Drug Therapy of Depression,

Mania and Anxiety Disorders

I. Overview
• Depression - feelings of sadness and hopelessness, as well as the
inability to experience pleasure in usual activities, changes in sleep
patterns and appetite, loss of energy, and suicidal thoughts
• Mania - the opposite behavior: enthusiasm, anger, rapid thought and
speech patterns, extreme self-confidence, and impaired judgment.
• Anxiety – feelings of fear or dread that are unfocused or out of scale
with the perceived threat.
II. Mechanism of Antidepressants
• Antidepressant drugs potentiate, either directly or indirectly, the
actions of norepinephrine and/or serotonin (5-HT) in the brain.
• Depression is due to a deficiency of monoamines, such as
norepinephrine and serotonin, at certain key sites in the brain.
• Mania is caused by an over-production of these neurotransmitters.
III. Selective Serotonin Reuptake Inhibitors
• a group of antidepressant drugs that specifically inhibit serotonin
reuptake,
• have 300- to 3000-fold greater selectivity for the serotonin
transporter, as compared to the norepinephrine transporter.
• This contrasts with the tricyclic anti-depressants (TCAs) and serotonin/
norepinephrine reuptake inhibitors (SNRIs) that nonselectively inhibit
the reuptake of norepinephrine and serotonin.
III. Selective Serotonin Reuptake Inhibitors
• SSRIs have little blocking
activity at muscarinic, α-
adrenergic, and histaminic
H1 receptors
III. Selective Serotonin Reuptake Inhibitors
A. Actions
• The SSRIs block the reuptake of
serotonin, leading to increased
concentrations of the neurotransmitter in
the synaptic cleft.
• Antidepressants, including SSRIs, typically
take at least 2 weeks to produce
significant improvement in mood, and
maximum benefit may require up to 12
weeks or more
III. Selective Serotonin Reuptake Inhibitors
B. Therapeutic uses
• The primary indication for SSRIs is depression, for which they are as
effective as the TCAs.
• other psychiatric disorders: obsessive–compulsive disorder, panic
disorder, generalized anxiety disorder, posttraumatic stress disorder,
social anxiety disorder, premenstrual dysphoric disorder, and bulimia
nervosa
III. Selective Serotonin Reuptake Inhibitors
C. Pharmacokinetics
• Well absorbed after oral intake
• Peak levels are seen in approximately 2 to 8 hours on average.
• Food has little effect on absorption (except with sertraline, for which
food increases its absorption).
• The majority of SSRIs have plasma half-lives that range between 16
and 36 hours. Fluoxetine has longer half life (50 hours)
• Metabolism by cytochrome P450 (CYP450)–dependent enzymes and
glucuronide or sulfate conjugation occur extensively.
III. Selective Serotonin Reuptake Inhibitors
D. Adverse effects
IV. Serotonin/Norepinephrine
Reuptake Inhibitor
• Venlafaxine
• Desvenlafaxine
• levomilnacipran
• duloxetine
IV. Serotonin/Norepinephrine Reuptake
Inhibitor
Venlafaxine and Desvenlafaxine
• a potent inhibitor of serotonin reuptake and, at medium to higher
doses, is an inhibitor of norepinephrine reuptake.
• has minimal inhibition of the CYP450 isoenzymes and is a substrate of
the CYP2D6 isoenzyme.
• Desvenlafaxine is the active, demethylated metabolite of venlafaxine.
• side effects : nausea, headache, sexual dysfunction, dizziness,
insomnia, sedation, and constipation.
• At high doses, there may be an increase in blood pressure and heart
rate.
IV. Serotonin/Norepinephrine Reuptake
Inhibitor
Duloxetine
• inhibits serotonin and norepinephrine reuptake at all doses.
• It is extensively metabolized in the liver to inactive metabolites and
should be avoided in patients with liver dysfunction.
• GI side effects are common, including nausea, dry mouth, and
constipation.
• Insomnia, dizziness, somnolence, sweating, and sexual dysfunction are
also seen.
IV. Serotonin/Norepinephrine Reuptake
Inhibitor
Levomilnacipran
• is an enantiomer of milnacipran, an older SNRI used for the treatment
of depression and fibromyalgia.
• adverse effect profile of levomilnacipran is similar to other SNRIs.
• is primarily metabolized by CYP3A4, and, thus, activity may be altered
by inducers or inhibitors of this enzyme system.
V. Atypical Antidepressants
• Bupropion
• Mirtazapine
• Nefazodone
• Trazodone
• Vilazodone
• Vortioxetine
V. Atypical Antidepressants
A. Bupropion
• Weak dopamine and norepinephrine reuptake inhibitor
• Decrease cravings
• side effects: dry mouth, sweating, nervousness, tremor, and a dose-
dependent increased risk for seizures. It has a very low incidence of
sexual dysfunction.
V. Atypical Antidepressants
B. Mirtazapine
• enhances serotonin and norepinephrine neurotransmission by serving
as an antagonist at presynaptic α2 receptors
• some of the antidepressant activity may be related to antagonism at
5-HT2 receptors.
• It is sedating because of its potent antihistaminic activity, but it does
not cause the antimuscarinic side effects of the TCAs, or interfere with
sexual function like the SSRIs.
• Increased appetite and weight gain frequently occur
V. Atypical Antidepressants
C. Nefazodone and trazodone
• weak inhibitors of serotonin reuptake.
• Their therapeutic benefit appears to be related to their ability to block
postsynaptic 5-HT2a receptors.
• Both are sedating
• Trazodone is commonly used for insomnia, associated with priapism,
• Nefazodone has been associated with a risk for hepatotoxicity.
• Both agents can contributing to orthostasis and dizziness.
V. Atypical Antidepressants
D. Vilazodone
• serotonin reuptake inhibitor and a 5-HT1a partial agonist.
• The adverse effect profile is similar to the SSRIs, including a risk for
discontinuation syndrome if abruptly stopped.
V. Atypical Antidepressants
E. Vortioxetine
• combination of serotonin reuptake inhibition, 5-HT1a agonism, and 5-
HT3 and 5-HT7 antagonism
• The common adverse effects include nausea, vomiting, and
constipation, which may be expected due to its serotonergic
mechanisms.
VI. Tricyclic Antidepressants
• Imipramine
• Amitriptyline
• Clomipramine
• Doxepin
• Trimipramine
• Desipramine
• Nortriptyline
• Protriptyline
• Maprotiline
• Amoxapine
VI. Tricyclic Antidepressants
A. Mechanism of action
• Inhibition of Neurotransmitter reuptake : potent inhibitors of the
neuronal reuptake of norepinephrine and serotonin
• Blocking of receptors : block serotonergic, α-adrenergic, histaminic,
and muscarinic receptors
VI. Tricyclic Antidepressants
B. Therapeutic uses
• Moderate to severe depression
• Panic disorder
• Control bed wetting
• Prevent migraine and chronic pain
• insomnia
VII. Treatment of Mania and Bipolar Disorder
A. Lithium
• used acutely and prophylactically for managing bipolar patients.
• effective in treating 60% to 80% of patients
• the mode of action is unknown.
• The therapeutic index is extremely low
• Common adverse effects: headache, dry mouth, polydipsia, polyuria,
polyphagia, GI distress (give lithium with food), fine hand tremor,
dizziness, fatigue, dermatologic reactions, and sedation.
• Adverse effects: ataxia, slurred speech, coarse tremors, confusion, and
convulsions.
• Thyroid function may be decreased and should be monitored.
• Renally eliminated,