The Pharmacology of Antidepressants Tracy Womble, Ph.D Florida A&M University, College of Pharmacy and Pharmaceutical Sciences Dept. Of Neuroscience

Objectives  What is depression  Pathophysiology of Depression  History  Classes  Pharmacology  Therapeutic use  Mechanism of action  pharmacokinetics  Adverse effects  toxicity

Depression  Depression is defined as intense feelings of sadness, mental slowing, hoplesness, despair, pessimistic worry, agitation, self-deprecation and inability to experience pleasure during usual activities

 Neurological disorder  Prolonged depression of mood and impairment of function  Causes include genetic predisposition, grief following the death of a loved one, abuse, major life changes, serious illness, personal disputes, and substance abuse  Complex illness with many contributing factors  Exact biological causes are not yet fully understood What is depression?

 Major Depressive Disorder  Symptoms interfere with ability to function normally  10% of people in the US suffer at any one time  2x more women are diagnosed than men  Chronic (Dysthymia)  Less severe, but symptoms linger for longer  Seasonal Affective Disorder (SAD)  Psychotic  Postpartum Types of Depression

Manic Depression  Mania is characterized by opposing behavior to depression; enthusiasim, rapid thought and speech patterns, extreme self-confidence and impaired judgement, and elevated “high” mood.  Talkative, go on-and-on about the things they will do.  Increased self-esteem.  Auditory hallucinations.  Decrease need to sleep.  indiscrete  SuperME

Pathophysiology of Depression  Biogenic amine Hypothesis  Neurotrophic Hypothesis  Neuroendocrine Factors

Biogenic Amine Hypothesis  Depression and mania are due to an alteration in neuronal and synaptic catecholamine concentration at adrenergic receptor sites in the brain  Depression: deficiency of biogenic amines ( NE, 5-HT)  Mania: excess amines (NE, 5-HT)

Neurotrophic Hypothesis  Loss of neurotrophic support or NGF’s  BDNF (brain-derived neurotrophic factor)  regulation of neural plasticity, resilience and neurogenesis.  Effective therapies increase neurogenesis and synaptic connectivity in cortical areas (hypothalamus)  Activation of tyrosine kinase receptor B in neurons and glia.

Neuroendocrine Factors  Abnormalities in HPA axis – hormonal abnormalities  Elevated cortisol levels  Clinical hypothyroidism  Sex steroids  Estrogen deficiency (postpartum and postmenopausal)  Testosterone deficiency

History of Antidepressants  Introduction of Reserpine in 1950’s  Used for hypertension and schizophrenia  Induced depression in these pts.  MOA – inhibit storage of NE and 5-HT  Reasoned that depression is associated with decrease in amine dependent synaptic transmission

Clinical Indications of Antidepressants  Depression  Anxiety Disorders  Pain Disorders  Premenstrual Dysmoric Disorder  Smoking Cessation  Eating Disorders  Off label usage – urinary stress incontinence, sexual disorders (premature ejaculation)

Antidepressant (Thymoleptic) Drugs  Tricyclic antidepressants (TCA’s)  Monoamine oxidase inhibitors (MAOIs)  Newer-generation antidepressants  Selective serotonin reuptake inhibitors (SSRIs)  Selective norepinephrine reuptake inhibitors (SNRIs)  5-HT Antagonists

Tricyclic Antidepressants First-Generation  mostly replaced as first-line antidepressant drugs by SSRIs in 80’s and 90’s.  Considered second-line  patients who fail with SSRIs or other newer-generation antidepressants  As adjunct therapy with newer antidepressants

Common TCA’s  Secondary Amine  Amoxapine  Nortiptyline  Desipramine  Protriptyline  Tertiary Amine  Imipramine *  Amitriptyline *  Clomipramine  Doxepin  Trimipramine  * prototype

Tricyclic Antidepressants TCA’s)  Characteristic three-ring structure  Block NE and 5-HT reuptake  Can not be used with MAOI’s  No food interactions  Antagonize 5-HT, α-adrenergic, H 1 and muscarinic receptors

Mechanism of Action of TCA’s  Block reuptake of neurotransmitters, (NE, 5-HT) causing accumulation at the nerve endings  increasing NE and 5-HT will correct the abnormally low levels that lead to depression

Tricyclic Antidepressants  Imipramine  strong anticholinergic action  strong NE and 5-HT reuptake inhibitor  Most likely to cause orthostatic hypotension  Desipramine  Metabolite of imipramine  Less anticholinergic, more potent, more selective for NET than imipramine  Nortriptyline  Least likely to cause orthostatic hypotension

Indications for TCA’s  Depression  Childhood enuresis (imipramine)  Obsessive-compulsive disorders (clomipramine)  Adjunctive analgesics for chronic pain conditions, such as trigeminal neuralgia, neuropathy

