Download Antidepressants

Antidepressants
Antidepressants
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Primarily used to relieve symptoms of
depression
Can also help patients with anxiety disorders
Not indicated for uncomplicated bereavement
Antidepressant Groups
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Tricyclic antidepressants
Selective serotonin reuptake inhibitors
(SSRIs)
Serotonin/norepinephrine reuptake inhibitors
(SNRIs)
Monoamine oxidase inhibitors (MAOIs)
Atypical antidepressants
Depression
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Most common psychiatric disorder
30% of the U.S. population will experience
some form during their lifetime
Approximately 5% of adult population is
depressed
Incidence in women twice as high as in men
Risk of suicide is high in depression
Often untreated
Clinical Features
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Depressed mood
Loss of pleasure or interest
Insomnia (or sometimes hypersomnia)
Anorexia (or sometimes hyperphagia)
Mental slowing and loss of concentration
Feelings of guilt, worthlessness, helplessness
Thoughts of death and suicide
Overt suicidal behavior
Symptoms must be present most of the day,
nearly every day, for at least 2 weeks
Pathogenesis
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Complex and incomplete
Possible contributing factors
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Genetic heritage
Difficult childhood
Chronic low self-esteem
Monoamine hypothesis of depression
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Depression is caused by functional insufficiency of
monoamine neurotransmitters
Treatment Modalities
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Pharmacotherapy
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Depression-specific psychotherapy (eg, cognitive
behavioral therapy)
Electroconvulsive therapy (ECT)
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Primary therapy
When drugs and psychotherapy have not worked
When a rapid response is needed
For severely depressed patients
For suicidal patients
Elderly patients at risk of starving
Vagus nerve stimulation
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Only after treatment with at least four drugs has failed
Suicide Risk with Antidepressants
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May increase suicidal tendency early in the
treatment
Patients should be observed closely for:
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Suicidality
Worsening mood
Changes in behavior
Precautions
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Prescriptions should be written for the smallest
number of doses consistent with good patient
management
Dosing of inpatients should be directly observed
Selective Serotonin Reuptake
Inhibitors (SSRIs)
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Introduced in 1987
Most commonly prescribed antidepressants
As effective as TCAs, but do not cause
hypotension, sedation, or anticholinergic
effects
Overdose does not cause cardiac toxicity
Death by overdose is extremely rare
Selective Serotonin Reuptake
Inhibitors (SSRIs)
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Fluoxetine (Prozac, Sarafem)
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Most widely prescribed SSRI in the United States
Other SSRIs
Mechanism of Action
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Produce selective inhibition of serotonin
reuptake
Produce CNS excitation
Therapeutic Uses
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Primarily used to treat major depression
Other uses
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Obsessive-compulsive disorder
Bulimia nervosa
Premenstrual dysphoric disorder
Adverse Effects
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Serotonin syndrome
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2–72 hours after treatment
Withdrawal syndrome
Neonatal effects when used in pregnancy
Teratogenesis
Extrapyramidal side effects
Bruxism
Bleeding disorders
Sexual dysfunction
Weight gain
Drug Interactions
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Monoamine oxidase inhibitors
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Risk of serotonin syndrome
Warfarin
Tricyclic antidepressants and lithium
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Can elevate levels of these drugs
Other SSRIs
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Sertraline (Zoloft)
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Blocks uptake of serotonin and dopamine
CNS stimulation
Minimal effects on seizure threshold
Therapeutic uses
• Major depression
• Panic disorder
• Obsessive-compulsive disorder
• Post-traumatic stress disorder
• Premenstrual dysphoric disorder
• Social anxiety disorder
Other SSRIs
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Sertraline (Zoloft) (cont’d)
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Side effects
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Headache
Nausea
Tremor
Diarrhea
Insomnia
Weight gain
Agitation
Sexual dysfunction
Neonatal abstinence syndrome (NAS) and persistent
pulmonary hypertension of the newborn (PPHN ) when used
late in pregnancy
• Nervousness
Other SSRIs
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Sertraline (Zoloft) (cont’d)
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Drug interactions
• MAOIs
• Pimozide
Other SSRIs
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Fluvoxamine (Luvox)
