Psychopharmacology of anxiety
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Psychopharmacology of Anxiety. Paul Glue [email protected] April 2010. Objectives. Definition (Re)Classification of anxiety Pharmacological theories of anxiety Pharmacology of antianxiety treatments Are there better options on the horizon?. Anxiety is….

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Objectives
Objectives

  • Definition

  • (Re)Classification of anxiety

  • Pharmacological theories of anxiety

  • Pharmacology of antianxiety treatments

    • Are there better options on the horizon?


Anxiety is
Anxiety is….

  • … a subjective experience of unpleasant anticipation, accompanied by characteristic behavioural and physiological responses (e.g. avoidance, vigilance and arousal)

  • Evolutionary value: to protect individuals from danger.

  • Present in most/?all higher animals – ? universal mechanism by which organisms adapt to adverse conditions.

  • Symptoms:

    • Cognitive (feelings of apprehension, fear)

    • Physical symptoms (shortness of breath, trembling, palpitations etc);

    • Endocrine and physiological changes

Normal Emotion Pathological State

Spectrum

severe symptoms & functional impairment


….and it’s very common

NZ Mental Health Survey 2006


Dsm and anxiety
DSM and anxiety

Clustering based on phenomenology; divorcing of depressive vs anxiety components


Factor Analysis of CIDI data from 10,641 participants in the Australian National Survey of Mental Health and Well-Being, a large-scale community epidemiological survey of mental disorders


Where does anxiety arise in the brain
Where does anxiety arise in the brain?

  • Multiple components

  • Amygdala (A) and insular cortex (B) activation– key structures in emotional processing/integration

    (Etkin Am J Psych 2007)


Drug treatments for anxiety

Fast Onset

-Effects noted within hours/days

-Generally act on amino acid systems (excitatory/inhibitory)

-Higher liability for tolerance, withdrawal on stopping Rx

Delayed Onset

-Effects noted after several weeks

-Act on modulatory central pathways (NE, 5HT)

-Lower liability for tolerance, withdrawal

Drug treatments for anxiety

 Both Types

-Effect size (mean symptom change) broadly similar for all agents; main points of differentiation may be in speed of onset; types of side effects; pharmacodynamic interactions (e.g. alcohol); metabolic interactions (some SSRIs)


Overview of available drugs by DSM disorder

Available drugs

Experimental

Depression

GAD

PD

SAD

PTSD

OCD

Slow

Onset

Fast

Onset

Antidepressants (SSRIs, SNRIs, TCAs)

Buspirone

BDZs

anti-H1

quetiapine/antihistaminergic antipsychotics

clonidine

a2ds

Antiglutamate Rx

Subtype selective benzodiazepines


Timecourse of ssri and bdz effects in e g panic disorder
Timecourse of SSRI and BDZ Effects in (e.g.) Panic Disorder

BDZs: high

relapse rate

Acute provocation by SSRIs

SSRIs: slower onset of action

~equivalent

efficacy

BDZs: faster onset of action

SSRIs: low

relapse rates

SSRI

BDZ

Anxiety Score

Pretreatment Treatment Withdrawal


Key neurotransmitters in anxiety
Key Neurotransmitters in Anxiety

  • Monoamines

    • Norepinephrine

    • Serotonin

    • Histamine

  • GABA (gamma-aminobutyric acid)

  • Glutamate

  • Drugs affecting central excitatory neurotransmitter release


Slow onset anti anxiety drugs

PRESYNAPTIC NEURON

MAO

MAO

MAO

SYNAPSE

POSTSYNAPTIC NEURON

SSRIs/SNRIs – block transporter

Buspirone - autoreceptor antagonist

Slow onset anti-anxiety drugs

  • Antidepressants

    • Inhibit reuptake of serotonin &/or norepinephrine

  • Buspirone

    • Serotonin 1a partial agonist

  • 6-8 weeks for full effect

  • Antianxiety effects are presumably indirect - ? via BDNF


Cortical Innervation – NE and 5HT Pathways

Common features:

Cell bodies arising in upper brainstem

Radiate to most cortical areas

Intense arborization of dendritic terminals

Consistent with modulatory role

Common features:

Cell bodies arising in upper brainstem

Radiate to most cortical areas

Intense arborization of dendritic terminals

Consistent with modulatory role

DOPAMINE

NOREPINEPHRINE

SEROTONIN

NE

Ventral Tegmental Area

Substantia Nigra

Substantia Nigra

Raphe Nuclei

DOPAMINE

Common features:

