Lecture 4 clinical depression and antidepressants

DRUGS USED IN DISORDERS OF THE CENTRAL NERVOUS SYSTEM AND TREATMENT OF PAIN Lecture 4:

Clinical Depression and Antidepressants Also includes Drugs Affecting Bipolar Disorder and OCD Marc Imhotep Cray, M.D.

Learning Objectives:

CNS Pharmacology Lecture 4

1. The primary sites of action of the different classes of antidepressant drugs responsible for their therapeutic efficacy.

2. The adverse/side effects of the different classes of antidepressant drugs and considerations for their use in certain populations (e.g. in elderly, pregnancy, etc.).

3. The pharmacologic sites of action of different antidepressant drugs that contribute to the acute and/or side effects of these drugs.

4. The proposed mechanisms underlying the delayed therapeutic effects of antidepressant drugs.

5. The considerations in using irreversible versus reversible MAOIs, the potential adverse effects of MAOIs, and the important considerations in switching between MAOIs and SSRIs or other antidepressant drugs.

Marc Imhotep Cray, M.D.

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CNS Pharmacology Lecture 4

Learning Objectives: cont.

6. The target sites of action of lithium, its pharmacokinetics, adverse effects and considerations in its use in the treatment of bipolar disorder.

7. The pharmacokinetics, adverse effects and considerations in using the anticonvulsants to treat bipolar affective disorder.

8. The sites of action, adverse effects and considerations in using the atypical antipsychotics to treat bipolar affective disorder.

9. The potential risk of birth defects with the use of lithium, valproate, carbamazepine and lamotrigine in pregnant women.

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Classification Schema: Antidepressants Tricyclic antidepressants (TCAs) Imipramine (generic; Tofranil) Amitriptyline (generic; Elavil) Clomipramine (Anafranil) Desipramine (Nopramin) Doxepin (Sinequan) Selective-serotonin reuptake inhibitors (SSRIs) Citalopram (Celexa) and Escitalopram (Lexapro) Fluoxetine (generic; Prozac) Fluvoxamine (Luvox) Paroxetine (Paxil) Sertraline (Zoloft) Mood Stabilizer Lithium Marc Imhotep Cray, M.D.

CNS Pharmacology Lecture 4

Atypical antidepressants Bupropion (Wellbutrin, Zyban) Mirtazapine (Remeron) Nefazodone (Serzone) Norepinephrine/serotonin reuptake inhibitors (SNRIs) Venlafaxine (Effexor) Desvenlafaxine (Pristig) Duloxetine (Cymbalta) MAOIs (monoamine oxidase inhibitors) Irreversible: Phenelzine (generic; Nardil) Tranylcypromine (generic; Parnate) Selegiline (L-deprenyl); Eldepryl, Emsam Reversible: Reversible inhibitors of monoamine oxidase A (RIMAs): Moclobemide (Manerix) 4

CNS Pharmacology Lecture 4

Overview of Mood Disorders Classification

Cutler JL. Psychiatry 3rd. Ed. New York, NY: Oxford University Press, 2014 Marc Imhotep Cray, M.D.

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Clinical Depression:

CNS Pharmacology Lecture 4

 Clinical (endogenous) depression, a heterogeneous biopsychosocial disorder with genetic predisposition, can occur at any time in life, unrelated to obvious stressors  Treatment is required: approximately 15% of these patients commit suicide  Severe (major depression) and mild (dysthymic disorder) forms exist  Findings that clinical depression may be related to an imbalance in endogenous amines (5-HT or NE) in CNS led to amine hypothesis of etiology and spurred efforts to enhance synaptic action of these amines Marc Imhotep Cray, M.D.