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Inhibition of serotonin reuptake
Used for obsessive-compulsive disorder
Rapidly absorbed from the GI tract
Half-life: about 15 hours
Interacts adversely with MAOIs
Other SSRIs
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Fluvoxamine (Luvox) (cont’d)
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Side effects
• Nausea
• Vomiting
• Constipation
• Weight gain
• Dry mouth
• Headache
• Sexual dysfunction
• Abnormal liver function
• Sedative effects
Other SSRIs
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Paroxetine (Paxil, Paxil CR, Pexeva)
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Inhibition of serotonin uptake
Indications
• Major depression
• Obsessive-compulsive disorder
• Social phobia
• Panic disorder
• Generalized anxiety disorder
• Post-traumatic stress disorder
• Premenstrual dysphoric disorder
Other SSRIs
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Citalopram (Celexa)
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Does not block receptors for serotonin,
acetylcholine, norepinephrine (NE), or histamine
Used for major depression
Half-life: about 35 hours
Side effects (most common)
• Nausea
• Somnolence
• Dry mouth
• Sexual dysfunction
Can cause neonatal abstinence syndrome
Interacts with MAOIs
Other SSRIs
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Escitalopram (Lexapro)
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S-isomer of citalopram
Better tolerated than citalopram
Side effects
• Nausea
• Insomnia
• Somnolence
• Sweating
• Fatigue
Interacts with MAOIs
Serotonin/Norepinephrine
Reuptake Inhibitors (SNRIs)
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Venlafaxine (Effexor)
Duloxetine (Cymbalta)
Venlafaxine (Effexor)
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Indications
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Major depression
Generalized anxiety disorder
Social anxiety disorder (social phobia)
Blocks NE and serotonin uptake
Does not block cholinergic, histaminergic, or
alpha1-adrenergic receptors
Serious reactions if combined with MAOIs
Venlafaxine (Effexor)
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Side effects
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Nausea
Headache
Anorexia
Nervousness
Sweating
Somnolence
Insomnia
Weight loss/anorexia
Diastolic hypertension
Sexual dysfunction
Hyponatremia (in older adult patients)
Neonatal withdrawal syndrome
Desvenlafaxine (Pristiq)
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Mechanism of action
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Strong inhibitor of 5-HT and NE reuptake
Does not block cholinergic, histaminergic, or
alpha1-adrenergic receptors
Desvenlafaxine (Pristiq)
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Side effects
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Nausea
Headache
Dizziness
Insomnia
Diarrhea
Dry mouth
Sweating
Constipation
Sexual effects, including erectile dysfunction
Decreased libido
Duloxetine (Cymbalta)
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Mechanism of action and therapeutic use
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Inhibits serotonin and NE reuptake
Weakly inhibits dopamine reuptake
Does not inhibit monoamine oxidase (MAO)
Relieves depression
Relieves pain of diabetic peripheral neuropathy
Pharmacokinetics
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Well absorbed following oral administration
Food reduces rate of absorption
Highly bound to albumin in the blood
Half-life: 12 hours
Duloxetine (Cymbalta)
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Adverse effects
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Effects in pregnancy and lactation
Drug interactions
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Nausea
Somnolence
Dry mouth
Sweating
Insomnia
Blurred vision
Alcohol
MAOIs
Drugs that inhibit CYP1A2 or CYP2D6
Preparations, dosage, and administration
Tricyclic Antidepressants
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Drugs of first choice for many patients with
major depression
Most common adverse effects: sedation,
orthostatic hypotension, and anticholinergic
effects
Most dangerous adverse effect: cardiac
toxicity
May increase risk of suicide early in treatment
Tricyclic Antidepressants
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Chemistry
Mechanism of action
Pharmacokinetics
Therapeutic uses
Adverse effects
Drug interactions
Dosage and routes of administration
Preparations and drug selection
Chemistry
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Nucleus of the tricyclic antidepressants has
three rings
Similar to phenothiazine antipsychotics
Produce varying degrees of:
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Sedation
Orthostatic hypotension
Anticholinergic effects
Fig. 32–1. Structural similarities between tricyclic antidepressants and phenothiazine
antipsychotics.
Mechanism of Action
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Block neuronal reuptake of two monoamine
transmitters
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Norepinephrine (NE)
Serotonin
Pharmacokinetics
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Long and variable half-lives
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Usually single daily dose
Requires individualization of dosage
Fig. 32–2. Mechanism of action of tricyclic antidepressants.
