5-HT1A receptors in depressed patients: Evidence from PET, post mortem and EEG based studies R. Hamish McAllister-Williams, MD, PhD, FRCPsych Reader in Clinical Psychopharmacology Newcastle University Hon. Consultant Psychiatrist Regional Affective Disorders Service, RVI 5-HT1A receptor distribution in the human brain Post synaptic receptors 2 Postsynaptic 5-HT1A receptors and depression • Function: – Prolactin and growth hormone responses to intravenous l-tryptophan • Blunted responses in depressed subjects in 5 studies1 • Number of receptors: – PET scanning of WAY-100635 binding • 10-30% decrease in binding in depressed2-5 and remitted depressed6 patients 1. Power and Cowen, 1992 Molec. Aspects Med. 13(3):205-220 2. Drevets et al. 1999 Biological Psychiatry 46:1375-1387 3. Sargent et al. 2000 Archives of General Psychiatry 57:174-180 4. Meltzer et al. 2004 Neuropsychopharmacology 29:2258-2265 5. Drevets et al. 2007 Nuclear Medicine & Biology 34:865-877 6. Bhagwagar et al. 2004 Molecular Psychiatry 9: 386-392 5-HT1A receptor binding across brain regions healthy controls () and MDD () 9 to 24% reduction in 5-HT1A binding across regions of interest in MDD Hirvonen et al. (2008) Int J Neuropsychopharm 11:465–476 5-HT1A receptor distribution in the human brain Post synaptic receptors Somatodendritic autoreceptors 5 5-HT1A receptor binding across brain regions healthy controls () and MDD () 9 to 24% reduction in 5-HT1A binding across regions of interest in MDD Hirvonen et al. (2008) Int J Neuropsychopharm 11:465–476 5-HT1A receptor binding – possible effect of antidepressant exposure Parsey et al. 2006 Biological Psychiatry 59:106 - 113 Replicated in new cohort: Parsey et al. 2010 Biological Psychiatry 68:170-178 5-HT1A Post-mortem data • Somatodendritic 5-HT1A binding capacity in depressed patients: – Increased1 – Decreased2 – Higher in caudal regions, but lower in rostral dorsal raphe3 1 – Arango et al. 2001 Neuropsychopharmacology 25:892-903 2 – Stockmeier et al. 1998 Journal of Neuroscience 18:7394-7401 3 – Boldrini et al. 2008 Journal of Psychiatric Research 42:433-442 5-HT1A receptor gene polymorphisms and depression • C(-1019)G polymorphism in repressor/enhancer region of gene – G allele associated with depression and suicide1 • Effect of G allele depends on cell type2 – Postsynaptic, non-serotonergic cells – enhances repression – Raphe, serotonergic cells – inhibition of repression • Increases in raphe 5-HT1A seen in pet studies correlates with G/G genotype3,4 1 – Albert et al. 2011 Molecular Brain 4:21 2 – Czesak et al. 2006 Journal of Neuroscience 26:1864-1871 3 - Parsey et al. 2006 Biological Psychiatry 59:106 - 113 4 - Parsey et al. 2010 Biological Psychiatry 68:170-178 EEG effect of buspirone – relative power (McAllister-Williams & Massey 2003) 7.5 Plac/plac Plac/busp 5.0 ReplicatingPind/plac work by: Murasaki et al. 1989; HollandPind/busp et al. 1994; 2.5 Anderer et al. 2000 Rel. Power Rel. 0.0 Delta Theta Alpha 1 Alpha 2 -2.5 1.5-6 6-8.5 8.5-10.5 10.5-12.5 Frequency Bands (Hz) 5-HT1A agonist effects on EEG • 5-HT1A receptor mediated effect – Seen with more selective agonists ipsapirone and alnespirone (Saito et al. 1993; Saletu et al. 2000) – Seen with 8-OH-DPAT in rats and not with haloperidol (Bogdanov & Bogdanov 1994) Location of buspirone EEG effects: Postsynaptic or somatodendritic? • LORETA demonstrates buspirone increases theta in hippocampus (Anderer et al. 2000) – Hippocampal theta under ascending serotonergic control (Vertes et