Ketamine as a Novel Antidepressant

Sunday 2012-10-07 12-12:45h Ruud Kortekaas, PhD

Ruud Kortekaas, Ph.D., Cognitive NeuroPsychiatry, Dept. Neuroscience, UMCG

overview
Intro
Ketamine
Pharmacology Legal status Abuse and toxicology

Depression
treatment-resistance

antidepressant effects ketamine

method
Phase II clinical trial protocol

The future

Ruud Kortekaas, Ph.D., Cognitive NeuroPsychiatry, Dept. Neuroscience, UMCG

ketamine
Dissociative anesthetic Chiral compound Similar to PCP Affinity for PCP, mu, sigma receptors

Ruud Kortekaas, Ph.D., Cognitive NeuroPsychiatry, Dept. Neuroscience, UMCG

Ruud Kortekaas, Ph.D., Cognitive NeuroPsychiatry, Dept. Neuroscience, UMCG

ketamine
glutamatergic system non-competitive antagonist at NMDA receptors Via PCP binding site

Ruud Kortekaas, Ph.D., Cognitive NeuroPsychiatry, Dept. Neuroscience, UMCG

Why ketamine?
Legal status Acknowledged as having merit a core medicine in the World Health Organization's "Essential Drugs List" Has potential merits, but also risks Entirely different from e.g. psilocybin 'No potential merits, only risks' (Legal status <> risk of harm) Can be obtained very pure (unlike iboga, ayahuasca)

Ruud Kortekaas, Ph.D., Cognitive NeuroPsychiatry, Dept. Neuroscience, UMCG

Non-medical use
Recreational use Abuse potential Toxicology

Ruud Kortekaas, Ph.D., Cognitive NeuroPsychiatry, Dept. Neuroscience, UMCG

Ketamine toxicology
Animal studies have shown that NMDA antagonists can cause irreversible neurotoxic effects (Farber et al., 2002). Never been described in humans despite the fact that some individuals have consumed large amounts of ketamine recreationally (Morgan and Curran, 2006). At least some of the neurotoxicity after ketamine administration is likely to be due to the presence of chlorobutanol, a common preservative in ketamine preparations [Malinovsky 1993]

Ruud Kortekaas, Ph.D., Cognitive NeuroPsychiatry, Dept. Neuroscience, UMCG

Ketamine toxicology
partly irreversible damage to the urinary system, esp. ureter and bladder described in very heavy ketamine users who consume >1 gram/day for prolonged periods [Tsai 2009]

Ruud Kortekaas, Ph.D., Cognitive NeuroPsychiatry, Dept. Neuroscience, UMCG

Ketamine toxicology
Retrograde pyelography showing bilateral hydronephrosis and ureteral strictures with segmental beading (arrows) and straightening of both ureters. Huang et al, Kidney International (2011) 80, 895; doi:10.1038/ki.2011.242

Ruud Kortekaas, Ph.D., Cognitive NeuroPsychiatry, Dept. Neuroscience, UMCG

Oral ketamine
oral ketamine palliative care: 19 articles No official clinical guidelines Soto et al. Am J Hosp Palliat Care. 2012 29(4):308-17. Starting dosage 0.5 mg/kg racemic ketamine 0.25 mg/kg S-ketamine The dosage is increased by the same amount if required. For a continuous analgesic effect it is usually given 3-4 times daily. injection fluid can be taken orally Blonk et al. Eur J Pain. 2010 14(5):466-72.

Ruud Kortekaas, Ph.D., Cognitive NeuroPsychiatry, Dept. Neuroscience, UMCG

Oral ketamine
A lozenge with [e.g.] 25 mg of ketamine can be formulated and manufactured in a hospital pharmacy Stable for at least 14 weeks Oral and sublingual bioavailability: 24% Chong et al Clin Drug Investig. 2009;29(5):31724.

Ruud Kortekaas, Ph.D., Cognitive NeuroPsychiatry, Dept. Neuroscience, UMCG

Depression
Not just sadness Major depressive disorder MDD DSM definition all-encompassing low mood, low self-esteem, loss of interest or pleasure in normally enjoyable activities. Lifetime incidence: The year prevalence in the Netherlands: 5.1% Life time incidence 24.3% in females, 13.1% in males (Maas 1997) 3.4% of people with MDD commit suicide Loss of quality of life, economic cost

Ruud Kortekaas, Ph.D., Cognitive NeuroPsychiatry, Dept. Neuroscience, UMCG

Depression
WHO: Depression is the leading cause of disability [...] and the 4th leading contributor to the global burden of disease in 2000. Depression is not only common, it commonly has a chronically recurring course The response to medication is unpredictable, slow in onset, incomplete in success rate (~70 %) and fraught with undesired side effects.

