Psychopharmacology of Anxiety

1. Psychopharmacology of Anxiety Paul Glue paul.glue@otago.ac.nz April 2010

2. Objectives • Definition • (Re)Classification of anxiety • Pharmacological theories of anxiety • Pharmacology of antianxiety treatments • Are there better options on the horizon?

3. 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

4. ….and it’s very common NZ Mental Health Survey 2006

5. DSM and anxiety Clustering based on phenomenology; divorcing of depressive vs anxiety components

6. 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

7. 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)

8. 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)

9. 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

10. 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

11. Key Neurotransmitters in Anxiety • Monoamines • Norepinephrine • Serotonin • Histamine • GABA (gamma-aminobutyric acid) • Glutamate • Drugs affecting central excitatory neurotransmitter release

12. 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

13. 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

14. 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

15. 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

16. 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

17. 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)

18. 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

19. 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

20. Can we make better benzodiazepines?

21. 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??

22. 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

23. 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)

24. 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

25. 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

26. 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

27. 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.

28. …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.

29. 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

30. 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….