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Clinical Depression(2)

CNS Pharmacology Lecture 4

 Antidepressants are classified according to a presumed MOA or chemical structure:  TCAs and heterocyclics nonselectively inhibit both 5-HT and NE  SSRIs specifically inhibit 5-HT reuptake, having 300- to 3000-fold greater selectivity for serotonin transporter, as compared to norepinephrine transporter.  MAOIs inhibit amine metabolism  Adverse effects (e.g., mania, agitation, serotonin syndrome) and drug interactions (MAOIs used with TCAs or SSRIs) occur not infrequently

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CNS Pharmacology Lecture 4

Clinical Depression(3) Symptomatology Symptoms of major depression include:  feelings of sadness and hopelessness  inability to experience pleasure in usual activities  changes in sleep patterns and appetite (too much or too little)  loss of energy and  suicidal thoughts

Marc Imhotep Cray, M.D.

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CNS Pharmacology Lecture 4

Clinical indication for antidepressants:  Primary clinical indication for antidepressants is major depression (unipolar disorder)  Onset of antidepressant effect is delayed, taking 2–3 weeks to develop  This supports the hypothesis that down-regulation of presynaptic inhibitory NE or 5-HT receptors may be necessary for clinical effect to occur  These drugs improve mood in depressed patients but not in normal subjects, which is the basis of the term “antidepressant.”

Marc Imhotep Cray, M.D.

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CNS Pharmacology Lecture 4

The Face of Depression:

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CNS Pharmacology Lecture 4

The Face of Depression(2) Associated Symptoms and Comorbidities:

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CNS Pharmacology Lecture 4

Antidepressants: Mechanisms of Action  Most antidepressants primarily enhance action of endogenous amine neurotransmitters  they act indirectly, not binding to 5-HT or NE receptors but enhancing NT action by inhibiting metabolism or removing neurotransmitters from synapses  Increased synaptic 5-HT or NE levels then counteract abnormally low levels that produce depression  5-HT enhancement may be more important than enhancement of NE, so SSRIs have become popular  MAOIs inhibit metabolism of 5-HT and NE, thus increasing amine levels Marc Imhotep Cray, M.D.

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CNS Pharmacology Lecture 4

Antidepressants MOA (2)  Mechanisms of newer drugs include direct binding to 5-HT or NE receptor subtypes (e.g., antagonist action at presynaptic α2adrenoceptors stimulates NE release, e.g. mirtazapine)  Action of bupropion does not seem to involve 5-HT or NE and therefore may represent a novel mechanism  The long-term mechanism of antidepressant action is unknown  All these drugs modify neurochemical pathways and can elicit adverse effects (e.g., sedation and excitation)

Marc Imhotep Cray, M.D.

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Antidepressants MOA Illustrated:

Marc Imhotep Cray, M.D.

CNS Pharmacology Lecture 4

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CNS Pharmacology Lecture 4

Tricyclic Antidepressants (TCAs)  TCAs have a structure that is similar to the phenothiazines (typical antipsychotics) MOA: Nonselectively inhibit both 5-HT and NE reuptake  Imipramine (Tofranil), a tertiary amine that is the prototype tricyclic drug, has many effects that are similar to the phenothiazines  However, imipramine o Produces very little D2-receptor antagonism o Reduces amine reuptake, which increases concentration of NE and 5-HT in CNS synapses

Marc Imhotep Cray, M.D.

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CNS Pharmacology Lecture 4

Side Effects:  Side effects vary among specific drugs (see next slide) but are generally similar to the phenothiazines They include:  Antihistaminergic effects from blocking the H1 receptors (e.g., sedation)  Anticholinergic effects, such as tachycardia, arrhythmias, urinary retention, constipation, xerostomia, and blurred vision  Antiadrenergic effects, such as orthostatic hypotension and reflex tachycardia due to blocking alpha 1 adrenoceptors  Weight gain  Anorgasmia and erectile dysfunction  Drug interactions (e.g., adrenergic agonists, ethanol, MAOIs)

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CNS Pharmacology Lecture 4

Side Effects from Select TCAs: Magnitude of Side Effects from TCAs Sedation and Anticholinergic Activity

Doxepin (Sinequan) Amitriptyline (Elavil) Clomipramine (Anafranil) Imipramine (Tofranil) Desipramine (Norpramin) Nortriptyline (Aventyl, Pamelor)

Marc Imhotep Cray, M.D.

