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Anxiolytics, Continued
• Benzodiazepines
• Buspirone (BuSpar®)
• Antiepileptics
• SSRI, SNRI antidepressants
Busprione (BuSpar®)
Buspirone (BuSpar®) – Selective serotonin 5-HT1A agonist
• Lacks risks of dependence and withdrawal compared to benzodiazepines
• Antianxiety effects after several weeks of treatment
(contrast to benzodiazepines – fast acting)
• Low oral bioavailability (4-5%) due to extensive first pass metabolism by CYP3A4
• May be taken with grapefruit juice to increase bioavailability
(furanocoumarins inhibit CYP3A4)
Antiepileptics (Anticonvulsants) – Expanded Use to Other Indications
• Bipolar disorder (“mood stabilizer”)
• Alcohol withdrawal
• Chronic pain
• Depression
• Anxiety disorders
Antiepileptics (Anticonvulsants) – Mechanisms of Action
Conventional antiepileptics
1. Block Na+ channels, reducing release of glutamate (excitatory NT)
or
2. Enhance GABA function
Glutamate
excitatory NT
GABA
inhibitory NT
Antiepileptics for Anxiety Disorders and Pain
Neurontin® and Lyrica® approved for neuropathic and chronic pain, anxiety disorders
Generalized anxiety disorder (GAD), social anxiety disoder (SAD), panic disorder
Gabapentin (Neurontin®)
Increases GABA synthesis via enzyme
modulation
Does not bind to GABA receptor
Pregabalin (Lyrica®)
More potent than gabapentin
Decreases release of glutamate,
norepinephrine, substance P
Does not affect GABA neurotransmission
Antidepressants
First marketed in late 1950s
Estimated 10% of Americans are using an antidepressant
Higher use among women, and non-Hispanic white people
Antidepressants also indicated for many anxiety disorders.
Stress believed to be most significant cause of depression.
http://www.health.harvard.edu/blog/astounding-increase-in-antidepressant-use-by-americans-201110203624
Efficacy of Antidepressants Greater in Severe or Chronic Cases
HDRS - Hamilton Depression Rating Scale - method of measuring severity of depression.
17 item questionnaire – maximum score of 52 (higher score = greater severity)
Antidepressants – Theories on Mechanism of Action
Classically, depression was attributed to a deficiency in the neurotransmitters serotonin,
norepinephrine and dopamine (“monoamines”). Prolonging the presence of NT in synaptic
cleft was thought to be responsible for improved mood.
Weakness of “monoamine” model:
1. NT changes occur rapidly though clinical effects require weeks of treatment.
2. >40% of patients do not respond to monoaminergic antidepressants.
3. Single IV infusion of ketamine (glutamate NMDA antagonist) can rapidly relieve symptoms.
Antidepressants – Theories on Mechanism of Action
Neurogenic theory of depression
Current view of antidepressant action is based neuronal repair and increased neurogenesis.
1. The brain is capable of synthesizing new neurons (hippocampus, frontal cortex)
2. Existing neurons are able to repair or remodel themselves
Support for theory
Stress reduces hippocampal and frontal cortical neurogenesis and damages existing neurons.
Antidepressants can reverse hippocampal shrinkage.
Molecular Mechanism of Action of Long-Term Antidepressant Treatment
Second-messenger systems
activate downstream
production of proteins
controlling gene expression.
BDNF = Brain Derived
Neurotropic Factor.
Protein supporting survival
and grown of neurons and
synapses
Therapeutic Delay in Clinical Effect of Antidepressants Due to Time Required for
New Neurons to Develop, Mature, and Become Functional
• BNDF levels decreased in depressed patients
• Antidepressants, exercise, light therapy, electroconvulsive therapy can increase BDNF
http://www.nature.com/mp/journal/v12/n12/fig_tab/4002075f1.html#figure-title
Antidepressant Drug Classes
Monoamine oxidase inhibitors (MAOIs)
Tricyclic antidepressants (TCAs)
Selective serotonin reuptake inhibitors (SSRIs)
Serotonin-norepinephrine reuptake inhibitors (SNRIs)
Others
Monoamine Oxidase Inhibitors (MAOIs) – First Generation Antidepressants
MAOIs increase the levels of released serotonin, norepinephrine and dopamine by
blocking the enzyme that breaks them down (via oxidation) in the presynaptic neurons.
norepinephrine
norepinephrine
aldehyde
ammonia
Monoamine Oxidase (MAO) – Two Subtypes
MAO-A: Metabolizes serotonin, norepinephrine, dopamine, tyramine
MAO-B: Metabolizes dopamine and phenethylamine
MAOIs - a partial list
Isocarboxazid (Marplan®) - Non-selective MAO-A/MAO-B inhibitor
Moclobemide (Aurorix®, Manerix®) – Selective MAO-A inhibitor
Selegiline (Deprenyl®, Eldepryl®, Emsam®) – Selective MAO-B inhibitor
Monoamine Oxidase Inhibitors (MAOIs)
• MAOIs most efficacious drugs developed for depression (developed late 1950s)
• Potentially serious side effects and drug-drug interactions limit use (last line of treatment)
• Older MAOIs – irreversible inhibitors , covalently modified enzymes (MAO-A, MAO-B).
