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Antidepressants 1
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Antidepressants Primarily used to relieve symptoms of depression
Can also help patients with anxiety disorders Not indicated for uncomplicated bereavement 2
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Antidepressant Groups
Tricyclic antidepressants Selective serotonin reuptake inhibitors (SSRIs) Serotonin/norepinephrine reuptake inhibitors (SNRIs) Monoamine oxidase inhibitors (MAOIs) Atypical antidepressants 3
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Depression 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 4
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Clinical Features 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 5
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Pathogenesis Complex and incomplete Possible contributing factors
Genetic heritage Difficult childhood Chronic low self-esteem Monoamine hypothesis of depression Depression is caused by functional insufficiency of monoamine neurotransmitters 6
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Treatment Modalities Pharmacotherapy
Primary therapy Depression-specific psychotherapy (eg, cognitive behavioral therapy) Electroconvulsive therapy (ECT) 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 Only after treatment with at least four drugs has failed 7
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Suicide Risk with Antidepressants
May increase suicidal tendency early in the treatment Patients should be observed closely for: Suicidality Worsening mood Changes in behavior Precautions Prescriptions should be written for the smallest number of doses consistent with good patient management Dosing of inpatients should be directly observed 8
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Selective Serotonin Reuptake Inhibitors (SSRIs)
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 9
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Selective Serotonin Reuptake Inhibitors (SSRIs)
Fluoxetine (Prozac, Sarafem) Most widely prescribed SSRI in the United States Other SSRIs 10
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Mechanism of Action Produce selective inhibition of serotonin reuptake
Produce CNS excitation 11
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Therapeutic Uses Primarily used to treat major depression Other uses
Obsessive-compulsive disorder Bulimia nervosa Premenstrual dysphoric disorder 12
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Adverse Effects Serotonin syndrome Withdrawal syndrome
2–72 hours after treatment Withdrawal syndrome Neonatal effects when used in pregnancy Teratogenesis Extrapyramidal side effects Bruxism Bleeding disorders Sexual dysfunction Weight gain 13
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Drug Interactions Monoamine oxidase inhibitors Warfarin
Risk of serotonin syndrome Warfarin Tricyclic antidepressants and lithium Can elevate levels of these drugs 14
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Other SSRIs Sertraline (Zoloft)
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 15
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Other SSRIs Sertraline (Zoloft) (cont’d) Side effects 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 16
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Other SSRIs Sertraline (Zoloft) (cont’d) Drug interactions MAOIs
Pimozide 17
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Other SSRIs Fluvoxamine (Luvox) Inhibition of serotonin reuptake
Used for obsessive-compulsive disorder Rapidly absorbed from the GI tract Half-life: about 15 hours Interacts adversely with MAOIs 18
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Other SSRIs Fluvoxamine (Luvox) (cont’d) Side effects Nausea Vomiting
Constipation Weight gain Dry mouth Headache Sexual dysfunction Abnormal liver function Sedative effects 19
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Other SSRIs Paroxetine (Paxil, Paxil CR, Pexeva)
Inhibition of serotonin uptake Indications Major depression Obsessive-compulsive disorder Social phobia Panic disorder Generalized anxiety disorder Post-traumatic stress disorder Premenstrual dysphoric disorder 20
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Other SSRIs Citalopram (Celexa)
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 21
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Other SSRIs Escitalopram (Lexapro) S-isomer of citalopram
Better tolerated than citalopram Side effects Nausea Insomnia Somnolence Sweating Fatigue Interacts with MAOIs 22
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Serotonin/Norepinephrine Reuptake Inhibitors (SNRIs)
Venlafaxine (Effexor) Duloxetine (Cymbalta) 23
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Venlafaxine (Effexor)
Indications 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 24
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Venlafaxine (Effexor)
Side effects Nausea Headache Anorexia Nervousness Sweating Somnolence Insomnia Weight loss/anorexia Diastolic hypertension Sexual dysfunction Hyponatremia (in older adult patients) Neonatal withdrawal syndrome 25
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Desvenlafaxine (Pristiq)
Mechanism of action Strong inhibitor of 5-HT and NE reuptake Does not block cholinergic, histaminergic, or alpha1-adrenergic receptors 26
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Desvenlafaxine (Pristiq)
Side effects Nausea Headache Dizziness Insomnia Diarrhea Dry mouth Sweating Constipation Sexual effects, including erectile dysfunction Decreased libido 27
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Duloxetine (Cymbalta)
Mechanism of action and therapeutic use Inhibits serotonin and NE reuptake Weakly inhibits dopamine reuptake Does not inhibit monoamine oxidase (MAO) Relieves depression Relieves pain of diabetic peripheral neuropathy Pharmacokinetics Well absorbed following oral administration Food reduces rate of absorption Highly bound to albumin in the blood Half-life: 12 hours 28
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Duloxetine (Cymbalta)
Adverse effects Nausea Somnolence Dry mouth Sweating Insomnia Blurred vision Effects in pregnancy and lactation Drug interactions Alcohol MAOIs Drugs that inhibit CYP1A2 or CYP2D6 Preparations, dosage, and administration 29
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Tricyclic Antidepressants
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 30
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Tricyclic Antidepressants
Chemistry Mechanism of action Pharmacokinetics Therapeutic uses Adverse effects Drug interactions Dosage and routes of administration Preparations and drug selection 31
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Chemistry Nucleus of the tricyclic antidepressants has three rings
Similar to phenothiazine antipsychotics Produce varying degrees of: Sedation Orthostatic hypotension Anticholinergic effects 32
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Fig. 32–1. Structural similarities between tricyclic antidepressants and phenothiazine
antipsychotics. 33
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Mechanism of Action Block neuronal reuptake of two monoamine transmitters Norepinephrine (NE) Serotonin 34
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Pharmacokinetics Long and variable half-lives
Usually single daily dose Requires individualization of dosage 35
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Fig. 32–2. Mechanism of action of tricyclic antidepressants.