TCA’s (cont’)  Mode of action – inhibit NE and 5HT reuptake into presynaptic nerve terminal  Actions – elevate mood  Therapeutic uses – severe depression, some panic disorders.  Pharmacokinetics – well absorbed PO, lipophilic, penetrate CNS  Fate – metab. By hepatic microsomal system

Adverse affects of TCA’s  Antimuscarinic  Cardiovascular  Orthostatic hypotension  Sedation  Precaution  Toxicity  Drugs used for toxicity

Drug Effects  Blockade of norepinephrine reuptake  Antidepressant*, tremors, tachycardia  Blockade of 5-HT reuptake  Antidepressant*, nausea, headache, anxiety, sexual dysfunction *Desired therapeutic effects

Overdose of TCA’s  Brief excitement and restlessness, myoclonus, tonic-clonic seizures, coma, depressed respiration, hypoxia, hypothermia, hypotension, mydriasis, urinary retention  Cardiac toxicity, hypotension

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  Provide basic life support

Overdose of TCA’s  Lethal—70% to 80% die before reaching the hospital  CNS and cardiovascular systems are mainly affected  Death results from seizures or dysrhythmias

Antidepressant (Thymoleptic) Drugs  Tricyclic antidepressants (TCA’s)  Monoamine oxidase inhibitors (MAOIs)  Newer-generation antidepressants  Selective serotonin reuptake inhibitors (SSRIs)  Selective norepinephrine reuptake inhibitors (SNRIs)  5-HT Antagonists

Monoamine Oxidase Inhibitors  Phenelzine  Isocarboxazid  Tranylcypromine  Selegeline Patch

Monoamine Oxidase Inhibitors

 Mitochondrial enzyme, (MAO) regulates metabolic degradation  Found in nerve terminal, intestinal mucosa (gut), liver, etc.  MAOI irreversibly/reversibly inactivate MAO  Allow NT to escape degradation

Monoamine Oxidase Inhibitors  Irreversible MAO inhibitors (Hydrazides)  Phenelzine, Isocarboxazid  Reversible MAO inhibitors (non-hydrazide)  Tranylcypromine

Monoamine Oxidase Inhibitors  2 forms of monoamine oxidase  MAO-A - present in both DA and NE neurons and found mostly in brain, gut, placenta and liver. (NE, 5-HT)  Mocolobemide, Clorgyline  MAO-B - present mainly in serotonergic and histaminergic neurons, distributed in brain, liver and platelets. (tyramine, DA)  Deprenyl, Seligiline

MAOI classification  Classified according to specificity for MAO-A or MAO-B and whether they are reversible or irreversible.  Non-selective  irreversible- phelnelzine, trancypromine  Selective  MAO-A reversible – moclobemide, displaced by tyramine  MAO-B irreversible – selegiline (low dose) used in PD, high dose becomes non-selective

Monoamine Oxidase Inhibitors (MAOI’s)  Considered second-line treatment for depression not responsive to TCA’s  Disadvantage: potential to cause hypertensive crisis when taken with tyramine  Use is limited due to dietary restrictions  Onset time and time to wear off – 2 wks

Wine and Cheese reaction  Fatal interaction w/ tyramine containing foods (fermented foods)  MAO-A breakdown tyramine in body – MAOI’s cause circulating NE – induces hypertensive crisis – can lead to intracranial bleeding, organ damage

Monoamine Oxidase Inhibitors  Prolong action of drugs metabolized by MAO and hepatic metabolic P450  Contraindicated in pts. Using TCA’s  Drug to drug interaction - use of SSRI’s cause life- threatening serotonin syndrome.  Drug to food interaction - hypertensive crisis when taken with tyramine

Monoamine Oxidase Inhibitors  Mechanism of action  inactivate MAO, result in increased stores of 5- HT, NE and DA.  Brain and peripheral (high drug-drug, drug-food interaction)  Therapeutic use  Depression not responsive to TCA’s  Used in phobic states  Very effective in atypical depression

Monoamine Oxidase Inhibitors  Pharmacokinetics  well absorbed p.o.  antidepressant effect (2-4 weeks)  wash out period(2 weeks) required when switching antidepressants  metabolized, excreted rapidly in urine

Monoamine Oxidase Inhibitors  Adverse Effects  drowsiness  orthostatic hypotension  blurred vision  dry mouth  dysuria  constipation  contraindicated w/ SSRI’s – serotonin syndrome

MAOI Toxicity  Toxic reactions may occur in hrs, despite therapeutic response delay  Agitation, hallucinations, hyperreflexia, hyperpyrexa and convulsions  Both hypertension and hypotension

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

Antidepressant (Thymoleptic) Drugs  Tricyclic antidepressants (TCA’s)  Monoamine oxidase inhibitors (MAOIs)  Newer-generation antidepressants  Selective serotonin reuptake inhibitors (SSRIs)  Selective norepinephrine reuptake inhibitors (SNRIs)  5-HT Antagonists

