Current and future research developments in mood disorders psychopharmacology
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Current approaches to treating mood disorders focus mainly on neurotransmitters like serotonin, norepinephrine, and dopamine. However, there are many limitations to this approach. Alternative biological systems may be involved, such as circadian rhythms, the melatonergic system, glutamatergic neurotransmission, the HPA axis, insulin resistance, the immune system, and oxidative stress. Novel therapies targeting these alternative systems show promise and may help address treatment-resistant cases.
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Current and future research developments in mood disorders psychopharmacology
- 1. Current & Future Research Developments in Mood Disorders Psychopharmacology Dr. Nick Stafford Consultant Psychiatrist, Black Country Partnership NHS Foundation Trust No Pharma declarations for the last 5 years
- 2. Content of today’s talk • Limitations of current approaches to the medication pipeline of depression and bipolar disorder • Novel therapeutics in bipolar disorder and treatment resistant depression
- 3. Traditional approaches limiting (DSM-5) • BP I; (BP II); Cyclothymia; BP NOS • Mania & Mixed / Depression • DSM-5 Specifiers, with: • Anxious distress • Mixed features • Rapid cycling • Melancholic features • Atypical features • Mood congruent psychosis • Mood incongruent psychosis • Catatonia • Peripartum onset • Seasonal pattern • Comorbidity (similar to conditions looking similar): • Any anxiety disorder • ADHD/impulse control/conduct • Substance misuse • Alcohol • Personality disorders • Medical conditions Underlined: current licensed medications • Biology focused on neurotransmitters • Serotonin / NOR / Dopamine / GABA
- 4. • RG2: olanzapine, olanzapine + valproate • RG3: (aripiprazole, paliperidone, quetiapine) & MST • RG4: asenapine, CBZ, cariprazine, clozapine, gabapentin & MST, oxcarbazepine & lithium, risperidone, typical AP, valproate, ziprasidone, ECT & TAU • RG5: topiramate & TAU Mixed episode Manic mixed episode Depressive mixed episode • RG3: ziprasidone & TAU • RG4: olanzapine, carbamazepine, lurasidone, ECT & TAU AcuteTreatment AcuteTreatment Unspecified index Manic index Mixed index Depressive index RG3: valproate RG5: lithium RG3: valproate RG5: olanzapine RG3: valproate RG5: olanzapine ? Prevention of index Prevention of future Mania Any Depression RG2: quetiapine & MST RG3: lithium, quetiapine RG4: ziprasidone RG2: quetiapine & MST RG3: lithium, olanzapine, quetiapine RG4: risperidone, ECT & TAU RG2: quetiapine & MST RG3: quetiapine RG4: aripiprazole & lamotrigine WFSBP Guidelines Mixed States – reduction ad absurdum & clinically unusable
- 5. Lithium – what is the central mechanisms? • Intracellular changes • Signal transduction pathways • Protein kinase C • CLOCK genes / GSK-3b • Na+ reduction • Neuronal plasticity • Brain structure • Reduced GM & WM atrophy/changes • Fronto-limbic (Hipp/Amyg/Striatum) • Connectivity • BDNF • Neurotransmitter modulation • DA / NMDA / GABA • Apoptosis • WBCs, treatment for neutrophilia • Pluripotential bone marrow cells • Possible action in other cells • Repairing damaged DNA • Suicide prevention • Reduced impulsivity • Raises plasma N20 levels • Quantum neural processing (Posner molecule entanglement, calcium, phosphate, lithium)
- 6. Circadian rhythms Circadian system directly impacts on function of: • Immune system • Oxidative & nitrosative stress • Inflammation • Insulin sensitivity • Peripheral metabolism
