Transcript The Neuroscience of Psychiatry

Anti-Anxiety Medications
Brian Ladds, M.D.
Anti-Anxiety Medications
• 1903: first barbiturate introduced in U.S.
– e.g., pentobarbital (Nembutal), amobarbital (Amytal)
– high abuse potential, lethality in overdose & in
withdrawal
• 1960: first benzodiazepine introduced
– e.g., chordiazepoxide (Librium), diazepam (Valium)
which is more potent
– now ~ 39 benzodiazepines
• Other med’s are also sedative (or “anxiolytic”)
Hypothesis of the
Neuro-biology of Anxiety
• Abnormalities in the gamma-aminobutyric
acid (GABA) system
• Monoamine systems are also involved
• NE
• SE
Amino Acid Neurotransmitters
• The most prevalent neurotransmitters (NT)
in the brain
– synthesized in the brain and well-insulated from
fluctuations in serum level
• Nearly all neurons:
– are activated by excitatory amino acid NT
– inhibited by inhibitory amino acid NT
Amino Acid Neurotransmitters
• Excitatory amino acid NT:
– Glutamate
• Inhibitory amino acid NT:
– GABA
– (Glycine)
• Glutamate and GABA differ by a single
carboxyl group
Amino Acid Neurotransmitters
• Actions mediated mostly at ligand-gated ion
channel type receptors
– rapid, short-lasting alterations in membrane potential
• (In contrast to many of the receptors for DA, NE,
and SE, which are G-protein coupled receptors
linked to second messengers)
GABA
• Gamma-Amino Butyric Acid (GABA)
– synthesized by glutamic acid decarboxylase
(GAD)
• rate-limiting step
– catabolized by GABA transaminase
• valproate and other medications inhibit this enzyme
GABA
• In the cortex, GABA is localized primarily
to intrinsic neurons
– local feedback loop
– tonic inhibition
• GABAergic dysfunction is sufficient for seizures
• In extrapyramidal motor system, GABA
efferent projection neurons
• e.g. striato-nigral pathway: inhibit dopaminergic
neurotransmission
GABAA Receptor Complex
• Ligand-gated chloride ion channel
– brief current flow, decreasing excitability
• Distinct sub-units
– has a multiplicity of isoforms
• >5000 possible combinations
• may permit development of novel drugs that are
selective
GABAA Receptor Complex
• 3 functional domains
– GABA recognition site
– ion channel site
– barbiturates prolong channel opening
– benzodiazepine receptor site
– 1 sub-type is the “central receptor” (only in brain)
» unclear endogenous ligand
– benzo’s increase affinity of GABA for its binding site
» inc. frequency of Cl- ion channel opening; influx of Clhyperpolarizes neuron, causing inhibition and decreased
excitability
Benzodiazepine Receptor
• The benzodiazepine receptor is unique in
that it mediates drugs that have opposite
effects.
Ligands of the
Benzodiazepine Receptor
• Agonists
• Inverse agonists
– decreases Cl- ion channel opening
– anxiogenic
• Antagonists
– inhibit agonists and inverse agonists
– restores the unmodified state
– flumazenil (Mazicon)
• treatment of benzo overdose
Benzodiazepines
• Benzodiazepines
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anti-convulsants
muscle relaxants (via spinal cord)
sedative-hypnotic
anxiolytic
prevent alcohol withdrawal symptoms
• e.g., Delirium Tremens “DT’s”
Benzodiazepines
• All BZ’s are equally efficacious
– different potencies, therefore different doses
• Rapid onset of action
– Unlike anti-depressants
• Few side effects
–
–
–
–
sedation
memory problems
dependence
withdrawal
Benzodiazepines
• Diazepam (Valium)
• long half-life
– less withdrawal
• but increased sedation
• Alprazolam (Xanax)
• short half-life
– more withdrawal
• multiple daily dosing
• Lorazepam (Ativan)
• intermediate half-life
Anxiolytics
• Benzodiazepines
• Barbiturates
– higher lethality in overdose
• Anti-depressants
• Zolpidem (Ambien)
– acts on the GABA receptor complex
– used for insomnia
• Anti-histamines
• Buspirone (Buspar)
Buspirone
• Novel anxiolytic (for GAD)
– non-sedative & non-benzodiazepine
– unclear mechanism of action
• may affect serotonin system in unique ways
• may affect GABA system in unique ways
• few side effects
– no dependence or withdrawal
• slow onset of action
Summary: Anxiety
• Low GABA ~ high anxiety (& sz. d/o)
• BZ -> inc GABA ->inc Cl-> dec excitability -> less anxiety (& sz d/o)
• Other neurotransmitters (NE, SE) are also
involved, and other medications are
efficacious