Selective Serotonin Reuptake Inhibitors (SSRI’s)  Mainly replaced TCA’s and MAOIs as drug of choice for depression  Do not affect reuptake of NE  Decreased incidence of anticholinergic and adrenergic action of TCA’s.  All admin. PO  May interfere with P450 (CYP2Ds) metabolism of other drugs (enzymes responsible for metabolism of TCA’s)

Selective Serotonin Reuptake Inhibitors  Fluoxetine (Prozac)  Citalopram (Celexa)  Fluvoxamine (Luvox)  Paroxetine (Paxil)  Sertraline (Zoloft)

Selective Serotonin Reuptake Inhibitors SSRIs  Selectively inhibit serotonin reuptake  Little or no effect on norepinephrine or dopamine reuptake  Result in increased serotonin concentrations at nerve endings  Advantage over TCA’s and MAOIs: little or no effect on cardiovascular system, and no CNS stimulation

Selective Serotonin Reuptake Inhibitors (SSRI’s)  Most widely prescribed drugs for depression, OCD,GAD, PDD, bulimia  They have few side effects and seem to be rather safe.  Adverse effects include: nausea, decreased libido,anorexia, anxiety, insomnia, tremors, sleepiness, sweating  Low threat for overdose. Suicide may be considered in severe depression.

SSRI’s indications  Fluoxetine (Prozac) - mental depression, OCD, Bulemia  Citalopram (Celexa) – mental depression  Fluvoxamine (Luvox) - OCD  Paroxetine (Paxil) – mental depression, panic disorder, OCD  Sertraline (Zoloft) - mental depression

Antidepressant (Thymoleptic) Drugs  Tricyclic antidepressants (TCA’s)  Monoamine oxidase inhibitors (MAOIs)  Newer-generation antidepressants  Selective serotonin reuptake inhibitors (SSRIs)  Selective norepinephrine reuptake inhibitors (SNRIs)  5-HT Antagonists

Serotonin-Norepinephrine Reuptake Inhibitors (SNRI’s)  2 classes of antidepressants act as combined NE and 5-HT reuptake inhibitors  SNRI’s and TCA’s  SNRI’s  Venlafaxine - weak inhibitor of NET  Duloxetine – inhibit both NET and SERT

Serotonin-Norepinephrine Reuptake Inhibitors (SNRI’s)  Additional indications  Major depression, pain disorders, generalized anxiety, urinary incontinence and vasomotor symptoms of menopause  Bind SERT and NET transporters  Differ from TCA’s - no α-adrenergic blocking, and anticholinergic effects

Pharmacokinetics of SNRI’s  Venlafaxine  extensively metabolized in the liver to Desvenlafaxine  Both have the lowest protein binding of all antidepressants  Desvenlafaxine  conjugated, does not undergo extensive oxidative metabolism  about 45% is excreted unchanged in the urine  Duloxetine  tightly bound to protein (97%)  Undergoes extensive oxidative metabolism  hepatic impairment alters levels, unlike Desvenlafaxine

Antidepressant (Thymoleptic) Drugs  Tricyclic antidepressants (TCA’s)  Monoamine oxidase inhibitors (MAOIs)  Newer-generation antidepressants  Selective serotonin reuptake inhibitors (SSRIs)  Selective norepinephrine reuptake inhibitors (SNRIs)  Tetracyclic and Unicyclic  5-HT 1 and 2 Antagonists

5-HT 1 Antagonists  Trazodone and Nefazodone  Mechanism of action  Therapeutic effect related to ability to block 5-HT 1  Weak but selective inhibitors of 5-HT reuptake  Little or no effect on NE or DA reuptake  Increased 5-HT concentrations  Both are sedating (antihistimine effect)  Trazodone associated with causing priapism

5-HT 2 Antagonists  Mirtazapine  Mechanism of action  Antagonist of 5-HT 2/3 – inc. release 5-HT  Antagonist of α 2 receptors-inc. release NE, 5-HT  Side effects  sedative due to antihistamine activity  effective in depressed having difficulty sleeping  no antimuscarinic (TCA)  does not interfere w/ sexual function (SSRIs)  increased appetite, weight gain

Tetracyclic, Unicyclic  Bupropion  Mechanism of action – poorly understood  Release of catocholamines – NE, DA  No effect on 5-HT  Decreases cravings for nicotine in tobacco users  Side effects – dry mouth, sweating, tremor, seizure at high dose  Lower seizure threshold

Tetracyclic, Unicyclic (cont)  Amoxapne and maprotiline  Mechanism of action – potent NET inhibitors and less potent SERT inhibitors  Side effects – both possess anticholinergic properties  inhibits D2 receptor  Possess antipsychotic properties  Lower seizure threshold

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