Cell bodies arising in upper brainstem

Radiate to most cortical areas

Intense arborization of dendritic terminals

Consistent with modulatory role on other cortical synapses


Pharmacological theories of anxiety
Pharmacological theories of anxiety

Serotonin theories (1):too much serotonin

Observations:

increasing brain 5HT (acute SSRIs) increases anxiety

serotonin agonists (mCPP) are anxiogenic in panic disorder

5HT1A, 2A and 3 receptor subtypes associated with anxiety in animals

5HT1A K/O mice highly fearful

drugs which decrease brain 5HT or 5HT partial agonists reduce anxiety

Serotonin theories (2):too little serotonin :

Observations:

5HT depletion can increase sensitivity to anxiogenic probes

infusion of 5HT precursors are anxiolytic

endocrine responses to 5HT probes reduced in anxiety disorders

reduced 5HT in depression; depression and anxiety frequently comorbid

high variability in reported findings within and between anxiety disorders


Pharmacological theories of anxiety ne

Observations:

increased NE firing/activity produces anxiety state

stimulation of locus ceruleus; a2-antagonists (yohimbine/idazoxan)

plasma NE responses to stress higher in GAD vs controls (not all studies)

inhibition of NE activity is anxiolytic (b-blockers; a2-agonist clonidine)

Prazosin, clonidine effective against flashbacks in PTSD

MHPG concs (NE metabolite) correlate with anxiety in panic d/o

Hypothesis:

NE neuronal overactivity causes anxiety

possibly due to reduced sensitivity of inhibitory (a2) autoreceptor

Problems:

not all panic disorder patients develop anxiety to NE probes

highly variable results across different anxiety disorders (GAD, SP, PTSD)

b-blockers; a2-agonists are relatively weak anxiolytics

Pharmacological theories of anxiety - NE

+

-

agonist - inhibits cell firing

+

-

antagonist - increases cell firing


Fast acting drugs bdzs bind to the gaba a receptor
Fast acting drugs: BDZs bind to the GABA-A Receptor

Resting state plus GABA plus GABA and BDZ

BDZ

GABA

GABA

Cl-

Cl-

Cl-

Cl-

Cl-

Cl-

Cl-

Cl-

Cl-

Cl-

Cl-

  • GABA-A: ligand-gated receptor complex

  • Made up of 5 helical columns surrounding

  • a chloride channel

  • Separate binding sites for

    • GABA, GABA agonists/antagonists

    • benzodiazepines

    • barbiturates

    • ethanol

    • neurosteroids (pregnanolone etc)

    • convulsants (picrotoxin; PTZ)

outside

Cell membrane

inside


Benzodiazepine pharmacology
Benzodiazepine pharmacology

Partial Partial Inverse Inverse

Agonists Agonists Antagonists Agonists Agonists

Anxiolytic Neutral/ Anxiogenic

Anticonvulsant no effect Convulsant

Amnestic Promnestic

Sedating Arousing

Diazepam Abecarnil Flumazenil FG7142

Lorazepam Bretazenil DMCM

Clonazepam

(all BDZs and

Z-drugs in

clinical use)


Pharmacological theories of anxiety 1 gaba theories
Pharmacological theories of Anxiety (1) - GABA theories

Observations:

positive modulators of GABA-A receptor are anxiolytic (BDZs; barbiturates; ethanol)

negative modulators are anxiogenic (FG7142; metrazol) in normals

flumazenil (BDZ antagonist) is anxiogenic in panic disorder but not in healthy controls; BDZs are less sedating/impairing in anxious patients than in controls

Agonists Antagonists Inverse

-anxiolytic -neutral/no effect Agonists

-diazepam, etc -flumazenil -anxiogenic

Normal

Panic

Disorder

Agonists are Antagonists

less sedating are anxiogenic


Pharmacological theories of anxiety 1 gaba theories1
Pharmacological theories of Anxiety (1) - GABA theories

Observations (cont’d):

Altered GABA-A PET binding in panic disorder

  • 15-BDZ naïve, drug free patients with panic disorder and 18 controls

  • Statistical parametric map illustrating an area where benzodiazepine receptor binding (11C-flumazenil) was decreased in subjects with panic disorder vs control subjects (R dorsal anterolateral prefrontal cortex). Arch Gen Psych 2008:1166



Gaba a subtype selective benzodiazepines
GABA-A subtype-selective benzodiazepines

  • GABA-A receptor subtypes: most common type in

    the brain is a pentamer comprising 2 α's, 2 β's, and 1 γ

    (α2β2γ). Available BDZs are nonselective agonists.

