Antidepressants

  • Scripting of antidepressants increased 400% from ‘05 to ‘08

    • 23% of women (ages 40-50) take antidepressants

    • 2/3 of scripts written are for patients who do not satisfy criteria for depression

  • Depression

    • feelings of hopelessness and inability to experience pleasure

  • Mania

    • feelings of enthusiasm and extreme self-confidence

  • Older antidepressants target prolactin

  • MOA

    • Monoamine theory

      • depression is caused by a decrease of norepinephrine, dopamine, and serotonin

        • drugs act to prolong activity of these neurotransmitters at the synapse

      • mania is caused by an overproduction

      • effect of drugs not well explained by theory

  • Selective Serotonin Reuptake Inhibitors (SSRI)

    • targets serotonin receptors

    • 1st drug of choice

      • better safety and efficacy

    • prolonged time required to build serotonin at synapse (2-12 weeks)

    • effective in depression, plus other disorders

    • Kinetics

      • good oral absorption

      • long half life (upwards of 50 hours)

      • hepatic metabolism

        • inhibits CYP2D6, prolonging the action of other drugs

    • Adverse effects

      • hyponatremia

      • sleep disturbances (drug dependent)

      • sexual dysfunction

        • decreased libido

          • prolactin gives a euphoric feeling → early antidepressants target prolactin → decreased libido

        • delayed ejaculation

          • off label use: premature ejaculation (low dose of SSRI ofc)

        • nausea

        • anxiety

        • drowsiness

        • insomnia

        • drug interactions

    • Discontinuation Syndrome

      • abrupt withdrawal is to be avoided

      • Serotonin syndrome

        • hyperreflexia

        • bruxism

        • fever/sweating

        • agitation

        • headache

  • Serotonin/Norepinephrine Reuptake Inhibitors (SNRI)

    • may be more effective for patients who do no respond to SSRIs

    • increasing NE also decreases pain perception

      • faster response than endogenous opiates

    • caution against rapid removal

    • Venlafaxine and Desvenlafaxine

      • primarily SRI, but will inhibit NE at higher doses

      • side effects similar to sympathetic activity

    • Duloxetine

      • inhibits both S and NE

      • hepatic metabolism

      • inhibits some CYP enzymes

    • Levomilnacipran

      • used for treatment of fibromyalgia

        • neuropathic pain

  • Atypical Antidepressants

    • Buproprion

      • mild antidepressant

      • used for nicotine withdrawal

      • has adverse effects in patients with seizures and those with eating disorders

    • Mirtazapine

      • inhibits inhibition of S and NE

      • 5-HT2 antagonism

      • antihistaminic

        • decreases alertness

    • Nefazodone and Trazodone

      • blocks 5-HT2A receptors

        • 5-HT2 are generally excitatory but 2A is believed to be inhibitory

          • greater expression 2A in individuals who have committed suicide

      • moderate alpha-1 antagonism

        • inhibits sympathetic response

        • orthostasis (light-headedness)

        • dizziness (low BP)

      • hepatotoxicity

      • priapism (prolonged erection of penis)

    • Vilazodone

      • blocks 5-HT1A receptors

      • unique MOA as compared to other SSRI

    • Vortioxetine

      • inhibits serotonin reuptake

      • inhibits 5-HT3 and 5-HT7

      • stimulates 5-HT1A

      • unclear

  • Tricyclic Antidepressants

    • older class of drugs

      • could be considered SNRIs

      • more pronounced side-effects

        • side-effects attributed to blocking

          • serotonergic

          • alpha-adrenergic

          • histaminic

            • drowsiness

          • muscarinic

            • tachycardia, arrhythmias, urinary retention

    • Side effects

      • weight gain

      • dry mouth

      • constipation

      • urinary retention

      • blurred vision

      • tachycardia

      • arrhythmias

      • nausea

      • drowsiness

    • Actions

      • mood elevation

        • may take 2 weeks to work

      • improved mental alertness

      • increase physical activity

      • reduced morbid preoccupations

      • dose can be reduced once desirable effects are achieved

    • Other uses

      • amitriptyline

        • migraines

        • neuropathic pain

        • idiopathic pain

      • doxepin

        • insomnia

    • Kinetics

      • lipid solubility (CNS)

      • variable bioavailability

        • first pass metabolism

    • Adverse effects

      • predominantly due to muscarinic blockade

        • unopposed sympathetic stimulation

      • histaminergic blockade

      • Low TI

        • side effects closer to normal dose

      • Exacerbates

        • BPH

        • Epilepsy

        • Arrhythmias

  • Monoamine Oxidase Inhibitor (MAOI)

    • monoamine oxidase

      • mitochondrial enzyme

        • neurons and liver

      • inactive excess neurotransmitters

        • may be reversible or irreversible

    • MOA

      • irreversible binding

        • increases NE, dopamine, and serotonin

      • in GI tract, inhibit detoxification of substances including food

        • avoid cheeses and any aged foods

      • delay in the therapeutic effect

      • some formulations have an amphetamine-like effect

    • therapeutic use

      • 3rd choice for depression

    • kinetics

      • good oral absorption

      • enzymes regenerate a few weeks after discontinuing

        • especially important when changing therapy

    • adverse effects

      • tyramine detoxification impaired

        • leads to catecholamine release

        • hypertensive episode

      • drowsiness

      • hypotension

      • risk of serotonin syndrome

  • Mania and Bipolar Disorder

    • Lithium

      • MOA → unknown

      • TI → low

      • Side effects → multiple

      • renally elimination

    • Other

      • atypical antipsychotics