Therapeutic Uses
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Depression
Bipolar disorder
Other uses
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Neuropathic pain
Chronic insomnia
Attention-deficit/hyperactivity disorder
Panic disorder
Obsessive-compulsive disorder
Adverse Effects
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Orthostatic hypotension
Anticholinergic effects
Diaphoresis
Sedation
Cardiac toxicity
Seizures
Hypomania
“Yawngasm”
Drug Interactions
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Monoamine oxidase inhibitors
Direct-acting sympathomimetic drugs
Indirect-acting sympathomimetic drugs
Anticholinergic agents
CNS depressants
Toxicity
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Clinical manifestations
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Primarily from anticholinergic and cardiotoxic
actions
• Dysrhythmias
• Tachycardia
• Intraventricular blocks
• Complete atrioventricular block
• Ventricular tachycardia
• Ventricular fibrillation
Toxicity
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Treatment
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Gastric lavage
Ingestion of activated charcoal
Physostigmine
Propranolol, lidocaine, or phenytoin
Dosage and Routes of Administration
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Dosage
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Initial doses should be low
Routes of administration
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All can be administered by mouth
Preparation and Drug Selection
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Nine equally effective tricyclic
antidepressants (TCAs)
Selection based on side effects
Monoamine Oxidase Inhibitors
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2nd- or 3rd-choice antidepressants for most
patients
As effective as TCAs or SSRIs, but more
dangerous
Risk of triggering hypertensive crisis if patient
eats foods rich in tyramine
Drug of choice for atypical depression
Monoamine Oxidase Inhibitors
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Mechanism of action
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Convert monoamine neurotransmitters (NE,
serotonin, and dopamine) into inactive products
Inactivate tyramine and other biogenic amines
Two forms of MAO in the body
• MAO-A and MAO-B
Monoamine Oxidase Inhibitors
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Mechanism of action (cont’d)
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Affected by antidepressants
Act on MAO in two ways: reversible and
irreversible
• Reversible: lasts 3 to 5 days
• Irreversible: lasts about 2 weeks
All of the MAOIs in current use cause irreversible
inhibition
Fig. 32–3. Mechanism of action of monoamine oxidase inhibitors.
Monoamine Oxidase Inhibitors
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Therapeutic uses
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Depression
Other uses
• Bulimia nervosa
• Obsessive-compulsive disorder
• Panic attacks
Adverse effects
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CNS stimulation
Orthostatic hypotension
 Hypertensive crisis from dietary tyramine
Monoamine Oxidase Inhibitors
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Drug interactions
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Indirect-acting sympathomimetic agents
Interactions secondary to inhibition of hepatic
MAO
Antidepressants: TCAs and SSRIs
Antihypertensive drugs
Meperidine
Preparations, dosage, and administration
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All MAOIs administered orally
Fig. 32–4. Interaction between dietary tyramine and MAOIs.
Transdermal MAOI: Selegiline
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Selegiline (Emsam)
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First transdermal treatment for depression
Much lower risk of hypertensive crisis with
transdermal route vs. oral route
Enters the system without going through GI tract
Adverse effects still occur when used with
sympathomimetic drugs
Atypical Antidepressants
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Bupropion (Wellbutrin)
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Actions and uses
• Acts as stimulant and suppresses appetite
• Antidepressant effects begin in 1–3 weeks
• Does not affect serotonergic, cholinergic, or
histaminergic transmission
• Does not cause weight gain
• Increases sexual desire and pleasure
Atypical Antidepressants
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Bupropion (Wellbutrin) (cont’d)
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Adverse effects
• Can cause seizures
• Agitation
• Tremor
• Tachycardia
• Blurred vision
• Dizziness
• Headache
• Insomnia
Atypical Antidepressants
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Bupropion (Wellbutrin) (cont’d)
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Adverse effects (cont’d)
• Dry mouth
• GI upset
• Constipation
• Weight loss
Drug interactions
• MAOIs can increase the risk of bupropion toxicity
Preparations, dosage, and administration
• Immediate-release, sustained-release, or extendedrelease tablets
Other Atypical Antidepressants
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Mirtazapine (Remeron)
Nefazodone (Serzone)
Trazodone (Oleptro)
Vilazodone (Vibryd)
Amoxapine (Asendin)
Reboxetine (Vestra)
Nonconventional Drugs
for Depression
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Ketamine
St. John’s wort (Hypericum perforatum)
S-Adenosylmethionine
Electroconvulsive Therapy
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Outside the realm of pharmacology
Valuable treatment for depression
Two desirable characteristics
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Two primary types of patients
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Effectiveness
Rapid onset (relative to antidepressant drugs)
Those who have failed to respond to drugs
Severely depressed, suicidal patients
Can terminate ongoing depressive episode
Adverse effect
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Some loss of memory for events immediately surrounding
treatment
Transcranial Magnetic Therapy
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Outside the realm of pharmacology
Reserved for major depression
Employs an insulated magnetic coil, placed against
the scalp, to deliver pulsed magnetic fields to the left
dorsolateral prefrontal cortex
Daily 40-minute sessions for 6 weeks
Adverse effects
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Transient headaches and scalp discomfort. Patients may
also experience eye pain, toothache, muscle twitching, and
seizures. Cognitive changes have not been reported
Vagus Nerve Stimulation
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For long-term therapy of treatment-resistant
depression (TRD)
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Mechanism of action
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When at least four antidepressant drugs have failed
An implanted device
Delivers electrical pulses to the vagus nerve
Side effects
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Hoarseness
Voice alteration
Cough
Dyspnea
Light Therapy
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Exposure to bright light
Effective treatment of seasonal affective disorder
(SAD) and for nonseasonal major depression
May enhance serotonergic neurotransmission
The more intense the light, the greater the response