  • Selective agonists for:

    > α1 subtype produce sedation and dependence

    > α2 and α3 are anxiolytic

    > α5 affect cognition and memory

  • MK-0343: α2/α3 partial agonist - reduced effects on alertness, memory and postural stability in healthy volunteers vs lorazepam

  • SL651498: full agonist at α2/3 subunits; partial agonist at α1 and α5 subunits

    > neither drug yet tested in anxious patients – will they work??


α1 subunits and dependence liability: GABA-A α1 subunit knockout mice show no tendency to increase consumption of midazolam compared with normal (wild type) mice Tan, Nature 2010, 463:769-774


Anxiety and histamine
Anxiety and Histamine

  • Brain histamine neurons arise

    in tuberomammillary nucleus

    in the posterior hypothalamus.

  • Project throughout the nervous

    system

  • May stimulate the cerebral cortex either directly or indirectly (5HT, ACh, galanin, GABA, substance P etc)

  • 4 receptors (H1-4)

  • Histamine is arousing/excitatory; increased release in stressed animals; associated with anxiety related behaviours (no human data)


Antihistamines are effective anxiolytics
Antihistamines are effective anxiolytics

Generalized Anxiety Disorder

Antihistamines (hydroxyzine)

50mg/day; rapid onset; equivalent efficacy to buspirone, bromazepam

No evidence of dependence, withdrawal

QT prolongation, delirium after OD

Antipsychotic drugs (quetiapine, trifluoperazine) efficacious; rapid onset

Much lower doses (~1/3-1/10) than those used for psychosis – presumably reflect antihistaminic effects

Dose-response is unclear (50 - 150 - 300mg equivalent)

No long term safety data


Glutamate and anxiety

COOH

COOH

Glutamate and Anxiety

H2N

  • Glutamate is the most abundant transmitter in the CNS

    • Fast, excitatory transmitter; receptors on almost all neurons. Transmitter in ~60% of neurons, esp cortex, limbic structures.

  • Glutamate binds to 4 classes of receptor

    • three "ionotropic" receptor classes - ligand-gated ion channels which are characterized by the different ligands that bind to them:

      • AMPA

      • kainic acid

      • N-methyl-D-aspartate or NMDA

    • one G-protein coupled or "metabotropic" receptor class.

  • Both direct and indirect effects on neurotransmission

    • Regulates release of many other neurotransmitters

  • Altered glutamate transmission linked with stress and anxiety

    • Different pharmacological interventions with the glutamate system can influence behavioural responses in preclinical anxiety models


Ly354740 in gad
LY354740 in GAD

mGlu2/3 agonist (decreases release of excitatory AAs)

Study stopped early because of tox problems (seizures)

LY354740 may be as effective as lorazepam 4-5mg/day, with a relatively rapid onset of action

Too early to say if this approach will be available clinically

LY354740

HAM-A

Neuropsychopharm 2008


Anxiety and gabapentin pregabalin

Binding site

a2

1

g

extracellular

d

GABA

II

III

I

IV

cytoplasmic

Gabapentin

II-III

b

Anxiety and Gabapentin/Pregabalin

- Drugs effective in epilepsy, neuropathic pain and GAD. Do not work in MDD.

- Bind to the 2- subunit of voltage-gated calcium channels and inhibit release of glutamate, substance P, NE, etc.


Pregabalin alprazolam placebo in gad

…but no clear dose-response in GAD

Pregabalin = Alprazolam > placebo in GAD

Week

EP

Mean baseline HAM-A score = 25.

Rickels et al. Arch Gen Psychiatry. 2005;62:1022-1030.


Non pharmacological treatments
Non-Pharmacological Treatments

Simple behavioural methods (breathing; relaxation) effective in mild anxiety

Certain psychotherapies (e.g. CBT) are as effective as SSRIs/TCAs in panic disorder and GAD

no clear advantage with combined CBT and drug Rx

Behaviour therapy is as effective as SSRIs/TCAs in OCD

Ideal combination(s) of drug therapy and psychological therapies not yet determined


The future for anxiety drug treatment
The future for anxiety drug treatment

  • Are current diagnostic categories tenable?

    …and will this be reflected in new DSM/ICD updates?

  • What is appropriate/best polypharmacy?

  • How to best manage real-world patients?

  • Alternatives to BDZs as fast-acting drugs– antihistamines; low dose quetiapine; clonidine

  • Best new drug prospects for 2015-2020

    • Subtype-selective BDZs

      • (less sedation, amnesia; maybe lower dependence liability; same efficacy)

    • mGlu2/3 agonists

  • Lots of recent drug failures as well

    • CRF1 antagonists; NK1 antagonists; CCK antagonists….


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