- 7. Neuroprogression - O&NS, Immune, TRYCAT O&NS Lipid peroxidation, DNA/RNA damage, nitric oxide ImmuneCellular, cytokines, biochemical TRYCAT Removing tryptophan from serotonin, NAS & melatonin synthesis Central effects Bipolar Disorder Anxiety disorders Depression Personality disorder Peripheral effects Cardiovascular disease Insulin resistance Metabolic syndrome Pain
- 8. Immune, O&NS, TRYCAT – Integration of causes Gut permeability Melatonin Cerebellum Inflammation Obesity Alcohol abuse Melatonin Unipolar research O3FAs Decreased in BD Antioxidant Anti-inflammatory Optimizes mitochondria Circadian rhythm regulation Reduced in adolescent BD Promotion phagocytic response (& less inflammation) IL-6 may reduce melatonin synth Role in mood regulation Difference UD / BD Incr. LPS from gut perm, effects cerebellum Protection by melatonin, less present in BD
- 9. Alternative biological systems in mood disorders Circadian rhythms & genes Melatonergic Glutaminergic (NMDA) Cholinergic HPA-axis Insulin resistance Immune system Oxidative stress
- 10. Glutamate / NMDA The major excitatory neurotransmitter system in the CNS
- 11. Glutamatergic system (NMDA-r antagonists) • Ketamine • Riluzole • Memantine • Dextromethorphan • D-cycloserine • Nitrous oxide • Rapastinel • Sarcosine • Lanicemine • CP101606 (Taxoprodil) • MK0657
- 12. Ketamine action NMDA Synaptic, extra-synaptic inhibition Downstream effects Plasticity, BDNF, eEF2, mTOR, GSK3beta Not involving NMDA inhibition (R) ketamine, metabolites Model similar for all neurotransmitters
- 13. Ketamine single dose Depression Rating Score Ionescu 2015 Cochrane: McCloud 2015 Single dose, anxious bipolar depression Cochrane: ketamine for bipolar depression
- 14. Ketamine IV Continuous Phase, TRD UP & BP TRD, UP, BPI, BPII & suicidal, non-psychotic •N=12 •Thrice weekly 2 weeks 7 responded 5 remitted •Remitters entered continuation phase Further improvement • Remitters • Weekly IV ketamine • 4 weeks 4 lost remission post continuation Benefit in all continued post trial •For “several weeks” ADRs mild and transient Lande Voort 2016
- 15. Memantine – long term treatment • Open-label study • N=30, Depressed, BPI=17; BPII=13 • Consistent morbidity >=3 years • Treatment resistant • Li, ACs, APs, ADs, ECT • Memantine 20-30mg/d added • Followed for additional 3 years • Morbidity measures & CGI-BP • Over 3 years improvements, P<0.01 • Morbidity reduced • 75% time ill (total, manic, depress) • 67.8% CGI-BP • 58.6% duration new episodes • 55.7% episodes per year • Patients with previous continuous or rapid cycling particularly improved (t=2.61, P=0.016) Serra 2015
- 16. Riluzole – clinical effect • Treatment for Amyotrophic Lateral Sclerosis (ALS) • Rapidly inhibits presynaptic release of Glutamate • Open-label, n=14, 6/52, BP depression, @ day 2 & week 6 • Gln/Glu ↑ cycling at day 2 • HAM-D (21) reduced, mean score 22 to 11, p<0.001, at 6 weeks Brennan 2010 • RCT, n=14, monotherapy vs. placebo, BP depression • No significant clinical difference Serra 2015
- 17. Riluzole 2D J-resolved proton MR spectroscopy Brennan 2010 ACC (BP) & POC (UP) measures using 2D J-resolved proton MR spectroscopy at 4T Gln/Glu ↑ cycling at day 2, (marker of enhanced plasticity) N-acetyl-aspartate (marker of neuronal integrity) ↑ from baseline to week 6 Putatively Gln/Glu & NAA = ↑ neuroplasticity & ↑neuronal integrity
- 18. Nitrous oxide (N20), laughing gas, anaesthetic • Lithium known to raise N2O levels • RCT crossover trial in TRD • 1hr inhalation of (50%N2O & 50%O2) vs. (50%N2 & 50%02) • Rapid and significant AD effect • No trial in bipolar yet Nagele 2015