Enzyme activity resumes after ca. 2 weeks, when new enzyme synthesized.
• Newer MAOIs are reversible inhibitors, some are selective for one subtype. MAO-B selective
reversible inhibitors do not require the same dietary restrictions.
Monoamine Oxidase Inhibitors (MAOIs) – Dietary Restrictions
Most MAOIs require avoiding tyramine-containing foods, since tyramine is oxidized by
MAO. Inhibition of MAO can result in high levels of tyramine, leading to hypertensive crisis
(high blood pressure, often termed the “cheese effect”)
tyramine
Monoamine Oxidase Inhibitors (MAOIs) – Drug-Drug Interactions
Lethal interactions can occur with MAOIs and some psychoactive drugs that affect serotonin
levels, such as:
• SSRIs
• MDMA
• Tricyclics
Dose reductions required for some drugs, such as those that affect epinephrine,
norepinephrine, or dopamine levels.
Tricyclic Antidepressants (TCAs) – Another Class of First-Generation Antidepressants
• Tricyclic antidepressants were developed in the late 1950s
• Categorized by their chemical structure
• Most act as serotonin and norepinephrine reuptake inhibitors.
Imipramine
(Tofranil®)
Desipramine
(Norpramin®)
Nortriptyline
(Pamelor®)
Tricyclic Antidepressants Largely Replaced by SSRIs and SNRIs Due to Side Effects
• TCAs also block postsynaptic receptors for histamine and acetylcholine
• Histamine receptor blockade results in drowsiness and sedation (similar to diphenhydramine)
• Acetylcholine receptor blockade leads to confusion, memory and cognitive impairments, dry
mouth, blurred vision, increased heart rate, urinary retention.
• Nortriptyline and desipramine generally favored over other TCAs due to less sedation and
fewer anticholinergic side effects
• Overdose (e.g. suicide attempts) can lead to cardiotoxicity
Selective Serotonin Reuptake Inhibitors (SSRIs)
Fluoxetine (Prozac®)
Paroxetine (Paxil®)
Sertraline (Zoloft®)
Fluvoxamine (Luvox®)
Citalopram (Celexa®)
Escitalopram (Lexapro®)
Vilazodone (Viibryd®)
Clinical differences between the SSRIs is small, though
pharmacokinetics and receptor selectivities differ.
SSRIs - similar efficacy as older antidepressants.
Fewer side effects with SSRIs versus older ADMs.
SSRI efficacy of ca. 17% versus placebo.
Selective Serotonin Reuptake Inhibitors (SSRIs)
SSRIs block the presynaptic transporter for
serotonin reuptake, resulting in higher levels of
serotonin in the synaptic cleft.
SSRIs do not block postsynaptic serotonin receptors.
SSRIs Therapeutic Actions and Side Effects Due to
Actions of Serotonin at Post-Synaptic Receptors
5-HT1A
Antidepressant and anxiolytic effects
5-HT2
Insomnia, anxiety, agitation, sexual dysfunction, serotonin syndrome at higher doses or when
combined with another serotonergic agent. Same receptor LSD and other psychedelics target.
5-HT3
Nausea
SSRI Discontinuation Syndrome
SSRIs not abuse-prone, though withdrawal symptoms can occur upon abrupt termination.
Onset within 2-5 days; symptoms persist 2-4 weeks.
Symptoms often associated with discontinuation of paroxetine (Paxil®).
Fluoxetine (Prozac®) has a long half-life, reducing discontinuation syndrome symptoms.
Flulike symptoms, insomnia, nausea, imbalance, sensory disturbances, hyperarousal
Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)
Development – Was believed that actions at two different synaptic sites may improve or
maintain efficacy while limiting side effects
Venlafaxine (Effexor®)
Duloxetine (Cymbalta®)
----------------------------------------Venlafaxine – significant sexual side effects, can increased blood pressure, can trigger manic
state in patients with bipolar disorder
Duloxetine – approved for neuropathic pain, may induce manic episode in bipolar disorder
Mirtazepine (Remeron®) – Alternate Mechanisms of Action
• Blocks autoreceptors (feedback mechanism) causing increase in release of
norepinephrine and serotonin
• Blocks 5-HT2 and 5-HT3 receptors – hence avoiding several side effects of SSRIs
(anxiety, insomnia, agitation, nausea, sexual dysfunction)
--------------------------------Side effects include drowsiness (often limiting), increased appetite and weight gain
Trazodone (Desyrel®, Oleptro®) – An Atypical Antidepressant
Partial agonist at 5HT1A, antagonist at other 5HT receptors
Most common side effects – drowsiness, decreased blood pressure, priaprism
One of the most prescribed prescriptions for insomnia.
Doses lower than those used for antidepressant activity for sleep (t1/2 = 7 h).
Buproprion (Wellbutrin®) – Dopamine and Norepinephrine Reuptake Inhibitor
• Monotherapy or add-on therapy for depression
• Clinical effects similar to psychostimulants with low abuse potential
• Lacks side effects associated with SSRIs (sexual side effects, weight gain)
• Side effects can include anxiety, restlessness, tremor, insomnia, seizures
• Also marketed as a smoking cessation (Zyban®)