1.  Tracy A. Womble, Ph.D  Florida A&M University College of Pharmacy and Pharmaceutical Sciences The Pharmacology of Major Depressive Disorder (MDD)

2. Types of Depression  Major Depression  Most serious, down mood, lasts week-months, lack of interest in sex,loss of appetite  Dysthymia  Less severe, each episode may last for years  Bipolar Disorder  Down /up, manic depressive  Seasonal Affective Disorder (SAD)  Seasonal depression, occurs in winter, pattern of down moods  Postpartum Depression  Hormonal changes following delivery, more severe than baby blues 

3. Manic Depression (Bi-polar Disorder)  Bipolar disorder (manic-depressive disorder) causes mood swings that range from the lows of depression to the highs of mania.

4. Major Depressive Disorder  Depression is defined as intense feelings of sadness, mental slowing, hoplessness, despair, pessimistic worry, agitation, self-deprecation and inability to experience pleasure during usual activities

5. Mania Core Symptoms:  characterized by an elevated “high” mood.  Talkative, go on-and-on about the things they will do.  Increased self-esteem.  Auditory hallucinations.  Decrease need to sleep.  Lack judgement, indiscrete.  SuperME

6. Pathophysiology of Depression  Monoamine Hypothesis  Deficit in amount of monoamines in the CNS, Norepinephrine (NE) Serotonin (5-HT) and Dopamine  Neurotrophic Hypothesis  NGF (BDNF) critical to neural plasticity, resilience and neurogenesis  Abnormalities in HPA in MDD pt’s, also associated with elevated cortisol levels  Neuroedndocrine factors  Thyroid dysregulation also found in depressed patients.  Estrogen deficiency in postpartum and postmenopausal periods

7. Antidepressant (Thymoleptic) Drugs  Tricyclic/Polycyclic (TCA)  Antagonize NE, 5-HT reuptake  Selective Serotonin Reuptake Inhibitors (SSRIs)  Antagonize 5-HT reuptake only  Monoamine Oxidase Inhibitors (MAOI’s)  Inhibit degrading enzyme of NE, 5-HT and DA  Drugs used to treat Mania

8. Tricyclic Antidepressants  Characteristic three-ring structure  Used for almost 4 decades  Block NE and 5-HT reuptake  Prolonged therapy may result in alterations in selected CNS receptors.  Most all admin PO (some injectables)  Onset of action – 2 wks  Can not be used with MAOI’s  No food interactions  Drug of choice depends on tolerance of s/e, DOA  Prototype drugs of this class are imipramine, and amitriptyline  Antagonize following receptors; 5-HT (presynaptic), α- adrenergic, histamine and muscarinic.

10. Antidepressants  TCA’s Imipramine (Tofranil), Amitriptyline (Elavil), Desipramine (Norpramin), Nortriptyline (Pamelor), Protriptyline (Vivactyl), Doxepin (Sinequan)  5HT 2 antagonists  Trazodone (Desyrel), Nefazodone (Serzone)  SSRIs  Sertraline (Zoloft), Paroxetine (Paxil), Fluoxetine (Prozac)  SNRIs  Duloxetine (Cymbalta), Venlafaxine, (Effexor)  MAOI’s  Isocarboxazid, Phenelzine, Tranylcypromine, Selegiline, Moclobemide  Tetracyclics and Unicyclics  Amoxapine, Bupropion (Wellbutrin), Maprotiline, Mirtazapine

11. TCA’s (cont’)  Mode of action – inhibit NE and 5HT reuptake into presynaptic nerve terminal  Actions – elevate mood (unseen in normal), improve mental alertness, increase physical activity, req. 2 wks, no CNS stimulation  Therapeutic uses – severe depression, some panic disorders, bed-wetting in children (Imipramine), used cautiously b/c of cardiac arrhythmias.  Pharmacokinetics – well absorbed PO, lipophilic, penetrate CNS, b/c of lipophilic nature have long half-lives (Imipramine -4-17 hrs.)

12. TCA’s (cont’) Adverse affects  Antimuscarinic – blockade of Achr – blurred vision, xerostomia, urinary retention, constipation and aggravation of glaucoma and epilepsy. (differ from MAOI’s)  Cardiovascular – inc. catecholamine activity – cardiac overstimulation, slowing of AV conduction in depressed elderly pts., MI, arrhythmias, CHF.  Orthostatic hypotension – block α-adrenergic receptors orthostatic hypo and reflex tachycardia.  Sedation  Precaution – may unmask manic behavior, narrow TI (5-6 times are lethal)  Toxicity – Tachycardia, arrhythmias, hypotension, CNS stim., delusions, hallucinations, convulsions, hyperreflexia, tremors  Drugs used for toxicity – Diazepam, vasopressors, lidocaine, physostigmine (i.v.)

13. Overdose of TCA’s  No specific antidote  Decrease drug absorption with activated charcoal  Speed elimination by alkalinizing urine  Sodium Bicarbonate  Manage seizures and dysrhythmias  Lidocaine, propranolol, phenytoin  Basic life support

14. MAO Inhibitors  Developed for the treatment of tuberculosis (iproniazid derivatives) - 1951.  These drugs are not widely used today, although a small number of patients appear to do better in MAOIs than TCAs or the newer drugs.  Are readily absorbed from GI tract and widely distributed throughout the body.  Effects persist even after these drugs are no longer detectable in plasma (1-3 weeks).

