Lect. 4 Clinical Depression and Antidepressants

1. DRUGS USED IN DISORDERS OF THE
CENTRAL NERVOUS SYSTEM AND
TREATMENT OF PAIN
Lecture 4:
Clinical Depression and Antidepressants
Marc Imhotep Cray, M.D.
Also includes Drugs Affecting Bipolar Disorder and OCD

2. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 4
Learning Objectives:
2
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.

3. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 4
Learning Objectives: cont.
3
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.

4. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 4
Classification Schema: Antidepressants
4
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)
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)
Mood Stabilizer
Lithium

5. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 4
Overview of Mood Disorders Classification
5
Cutler JL. Psychiatry 3rd. Ed. New York, NY: Oxford University Press, 2014

6. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 4
Clinical Depression:
6
 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

7. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 4
Clinical Depression(2)
7
 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

8. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 4
Clinical Depression(3) Symptomatology
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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

9. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 4
Clinical indication for antidepressants:
9
 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.”

10. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 4
The Face of Depression:
10

11. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 4
The Face of Depression(2)
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Associated Symptoms and Comorbidities:

12. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 4
Antidepressants: Mechanisms of Action
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 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

13. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 4
Antidepressants MOA (2)
13
 Mechanisms of newer drugs include direct binding to 5-HT or NE
receptor subtypes (e.g., antagonist action at presynaptic α2-
adrenoceptors 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)

14. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 4
14
Antidepressants MOA Illustrated:

15. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 4
Tricyclic Antidepressants (TCAs)
15
 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

16. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 4
Side Effects:
16
 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)

17. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 4
Side Effects from Select TCAs:
17
Magnitude of Side Effects from TCAs
Sedation and Anticholinergic Activity
Doxepin (Sinequan) High
Amitriptyline (Elavil) High
Clomipramine (Anafranil) High
Imipramine (Tofranil) Moderate
Desipramine (Norpramin) Low
Nortriptyline (Aventyl, Pamelor) Low

18. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 4
5-HT and NE Reuptake Inhibitors (SNRIs):
18
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

19. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 4
Selective Serotonin Reuptake Inhibitors
(SSRIs)
19
 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)

20. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 4
Advantages of SSRIs:
20
Main advantage is that they are much safer due to a lack of:
 Sedation
 Orthostatic hypotension
 Anticholinergic effects
 Overdose potential when used alone

21. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 4
Side Effects of SSRIs:
21
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

22. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 4
Monoamine Oxidase Inhibitors (MAOIs):
22
 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

23. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 4
MAOIs Side Effects:
23
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

24. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 4
MAOIs Contraindications:
24
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

25. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 4
Atypical Antidepressants
25
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

26. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 4
Bipolar Disorder –Manic Phase
(Manic-Depressive Disorder)
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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

27. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 4
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Bipolar Disorder,
Mania Episode

28. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 4
Bipolar Disorder (2)
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 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

29. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 4
29
Mechanism of action of Lithium Illustrated:

30. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 4
Lithium Carbonate:
30
 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

31. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 4
Lithium Carbonate (2)
31
 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

32. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 4
Lithium Carbonate (3)
32
 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).

33. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 4
Compulsive Behavior
Obsessive-Compulsive Disorder (OCD):
33
 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

34. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 4
OCD:
34

35. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 4
THE END
35

36. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 4
36
Lectures/discussions to follow:
5. Antipsychotic Agents
6. Drugs Affecting Movement Disorders and
Other Neurodegenerative Disorders
7. Analgesics
8. Anesthetics
Further study (SDL):
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