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Therapeutic Uses Depression Bipolar disorder Other uses
Neuropathic pain Chronic insomnia Attention-deficit/hyperactivity disorder Panic disorder Obsessive-compulsive disorder 37
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Adverse Effects Orthostatic hypotension Anticholinergic effects
Diaphoresis Sedation Cardiac toxicity Seizures Hypomania “Yawngasm” 38
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Drug Interactions Monoamine oxidase inhibitors
Direct-acting sympathomimetic drugs Indirect-acting sympathomimetic drugs Anticholinergic agents CNS depressants 39
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Toxicity Clinical manifestations
Primarily from anticholinergic and cardiotoxic actions Dysrhythmias Tachycardia Intraventricular blocks Complete atrioventricular block Ventricular tachycardia Ventricular fibrillation 40
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Toxicity Treatment Gastric lavage Ingestion of activated charcoal
Physostigmine Propranolol, lidocaine, or phenytoin 41
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Dosage and Routes of Administration
Initial doses should be low Routes of administration All can be administered by mouth 42
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Preparation and Drug Selection
Nine equally effective tricyclic antidepressants (TCAs) Selection based on side effects 43
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Monoamine Oxidase Inhibitors
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 44
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Monoamine Oxidase Inhibitors
Mechanism of action 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 45
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Monoamine Oxidase Inhibitors
Mechanism of action (cont’d) 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 46
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Fig. 32–3. Mechanism of action of monoamine oxidase inhibitors.
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Monoamine Oxidase Inhibitors
Therapeutic uses Depression Other uses Bulimia nervosa Obsessive-compulsive disorder Panic attacks Adverse effects CNS stimulation Orthostatic hypotension Hypertensive crisis from dietary tyramine 48
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Monoamine Oxidase Inhibitors
Drug interactions Indirect-acting sympathomimetic agents Interactions secondary to inhibition of hepatic MAO Antidepressants: TCAs and SSRIs Antihypertensive drugs Meperidine Preparations, dosage, and administration All MAOIs administered orally 49
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Fig. 32–4. Interaction between dietary tyramine and MAOIs.
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Transdermal MAOI: Selegiline
Selegiline (Emsam) 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 51
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Atypical Antidepressants
Bupropion (Wellbutrin) 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 52
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Atypical Antidepressants
Bupropion (Wellbutrin) (cont’d) Adverse effects Can cause seizures Agitation Tremor Tachycardia Blurred vision Dizziness Headache Insomnia 53
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Atypical Antidepressants
Bupropion (Wellbutrin) (cont’d) 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 extended-release tablets 54
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Other Atypical Antidepressants
Mirtazapine (Remeron) Nefazodone (Serzone) Trazodone (Oleptro) Vilazodone (Vibryd) Amoxapine (Asendin) Reboxetine (Vestra) 55
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Nonconventional Drugs for Depression
Ketamine St. John’s wort (Hypericum perforatum) S-Adenosylmethionine 56
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Electroconvulsive Therapy
Outside the realm of pharmacology Valuable treatment for depression Two desirable characteristics Effectiveness Rapid onset (relative to antidepressant drugs) Two primary types of patients Those who have failed to respond to drugs Severely depressed, suicidal patients Can terminate ongoing depressive episode Adverse effect Some loss of memory for events immediately surrounding treatment 57
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Transcranial Magnetic Therapy
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 Transient headaches and scalp discomfort. Patients may also experience eye pain, toothache, muscle twitching, and seizures. Cognitive changes have not been reported 58
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Vagus Nerve Stimulation
For long-term therapy of treatment-resistant depression (TRD) When at least four antidepressant drugs have failed Mechanism of action An implanted device Delivers electrical pulses to the vagus nerve Side effects Hoarseness Voice alteration Cough Dyspnea 59
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Light Therapy 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 60
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