Neural model of emotional regulation structures - Circuits involving prefrontal cortex and subcortical limbic structures - MDE associated with

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2 Topics Brain and signalling changes in depression Ketamine activity in refractory depression Mechanism of Action New Data Dose finding Route of Administration Activity in Other Disorders

3 Neural model of emotional regulation structures - Circuits involving prefrontal cortex and subcortical limbic structures - MDE associated with altered activity in some of these areas Mol Psychiatry. 2008; 13(9):

4 Blood Flow Changes in Major Depression Changes in : regional cerebral blood flow and metabolism in the amygdala, orbital cortex, and medial thalamus in the dorsomedial/dorsal anterolateral PFC and anterior cingulate cortex Human Brain Mapping 29: (2008)

5 BA25 and Treatment Resistant Depression Subgenual cingulate gyrus (BA 25) is metabolically overactive in treatment-resistant depression Functionally: involved in generation of emotional states activity predicts non-response to drugs, psychotherapy Subgenual cingulate (Brodmann area 25) Regional cerebral bloodflow pre-stimulation (difference vs control subjects) Mayberg; Neuron 2005, 45:651

6 Immediate mood improvement with DBS of BA25 In general, patients described a sudden disappearance of something negative, which was more often than not a change in a visceral state: a sudden sense of intense calm and relief, clearing of mental heaviness, lifting of a black cloud, the disappearance of a void Such effects, when present, were contact- and dosespecific and could be reproduced in a blinded fashion with repeated testing. Their time course was quite rapid, occurring approximately seconds after initiating stimulation at the specific electrode contact. Deep brain stimulation reduced BA25 metabolic activity - 6 months: 60% responders, 35% remitted - 36 months: 75% responders, 50% remitted (Int Rev Psych 2011, 23:424) Regional cerebral bloodflow, 3 months stimulation (difference vs baseline)

7 Ketamine Glutamate (NMDA) antagonist Developed in 1962 as an anaesthetic Current clinical indications Paediatric anaesthesia (approved) Still widely used in children use in adults limited due to psychotogenic effects Pain (off-label) Depression Analgesia Anaesthesia (IM) Ketamine dose (mg/kg) Scheduled due to abuse liability

8 John Krystal Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psych 1994: 51: Ketamine 0.5mg/kg infusion over 40 mins produced perceptual, cognitive and dissociative changes in healthy volunteers Model of psychosis; could be useful in screening novel antipsychotic drugs Tested in refractory MDE in late 1990s with apparent expectation that it would not show activity

9 Antidepressant Effects in Patients with Refractory MDD Randomized, double blind, 2 period Ketamine (0.5mg/kg) or placebo 40 minute infusions separated by 1 week; assessments to 72h Berman, Biol Psych 2000, 47: patients MDD, unmedicated 2 w Baseline HAM-D ~30 Change from baseline, HAM-D score Pre Early Late hours Ketamine Placebo

10 Replication Study in Refractory MDD Randomized, double blind, 2 period Ketamine (0.5mg/kg) or placebo 40 minute infusions separated by 1 week; assessments to h Zarate, Arch Gen Psych 2006, 63: Patients Treatment resistant MDD, unmedicated 2 w Baseline HAM-D ~ Change from baseline, HAM-D score Pre Early Late mins hours- - - Ketamine Placebo

11 MADRS Responders (%) MADRS score Refractory Bipolar Depression Pre Early Late Diazgranados; Arch Gen Psych 2010 Treatment refractory bipolar depression, unmedicated (n=18) Randomized, double blind, 2 period crossover Ketamine (0.5mg/kg) or placebo via 40 minute IV infusions Assessments to 14 days Minutes Time after infusion Days Ketamine Placebo Ketamine Placebo Minutes Time after infusion Days