High High High Moderate Low Low

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5-HT and NE Reuptake Inhibitors (SNRIs):

CNS Pharmacology Lecture 4

SNRIs decrease reuptake of both serotonin and norepinephrine They have similar actions as tricyclics, but with fewer anticholinergic side effects Venlafaxine (Effexor) inhibits 5-HT reuptake at low doses and both 5-HT and NE reuptake at higher doses  It is associated with hypertension at higher doses Duloxetine (Cymbalta) inhibits 5-HT and NE reuptake at all doses  It is extensively metabolized and should be avoided in patients with severe liver or kidney disease Major side effects are GI effects and sexual dysfunction

Marc Imhotep Cray, M.D.

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Selective Serotonin Reuptake Inhibitors (SSRIs)

CNS Pharmacology Lecture 4

 SSRIs inhibit serotonin reuptake but do not affect NE reuptake  They include fluoxetine (Prozac), sertraline (Zoloft), fluvoxamine (Luvox), citalopram (Celexa), escitalopram (Lexapro), and paroxetine (Paxil)  They are similar in efficacy to tricyclics for treatment of major depression  Other uses include panic disorder, anxiety, and obsessive– compulsive disorder (fluvoxamine)

Marc Imhotep Cray, M.D.

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CNS Pharmacology Lecture 4

Advantages of SSRIs: Main advantage is that they are much safer due to a lack of:  Sedation  Orthostatic hypotension  Anticholinergic effects  Overdose potential when used alone

Marc Imhotep Cray, M.D.

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Side Effects of SSRIs:

CNS Pharmacology Lecture 4

Side effects include:    

Sexual dysfunction CNS stimulation, leading to insomnia (fluoxetine) Drowsiness (paroxetine, fluvoxamine) Drug interactions due to inhibition of CYP450s (fluoxetine, paroxetine)  Disinhibition, possibly with bipolar underpinnings  Increased suicidal ideation and attempts; patients on SSRIs must be monitored for suicidal ideation  Weight gain with prolonged use

Marc Imhotep Cray, M.D.

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CNS Pharmacology Lecture 4

Monoamine Oxidase Inhibitors (MAOIs):  MAOIs (e.g., tranylcypromine [Parnat] and phenelzine [Nardil]) are competitive irreversible inhibitors of both MAOA and MAOB

 This inhibition increases concentrations of NE, DA, and 5-HT in granules, which increases amine release  MAO inhibitors elevate mood in both normal and depressed people

Marc Imhotep Cray, M.D.

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CNS Pharmacology Lecture 4

MAOIs Side Effects: Side effects can be severe, including:    

Hepatotoxicity CNS stimulation Postural hypotension Hypertensive crisis and stroke when taken with o Foods containing tyramine, such as cheeses, beans, pickled herring, beer, and wine o Sympathomimetics

Marc Imhotep Cray, M.D.

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CNS Pharmacology Lecture 4

MAOIs Contraindications: Combinations of tricyclics or SSRIs with MAOIs must be avoided because this can cause the serotonin syndrome (hyperthermia, clonus, CNS effects)  A washout period of 2–6 weeks is needed before switching patients from other drug classes to MAOIs and vice versa

Marc Imhotep Cray, M.D.

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Atypical Antidepressants

CNS Pharmacology Lecture 4

Atypical Antidepressants affect mood by different mechanisms: Bupropion (Wellbutrin) improves depression by an unknown mechanism  It is used for tobacco cessation (Zyban) as well as for depression  High doses may lead to seizures  However, it does not cause weight gain or sexual dysfunction Mirtazapine (Remeron) blocks 5-HT and α2 receptors  Side effects include increased appetite, weight gain, and sedation  Nefazodone and trazodone (Desyrel) block 5-HT autoreceptors on presynaptic neurons  Both are sedating, and trazodone can cause priapism

Marc Imhotep Cray, M.D.

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Bipolar Disorder –Manic Phase

CNS Pharmacology Lecture 4

(Manic-Depressive Disorder) Mania is characterized by opposite behavior of depression:  enthusiasm>>>grandiosity  anger  rapid thought and speech patterns  extreme self-confidence, and  impaired judgment (e.g. spending sprees and hypersexuality)  Pts with severe mania episodes can have psychotic features, i.e. loss of touch with reality=delusions and hallucinations

Marc Imhotep Cray, M.D.