Ruud Kortekaas, Ph.D., Cognitive NeuroPsychiatry, Dept. Neuroscience, UMCG

Therapy
Selective serotonin reuptake inhibitor (SSRI)
fluoxetine (Prozac) fluvoxamine paroxetine (Paxil, Seroxat) sertraline (Zoloft) citalopram escitalopram

Augmentation Electroconvulsive therapy (ECT)

Ruud Kortekaas, Ph.D., Cognitive NeuroPsychiatry, Dept. Neuroscience, UMCG

STAR*D trial
Sequenced Treatment Alternatives to Relieve Depression trial 3,671 MDD patients 36.8% achieved remission ('cured') following optimized trial of the SSRI citalopram for up to 12 weeks

Ruud Kortekaas, Ph.D., Cognitive NeuroPsychiatry, Dept. Neuroscience, UMCG

CO-MED
Combining Medications to Enhance Depression Outcomes (CO-MED) large-scale study remission rates were modest (37.738.9%) similar to STAR*D

Ruud Kortekaas, Ph.D., Cognitive NeuroPsychiatry, Dept. Neuroscience, UMCG

Treatment resistance
Sackeim, The definition and meaning of treatment-resistant depression. J Clin Psychiatry. 2001; 62,16:10-7. Ruh et al., Staging methods for treatment resistant depression. A systematic review. J Affect Disord. 2012; 137(1-3):35-45.

Ruud Kortekaas, Ph.D., Cognitive NeuroPsychiatry, Dept. Neuroscience, UMCG

Ketamine as AD

Ruud Kortekaas, Ph.D., Cognitive NeuroPsychiatry, Dept. Neuroscience, UMCG

Murrough, Clin. Pharmacol. & Therapeutics 91(2) 2012 Ruud Kortekaas, Ph.D., Cognitive NeuroPsychiatry, Dept. Neuroscience, UMCG

Murrough, Clin. Pharmacol. & Therapeutics 91(2) 2012 Ruud Kortekaas, Ph.D., Cognitive NeuroPsychiatry, Dept. Neuroscience, UMCG

Objective
Replication of the antidepressant effects of ketamine in patients with a refractory depression Oral formulation Longer follow up Primary outcome HAMD17 effects on brain activation, -1, 3, 10, 20. task and task free. Effects on brain derived neuronal growth factor (BDNF) levels in blood, -1, 3, 10, 20

Ruud Kortekaas, Ph.D., Cognitive NeuroPsychiatry, Dept. Neuroscience, UMCG

Intervention
Oral formulation, 20 mg/70 kg, S-ketamine. Once daily for three weeks

Ruud Kortekaas, Ph.D., Cognitive NeuroPsychiatry, Dept. Neuroscience, UMCG

Study design randomized, double-blind intervention study. Not an active control stratified and minimised, controlled

placebo

Ruud Kortekaas, Ph.D., Cognitive NeuroPsychiatry, Dept. Neuroscience, UMCG

Study population

In-patients and out-patients with at least moderately severe MDD, 18 - 80 yr old, not having responded to two different antidepressants.

Ruud Kortekaas, Ph.D., Cognitive NeuroPsychiatry, Dept. Neuroscience, UMCG

End points
The primary outcome HAMD17 Secondary outcomes
magnetic resonance spectroscopy fMRI and neuroplasticity biomarkers in plasma.

Ruud Kortekaas, Ph.D., Cognitive NeuroPsychiatry, Dept. Neuroscience, UMCG

Phases
Formulation of aims/questions/hypotheses Formation of project team Negotiate political obstacles Write protocol (30 page document) Acquire funding (100-150 k) Obtain ethical approval Patient inclusion, data acquisition, report

Ruud Kortekaas, Ph.D., Cognitive NeuroPsychiatry, Dept. Neuroscience, UMCG

microTMS
19 iron core electromagnets, modified reed relays, all are wired parallel EEG cap, 10/20 system, anatomical reference

Ruud Kortekaas, Ph.D., Cognitive NeuroPsychiatry, Dept. Neuroscience, UMCG

Future directions
Analgesic activity of PEMF in a neuropathic pain model Tolerability to PEMF in NP patients Analgesic activity of PEMF in NP patients: QST and spontaneous pain EEG fNIRS Depression Multichannel PEMF Scale down

Ruud Kortekaas, Ph.D., Cognitive NeuroPsychiatry, Dept. Neuroscience, UMCG

Acknowledgements
coworkers UMCG technical support intern students Post-doc Aleman, Maurits,Schoever, Ruh, van Belkum financial support (innovation fund) L. Dijck, P. Albronda, K. Vaartjes, Y. Bloemhof L. van Nierop, V. Baas, M. van Dijk, H.T. Mulder Curcic-Blake

R. Kortekaas, mentor 30 Ruud Kortekaas, Ph.D., Cognitive NeuroPsychiatry, Dept. Neuroscience, UMCG