al.) – Hippocampal theta in animals induced by direct injection of 8-OH-DPAT into raphé (Nitz & McNaughton, 1999) • Relative effects of buspirone and pindolol? (Clifford et al. 1998) Relative effect of buspirone and pindolol McAllister-Williams & Massey (2003) Psychopharmacology • 14 healthy males • 4-way, random order, cross-over, double blind study – placebo + placebo – placebo + buspirone (30 mg) – pindolol (20 mg) + placebo – pindolol + buspirone Pind/plac Busp/plac 0 1:30 2:00 2:30 3:00 EEG EEG EEG EEG Temp Temp Temp Temp Blood Blood Blood Blood VAS VAS VAS VAS Prolactin response to buspirone: Presumed postsynaptic effect Prolactin levels 1000 Plac/Plac Plac/Busp 750 Pin/Plac Pin/Busp 500 mIU/l 250 0 0 30 60 90 Time EEG frequency spectrum – effect of buspirone (Massey & McAllister-Williams 2003) Rel P7 0.02 Delta Theta Alpha1 Alpha2 Plac/Plac Plac/Plac Plac/Busp Plac/Busp Centroid frequency 6-10.5 Hz 0.01 0.00 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Frequency EEG frequency spectrum (FFT) data Rel P7 0.02 Plac/Plac Pin/Plac Plac/Busp Pin/Busp 0.01 0.00 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Frequency Shift in centroid frequency with buspirone and pindolol (McAllister-Williams & Massey 2003) Prolactin response to buspirone: Presumed postsynaptic effect Prolactin levels 1000 Plac/Plac Plac/Busp 750 Pin/Plac Pin/Busp 500 mIU/l 250 0 0 30 60 90 Time Effect of buspirone and pindolol on the EEG frequency spectrum: A somatodendritic effect? (McAllister-Williams & Massey 2003) Somatodendritic 5-HT1A receptor function in drug free depressed patients McAllister-Williams et al. 2014 Psychological Medicine Patients (n=15) Controls (n=15) P Mean ± SEM Range Mean ± SEM Range Age (years) 47.3 ± 3.0 20 – 64 47.9 ± 3.1 19 – 64 0.89 Gender 9/6/2 9/6/2 (male/female/premenopausal) IQ (NART score) 116.3 ± 2.2 98 – 127 118 ± 1.3 110 - 127 0.37 Alcohol (units/week) 6.2 ± 2.3 0 – 25 9.9 ± 2.1 0 - 25 0.25 HDRS score 21.3 ± 0.8 17 – 26 1.3 ± 0.4 0 - 5 <0.001 MADRS Score 29.3 ± 1.0 26 – 33 0.9 ± 0.3 0 - 4 <0.001 BDI score 28.8 ± 1.7 17 – 46 1.6 ± 0.6 0 - 6 <0.001 Duration of current episode 24 months 1 – 120 months Number of previous episodes 3.9 1-10 Duration drug free (number 13 months (4) 2 – 60 25naïve) months Prolactin response McAllister-Williams et al. 2013 Psychological Medicine No significant difference between patients and controls 26 EEG frequency spectrum response McAllister-Williams et al. 2013 Psychological Medicine Significant group by time interaction (F(3,84) = 3.38, p = 0.038) Conclusions • Regarding postsynaptic 5-HT1A receptors – Replicated data suggesting deceased function – Replicated data suggested decrease number on PET imaging • NB may depend on if drug naïve; if arterial input used; reference region used – Such effects suggest impaired 5-HT neurotransmission • Regarding somatodendritic 5-HT1A receptors – PET and post-mortem data inconsistent – Genetic data suggests that the polymorphism associated with depression leads to increased 5-HT1A expression – Buspirone EEG functional assay suggests attenuated function – This potentially would also lead to impaired 5-HT neurotransmission Future questions • How does somatodendritic 5-HT1A functional status correlate with its PET determined binding potential? • Does somatodendritic 5-HT1A receptor function correlate with genotype? • What impact does somatodendritic 5-HT1A functional status have on response to SSRIs (given these are hypothesised to down-regulate this receptors)? .