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Bipolar Disorder, Mania Episode

Marc Imhotep Cray, M.D.

CNS Pharmacology Lecture 4

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CNS Pharmacology Lecture 4

Bipolar Disorder (2)  Bipolar disorder is characterized by alternating periods of mania and depression  The manic phase can be productive but can also be disruptive and physically exhausting  Bipolar disorder often responds to treatment with lithium, which is rapidly absorbed from the GI tract and is distributed throughout the body  MOA: (also see next slide illustrates.)  Lithium may reduce neuronal activity by inhibiting cellular phosphoinositide pathways involving the second messengers inositol trisphosphate and diacylglycerol

Marc Imhotep Cray, M.D.

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CNS Pharmacology Lecture 4

Mechanism of action of Lithium Illustrated:

Marc Imhotep Cray, M.D.

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CNS Pharmacology Lecture 4

Lithium Carbonate:  Clinical indications for lithium are treatment of manic-depressive illness (bipolar disorder) and augmentation in unipolar depression, including:  Acute treatment of manic phase  Acute treatment of depressive phase in combination with other agents  Prophylaxis  A delay of 7–10 days occurs before lithium has a clinical effect

Marc Imhotep Cray, M.D.

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CNS Pharmacology Lecture 4

Lithium Carbonate (2)  Side Effects are common if blood lithium concentration gets into toxic range; thus,  it is important to monitor blood lithium concentrations to avoid toxicity  Tremor, ataxia, and confusion can occur and occasionally lead to convulsions  Nephrogenic diabetes insipidus can occur  treated with potassium sparing diuretic amiloride or by switching patient from lithium to an anticonvulsant  Hypothyroidism can occur, and thyroid function must be monitored

Marc Imhotep Cray, M.D.

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Lithium Carbonate (3)

CNS Pharmacology Lecture 4

 There is no specific antidote for lithium toxicity  Drug-Drug Interactions:  Thiazide diuretics and calcium channel blockers will increase lithium retention and enhance toxicity; thus, o they should be avoided in patients being treated with lithium  NSAIDs decrease lithium clearance and increase lithium blood levels  ACE inhibitors cause an increased lithium level due to sodium depletion  Drug-Diet Interaction:  A high sodium diet will increase lithium excretion Note: Alternate drugs for bipolar depression are the anticonvulsants carbamazepine (Tegretol), lamotrigine (Lamictal), and valproic acid (Depakene).

Marc Imhotep Cray, M.D.

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Compulsive Behavior Obsessive-Compulsive Disorder (OCD):

CNS Pharmacology Lecture 4

 Compulsive behaviors impair social interaction and disrupt daily activities  OCD affects at least 2% of the population (males and females approximately equally), with a genetic predisposition  The TCA clomipramine and SSRIs are usually chosen for OCD therapy  Other drugs, given individually or as combination therapy, include different TCAs, lithium, buspirone, clonazepam, dopamine antagonists (e.g., haloperidol), and trazodone  Drugs used together with behavioral or psychosocial therapy are usually optimal Marc Imhotep Cray, M.D.

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CNS Pharmacology Lecture 4

OCD:

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THE END

Marc Imhotep Cray, M.D.

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Further study (SDL):

CNS Pharmacology Lecture 4

MedPharm Digital Guidebook: Unit 3-Drugs Used for CNS Disorders Companion eNotes: CNS- Central Nervous System Pharmacology Textbook Reading: DeBattista C. Ch. 30 Antidepressant Agents. Pgs. 521-39, Meltzer H. Ch. 29 Antipsychotic Agents & Lithium. Pgs. 513-17 In: Katzung BG, ed. Basic & Clinical Pharmacology. 12th ed.

Online resource center: Medical Pharmacology Cloud Folder

Lectures/discussions to follow: 5. Antipsychotic Agents 6. Drugs Affecting Movement Disorders and Other Neurodegenerative Disorders 7. Analgesics 8. Anesthetics

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