12 Consistent findings from subsequent publications Publication /design N Ket N Pbo Machado-Viera 2009 MDE/OL 23-48% Responders Ketamine Placebo responders Phelps 2009 MDE/OL 26-67% Mathew 2010 MDE/OL 26-65% Aan het Rot 2010 MDE/OL/MD 10-90% Ibrahim 2012 MDE/OL 42-62% - Thakurta 2012 MDE/OL 22-77% Zarate 2012 BPD/XO % 0% Murrough 2013 MDE/parallel group/midaz % 28% Sos 2013 MDE/XO % 4% Rasmussen 2013 MDE/OL/MD 10-80% Shiroma 2014 MDE/OL 14-92%

13 How is ketamine working? by switching off overactive neurons in BA25? Unlikely. Peak blood levels at ~40 minutes vs peak mood change at 24h. also t1/2 is ~3h This has highlighted new targets for depression treatments..

14 Ketamine enhances processes associated with synaptic plasticity Activation of mtor signalling levels of synaptic proteins BDNF translation

15 Ketamine has neurotropic effects Saline Ketamine spine density in medial prefrontal cortex (24h post-ketamine ) (layer V pyramidal cells; 2-photon microscopy) May be due to BDNF transcription Science 2010, 329:959 Neurotropic effects may normalize activity of over- /underactive areas contributing to depressed mood

16 BDNF: Brain Derived Neurotrophic Factor - Neurotrophins stimulate/control neurogenesis/synaptogenesis - BDNF is one of the most active of these - one of the most prevalent neural growth regulators in adult brain - Large peptide 2 subunits of 119 amino acids

17 BDNF and depression hippocampal BDNF signalling produces certain depression-related behaviours, impairs the actions of antidepressants in animal models hippocampal BDNF levels produce antidepressant-like effects hippocampal BDNF levels postmortem in depressed humans could account for cognitive impairments and hippocampal atrophy seen in depression

18 Biol Psych 2008;64:

19 Loss of brain volume in depression Reduced hippocampal volume in depressed patients vs controls PNAS 1996, 93:3908 Degree of atrophy related to duration of depression Am J Psychiatry 2003, 160:1516

20 serum BDNF (ng/ml) Depression Rating (HAM-D) Increased BDNF: A common mechanism for antidepressants? Increased slowly by antidepressants; timecourse parallels mood improvement Sertraline Control BDNF range (+1SD) time (d) time (d) Brain Res Bull 2009, 80:158

21 Antidepressants increase brain BDNF human postmortem data BDNF concentrations in several hippocampal regions higher in patients on antidepressants at time of death Biol Psych 2001, 50:260

22 Biol Psych 2008;64: Antidepressants increase serum BDNF in man meta-analysis

23 ECT increases serum BDNF in Rx responders 12 ECT S; Prog Neuro-Psychopharmacol Biol Psych 2008, 32:1185

24 Greater rise in serum BDNF in depressed patients who respond to IV Ketamine response biomarker? Int J Neuropsychopharm 2013

25 Bilateral increase in hippocampal volume after 8 weeks SSRI treatment Molecular Psychiatry (2012) 18,

26 Bilateral increase in hippocampal and amygdala volume after ECT Psychiatry Res Neuroimaging 2013, 214:197 P<0.05 P<0.03

27 Euthymic Depressed Treated depression

28 New Data Dose Response and Influence of Route of Administration (Colleen Loo UNSW) Double-blind, placebo controlled, ascending dose trial. N=15 depressed subjects (MADRS 20) with >1 adequate antidepressant trial failed. Ketamine: IV, IM or SC; Single doses, given 1 week apart; ascending protocol (0.1, 0.2, 0.3, 0.4, 0.5 mg/kg) Random insertion of placebo in first 3 sessions (midazolam 0.01 mg/kg) Outcome: MADRS (efficacy) Analysis: mixed-effects repeated measures model (MERM) to evaluate effects of route and dose on mood scores.