- 19. NR2B subunit of NMDA-r (for less SEs) • (Associated with age and visual experience dependent plasticity in the neocortex) • Less potential for psychotomimetic SEs, no dissociation symptoms • CP-101606 (Traxoprodil), RCT • TRD, well tolerated, good rapid AD effect, within 1 week, 78% of treatment responders • Problematic SEs: Cardiotoxicity • MK-0657, RCT • TRD, monotherapy, improves depressive symptoms within 5 days • Nothing yet in bipolar Preskorn 2008 Ibrahim 2012
- 20. Cholinergic system Sympathetic and Parasympathetic Nervous Systems, Basal Forebrain, Alzheimer’s disease, Neuromuscular junctions
- 21. Cholinergic system - Scopolomine • Cholinergic system hyper-responsive in depression • Scopolamine hydrobromide (non-selective M blocker): • RCT, crossover TRD (n=9) & bipolar (n=9), dosed twice weekly • Rapid (within 3 days) & significant AD action • AD effect varies according to patient characteristics • Larger AD and anxiolytic effects in women cf. men • Well tolerated overall but some worrisome SEs (cadiotoxicity, delirium, psychosis) • Potential for mania but not yet seen. • Promising for bipolar Furey 2010 Drevets 2013
- 24. Agomelatine in bipolar II depression Bipolar II depression • Open-label trial • N=28, 25mg + Li / Val , 6/52 + ext. 30/52 • 1ryom: HAMD17, PSQI, CGIBP, YMRS, BMI • 64% response HAM @6/52 • 86% response HAM @36/52 • Sleep improved @ 36/52 Fornano 2013 Bipolar I depression • Open-label trial • N=21, 25mg + Li / Val • @6/52 + ext. 46/52 • 1ryom: HAMD17 • 86% response HAM 6/52 • 48% (HAM>25.2) response 1/52 Calabrese 2007
- 25. Agomelatine in bipolar I depression (RCT) • BP I depressed <6/52 on Li / Val • Randomized • N=172 agomelatine • N=172 placebo • 8/52 acute treatment • Ext. 44/52 continuation treatment • No significant difference @ 8 or 52 weeks Yatham 2016
- 26. HPA Axis System Hypothalamic – Pituitary – Adrenal
- 27. HPA axis, FKBP5 (binding protein) epigenetics • Decreased Glucocorticoid Receptor (GR) responsiveness • Increased levels of methylation of FKBP5 • Epigenetic modulation of FKBP5 Pace 2007, Carroll 2012, O’Leary 2013, Zannas 2016
- 28. HPA axis – anti-glucocorticoid agents • HPA dysregulation leads to blunted cortisol feedback • ↑ CRH – ↑ Cortisol: • Disruptions to immune system, metabolism, mood, appetite, circadian rhythms, sexual activity. • Poor treatment response to conventional ADs • Anti-glucocorticoid agents: Good preclinical results BUT Poor clinical trial results in TRD & BP depression for • Cortisol synthesis inhibitors (ketoconazole, metyrapone) • Corticosteroid receptor antagonist (mifepristone, pregnenalone, DHEA) Review: Kling 2009
- 30. Metformin, obesity, weight loss • Pioglitazone, Diabetes Medication (thiazolidinedione), Meta-analysis • Moderate AD effect in TRD, bipolar depression and assoc. diabetes (Goldstein 2018) • Metformin AD effect by improving cognition (Guo 2014) • Metformin as a weight management strategy in BP • Reduction of Olanzapine weight gain (5kg in 12 weeks) • Prevention of weight gain in SGA naïve • Metformin + intense life-style modification, reduce T2DM, 29-22% • Less obesity leads to more positive mental & physical outcomes for bipolar & TRD • Recommend using metformin in BP with those at risk of T2DM • Obesity & T2DM - wide variety of mental & physical health problems
- 32. Immune, O&NS, TRYCAT – Potential Therapies • N-acetylcysteine, RCT • Significant AD effect in TRD & bipolar, incl. meta-analysis incl. functionality, BUT effects are short lived (Fernandes 2016) • Omega 3 Fatty Acids, Meta-analysis (Cochrane review) • Moderate AD effect, limited clinical data in TRD & BP depression (Montgomery 2008) • Infliximab, RCT • TNF-alpha inhibitor not superior to placebo in bipolar depression (Raison 2013) • Pioglitazone, Diabetes Drug, Meta-analysis • Moderate AD effect in TRD, bipolar depression and assoc. diabetes (Goldstein 2018)
