. Bouillon cubes or broth made with meat extracts. Soy-based meat

alternatives.

2. fish - Caviar, cured fish, dried or pickled herring, and anything that contains shrimp paste.

3. milk - aged, mature, or hard cheeses

4. produce - overripe fruits, dried fruit, avocados, banana peels, fava beans, italian green beans, edamame, snow peas and canned figs

5. alcohol

6. yeasts

7. pickled or fermented products

8. desserts - coffee (limited amount)

zuranolone - zurzuvae pharmacology

1. clinical use - 1st oral treatment for postpartum depression

2. MOA - neuroactive steroid GABA-A receptor positive modulator

3. ADRs - drowsiness, fatigue, nasopharyngitis, UT infection; suicidal thoughts

4. BW: driving impairment 

gepirone - exxua

1. clinical use - MDD in adults

2. MOA - selective 5HT1A receptor agonist

3. ADRs - dizziness, nausea, insomnia, abdominal pain, dyspepsia

4. BW - risk of suicidal thoughts

other antidepressant treatments?

1. diet

2. sleep

3. psychotherapy

4. ECT and TMS

5. esketamine (spravato) - NMDA channel inhibitor

6. Auvelity - dextromethorphan (NMDA channel inhibitor) and bupropion

other ways to reduce risk of low mood?

1. challenge negative thoughts

2. talk to someone

3. stay active

4. practice relaxation

5. get outside

6. do things you enjoy

7. avoid alcohol and drugs