15. Monoamine Oxidase Inhibitors  Inhibit MAO and cause accumulation of 5- HT, NE and DA in CNS and Periphery  A mitochondrial enzyme found in neural and other tissue such as gut and liver.  In neuron, serves to oxidatively deaminate and inactivate excess NT leaking out of synaptic vesicles when at rest.  MAOI’s may reversibly or irreversibly inactivate enzyme  Use is limited due to dietary restrictions  Onset time and time to wear off – 2 wks  Irreversible - Phenelzine (Nardil), Isocarboxazid (Marplan)  [MAO-A]  Reversible [MAO-B]- Tranylcypromine (Parnate), Selegiline (Deprenyl)  [MAO-A] - Moclobemide

16. Monoamine Oxidase Inhibitors  Prolong action of drugs metabolized by MAO and hepatic metabolic P450  Contraindicated in pts. Using TCA’s  Food containing tyramine (indirect sympathomimetic) metab of tyrosine normally inactivated in gut.  Tyramine causes release of stored catecholamines – h/a, tachycardia, nausea, hypertension, cardiac arrhythmias and stroke.  Beer, wine, cheese, chicken liver, avacodos, chocolate bananas  Should not be used with SSRI’s – life-threatening serotonin syndrome. (req. washout period of 6 wks.)  s/e – CNS stim., restlessness, anxiety, tremors, ortho. Hypotension ( due to mild α-blockade)

17. MAO Inhibitors Negative drug interactions with: Any drug metabolized by MAOs * including SSRIs, TCAs and meperidine, alcohol, CNS depressants, sympathomimetics, phenylephrine (O/C nasal decongestants), ampetamines, and other indirect-acting adrenergic drugs.

18. Wine-and-Cheese Reaction - Fatal interaction with tyramine- containing foods (fermented foods in particular, such as wine and cheese). -  MAO-A =>  Tyramine in the body =>  NE in circulation => induces hypertensive crisis => can lead to intracranial bleeding and other organ damage.

19. MAOI Toxicity  Symptoms appear 12 hours after ingestion  Tachycardia, circulatory collapse, seizures, coma  Treatment: protect brain and heart, eliminate toxin  Gastric lavage  Urine acidification  Hemodialysis

20. Selective Serotonin Reuptake Inhibitors (SSRI’s)  Do not affect reuptake of NE  Decreased incidence of anticholinergic and adrenergic action of TCA’s.  All admin. PO  May interfere with P450 metabolism of other drugs (enzymes responsible for metabolism of TCA’s)

21. Selective Serotonin Reuptake Inhibitors (SSRI’s)  Most widely prescribed drugs for depression.  They have few side effects and seem to be rather safe. More rational prescribing and better patient compliance.  Adverse effects include: nausea, decreased libido,anorexia, anxiety, insomnia, tremors, sleepiness, sweating  Low threat for overdose.

22. SSRI’s  Fluoxetine (Prozac) - Mental depression, OCD, Bulemia  Citalopram (Celexa) – mental depression  Fluvoxamine (Luvox) - OCD  Paroxetine (Paxil) – mental depression, panic disorder, OCD  Sertraline (Zoloft) - Mental depression  Cymbalta (Duloxetine) – inhibits both 5-HT and NE reuptake  Celexa (Citalopram) – one of first, Cl derivative, high incidence of Anticholinergic effects, no adrenergic side effects (no inhibition of NE reuptake), high incidence of seizures

23. SSRI’s Drug-drug interactions: dangerous with other antidepressant drugs, MAOIs in particular. ”Serotonin Syndrome”:  hyperthermia, muscle rigidity, myoclonus, rapid changes in mental status and vital signs. Thus it is important to wait up to 6 weeks after medication is stopped, before starting with another drug.

24. Anti-manic drugs Lithium (Li + ) is no longer the universal drug of choice for the manic state of Bipolar disorder. valproate, olanzapine, risperidone, carbamezepmine, valproic acid  Acute manic episodes are managed with lithium salts (carbonate or citrate) alone, or in combination with: 1) Antipsychotics (carbamazepine, similar in structure to TCAs but not effective in depression). 2) Valproic acid 3) Calcium-channel blockers (nifendipine, diltiazem, verapamil).

25. Anti-manic drugs Li +  Small monovalent cation (between H + and Na + ).  Distributed in total body water, similar to sodium.  May partially inhibit Na + -K + ATPase.  Inhibits ADH => diuresis.  May decrease thyroid function.  Teratogenic (tricuspid valve malformation).  Excreted by kidney.

26. Anti-manic drugs  Not to be taken with thiazide diuretics (e.g. chlorthiazide).  Lithium clearance is reduced by 25%.

27. Anti-manic drugs  Helps alleviate the manic phase of bipolar illness.  May be used in conjunction with SSRIs or TCAs, but not a good antidepressant alone.  No effect on normal individuals  TI is extremely low,

28. Anti-manic drugs Valproic Acid A well known antiepileptic has been found to have antimanic effects. May be used as first line treatment for mania, although it may not be as effective in maintenance treatment as lithium for some patients. Mechanism of action: ???

29. Anti-manic drugs Carbamazepine Effective as an antimania medication Mechanism of action May be due to decrease overexcitability of neurons (anticonvulsive effect).

30. Conclusion  Main similarities and differences, which explain why SSRIs are more commonly prescribed than TCAs in the treatment for depression:  SSRIs and TCAs have similar efficacy for the treatment of depression  SSRIs have fewer anticholinergic and cardiovascular side effects  TCA have fewer sexual and gastrointestinal side effects  SSRIs are better tolerated by patients  SSRIs are safer in overdose than TCAs