- 33. Immune, O&NS, TRYCAT - Medications • Celecoxib (COX2 NSAID), both RCTs • Adjunct, in bipolar, rapid AD effect, but short lived (Nery 2008) • Adjunct VAL, effective for mania (Arabzadeh 2015) • Aspirin (NSAID), pharmaco-epidemiological study (n=5,145) • ↓ RR of deterioration in bipolar on Li. Independent of Tx duration • Other NSAIDs and glucocorticoids did not have this effect (Stolk 2010) • Minocycline (tetracycline antibiotic), open trial • Adj. with Li/Val may be AD in BP I & II (Soczynska 2017) • Smoking cessation (George 2012) – greatest effect on life span in bipolar
- 34. Summary • Is it just about? • Serotonin • Noradrenaline • Dopamine • Or is it a bit more complex?
Editor's Notes
- Psycho pharmacological therapeutic approaches to the treatment of bipolar disorder and depression have been Limited over recent years to a relatively small number of medication families Today I’m going to introduce you to current and future research of medication approaches too these conditions which is different To the current norm
- If you look at the diagnostic definitions and criteria for bipolar disorder in DSM five you will see rich description of tights, specifies and comorbidities Despite this knowledge licensed medication for the treatment bipolar disorder is very limited, the evidence coming mainly from bipolar type one disorder, mixed or manic states or depression Four example there are no licensed medications for the treatment of any of the comorbid conditions found in bipolar disorder
- Examples of each [EVIDENCE IN EACH AREA BUT BY NO MEANS CLEAR OR REPLICATED] Processes: Clinical correlates: CSF as central measures Cognition Confunders
- Whilst we are aware of the commonly associated neurotransmitter series of bipolar disorder, which is led to the development other use Of many second-generation antipsychotics in bipolar, and monoamine systems of dopamine and noradrenaline in depression there has been a little exploration within the pharmaceutical industry in current pipeline drugs that use other biological symptoms we know to be of importance in these conditions Whilst this is a complex field I tried to simplify these in this life and will now present in more detail how these systems work and what medications are in development in
- First of the glutamate system or NMDA receptors which form the major excitatory neurotransmitter system in the CNS
- The glutamate system is widespread in the CNS and in recent years, mainly initiated by research into Ketamine, more NMDA-r antagonists have been studied in TRD and bipolar
- Here is a list of some of those I will talk about today [READ THROUGH THE LIST QUICKLY]
- First Ketamine, the most well known of this group. Single doses have been shown to be effective in rapidly reducing the depressive symptoms, anxiety symptoms and suicidality of both TRD and bipolar disorder In this 2015 study we see the effective use of a single dose of ketamine in reducing anxious bipolar depression Meta-analyses confirm these effects, but they are not sustained beyond 5 days to a week
- This study published in 2016 evidenced the continuous use of ketamine in the treatment of TRD UP, BP I & BP II non-psychotic but suicidal depression. [TALK THROUGH SLIDE]
- Memantine, a medication used to treat cognitive decline in Alzheimers disease has shown interesting long term benefits in bipolar type I & II teatent depression depression [TALK THROUGH EVIDENCE]
- Riluzole – [READ FROM THE SLIDE]
- Dextromethorphan – [READ FROM THE SLIDE]
- D-Cycloserine is an antibiotic for TB
- Nitrous oxide is a gaseous anaesthetic and known as laughing gas
- Rapastinel – [READ FROM THE SLIDE]
- Sarcosine – an amino acide biomarker for prostate cancer
- Lanicemine – [READ FROM THE SLIDE]
- This subunit of the NMDA-r