29 Demographics N=15 IV (n=4) IM (n=5) SC (n=6) p Age (Years) 52.8 (9.5) 45.6 (13.3) 48.2 (11.0).656 Gender (Male/Female) 2/2 4/1 5/1.233 Current Episode duration (months) Concomitant antidepressant treatment No. of Failed Antidepressants in Current Episode No. of Failed Antidepressants in Lifetime Maudsley Scale of Severity (211.2) 57.9 (81.4) 51.8 (39.7).107 4/4 3/5 5/ (5.1) 3.6 (4.8) 3 (2.5) (4.3) 4.4 (4.6) 4.7 (2.07) (3.5) 8.2 (4.0) 8.2 (3.1).462

30 Mean % change in MADRS at 24 hours Efficacy (1): - 13 subjects responded to ketamine, 11 remitters - - Route of administration did not affect response IV IM SC

31 % responders Efficacy (2): All subjects who responded did so at or below 0.3 mg/kg. - Dose at which initial response occurred dose (mg/kg)

32 MADRS MADRS MADRS Individual dose response data, 0, 0.1, 0.2mg/kg 14 patients Dosage: 0.0 mg 15 patients Dosage: 0.1 mg 0 4 hrs 1 day 3 days 7 days 0 4 hrs 1 day 3 days 7 days 14 patients Dosage: 0.2 mg 0 4 hrs 1 day 3 days 7 days

33 Tolerability SC>IM>IV (dissociative side effects) Analysis MERM analysis for doses 0.1, 0.2 mg/kg yielded main effects: route (NS), dose (p=0.038), time (linear, p=0.014; quadratic, p=0.005), and time x dose interactions (linear, p=0.057; quadratic, p=0.056)

34 How useful is a 1-week antidepressant? Not a unique problem for ketamine Increased relapse rates if antidepressants stopped <6/12, if MS/ADs not given post-ect How can the antidepressant effects be sustained?

35 What hasn t worked Use of add-on riluzole (Mathew 2010) TIW dosing for 2 weeks (aan het Rot 2010) What may work Add memantine (Kollmar 2008) Procyclidine or amantadine should also be active Infuse over 5 days (Correll 2006) Weekly dosing for >6/12 (Zanicotti 2012)

36 Sustained mood improvement after 10 months of weekly ketamine treatment Zanicotti 2012

37 Will Medsafe approve ketamine for depression? Unlikely needs a commercial sponsor Janssen currently running Ph2 studies of S-ketamine in a nasal spray formulation Belgium Intranasal ketamine works clinically 50mg IN ketamine is effective in reducing depression scores (Lapidus, Biol Psych 2014, epub)

38 Impact of Event Scale Score Activity in other conditions OCD Rodriguez, Neuropsychopharm 2013, 38:2475 PTSD Feder, JAMA Psychiatry 2014, epub

39 Summary (1) Rapid antidepressant effects of low-dose ketamine have been confirmed in 6 RCTs, multiple case series Typically ~2/3 patients respond Well tolerated Response duration ~1 week Threshold dose for responsive patients mg/kg Therapeutic dose may be higher SC appears to be better tolerated than IV, IM

40 Summary (2) Has highlighted role of BDNF in antidepressant activity Increasing BDNF translation may be (one) final common pathway for antidepressant action Ultimate antidepressant effect may be via synaptogenesis Differences in speed of onset of antidepressant effect may be due to differences in rate of BDNF translation Ketamine > ECT > antidepressants, mood stabilizers Differences in antidepressant efficacy may be due to differences in potency of BDNF translation ECT > Ketamine > antidepressants, mood stabilizers

41 Thank you! Any questions?

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43 Expression (x baseline) What is the activity due to parent or metabolite? Anesthesiology 2014; 121: Effect of ( R,S)-ketamine, ( R,S)-norketamine, and ( 2S,6S)-hydroxynorketamine on the phosphorylation of mtor in rat brain Ket Norket HNK