Affective Disorders (Depression Lectures) 2024-2025 PDF

2024 Affective Disorders: Depression (3 lectures) and Anxiety (1- lecture). Journal Club (to promote post lecture reflection). General points-clinical problem with an underlying basic science. 1.Introduce and discuss the clinical and neurobiological basis for psychiatric disorders. 2.Addres...

2024 Affective Disorders: Depression (3 lectures) and Anxiety (1- lecture). Journal Club (to promote post lecture reflection). General points-clinical problem with an underlying basic science. 1.Introduce and discuss the clinical and neurobiological basis for psychiatric disorders. 2.Address current issues about diagnosis and pathophysiology; exemplify this in depression. Depression (3 lectures) 1.Describe the major features of Depression using clinical description. 2.Highlight the monoamine hypothesis of depression and “empiriscm” 3. Describe classic anti-depressant drugs monomaine modulating drugs. 4. Detail the molecular basis for their mode of action and limitations of understanding. Touch on the issue do these drugs work? 5. Describe the re-purposing of ketamine as a novel anti-depression route. Anxiety 1 lecture (1 slot) 1.Introduce pathophysiological state anxiety and list the current classification and complexity of anxiety disorders. 2. Highlight the fear pathway as a template to understand anxiety as a brain disease. 3. Benzodiazepines and GABA receptors addressing how their wide expression can achieve some selectivity (anxiolytics). 4. Discuss confounds to their use. Depression References. Interest reading 1.Malignant Sadness. The anatomy of depression Lewis Wolpert. Free Press. Text Book Pharmacology (9thth Edition) Chapters 45 and 48. Rang, H.P., Dale, M.M., Ritter,J.M and Moore, P.K. Good coverage of major background in the topic. Wider perspective M.J.Owen (2014) New approaches to psychiatric diagnostic classification. Neuron 84. 555-571. Depression Lectures. Berton, O. and Nestler, E.J (2006) New approaches to antidepressant drug discovery: beyond monoamines. Nat Rev Neuroscience 7 137-151. One of several reviews highlighting limitations of the monoamine hypothesis, mechanisms underlying and novel approaches to treatment of depression. Some additional reference embedded in lecture slides. Critical Reading-really come back to the clinical issue based on the new knowledge. Journal Club Paper. Towards the end of the module to reinforce both generic issues (drug specificity) and depression specific information (mode of action of anti-depressants).  Diagnosis of psychiatric diseases. Largely based on categorization: Clinical classification expert view on what you have (inclusion) and don’t have (exclusion). Diagnostic Statistical Manual (DSM currently version V) International Classification of Disease (ICD currently version 11) Pros: Has improved diagnosis but lacks pathophysiological definition. Cons: Do not consider symptom overlap in distinct classifications (co-morbidities). Do not resolve specific disease causation hindering mechanism and drug development. Categorizations other limitation is that it does not take into account the dimensional expression or causes of psychiatric disorder and disease. “Schizoaffective disorder is not as well understood or well defined as other mental health conditions. This is largely because schizoaffective disorder is a mix of mental health conditions ― including schizophrenic and mood disorder features ― that may run a unique course in each affected person.” Research Domain Criteria (RDoC) basic science approach Better Classification -clearer indication of pathology - help understand and treat. Premise is that the inclusion exclusion criteria has got it wrong?  Depression: Pathophysiology of Mood. Major health problem 6% of world and above 20% developed health burden. Cost of mental health burden in 120 Billion per year based on an LSE report (2022) Depression Cost are > 15 billion/year in lost revenue in UK based on estimates (2002). Very much a human condition “A grief without pang, void, dark and drear. A drowsy stifled, unimpassioned, grief Which finds no natural outlet or relief In word, or sigh or tear.” Coleridge’s Dejection Very difficult to model in Where the best biomarker is a preclinical models. complex behavioural trait  Depression its Biological Context Mood reflects a change in behavioural state Low mood associated with negative thoughts. Averseness = strong reinforcer to modify behaviour, associated with focus “concentration”. Thus impart evolutionary advantage (selected for). Depression (sustained reflection on negative thoughts) may provide debilitating focus. A. Pathways that control focus (e.g. prefrontal cortex B. Modulation of pathways that control focus (5- hydroxytryptamine (serotonin). A+B=Biological function D(A+B)=Disease; where D (dysfunction)  Diagnosis of Psychiatric Disorders (e.g. Depression). American Society of Psychiatry: Diagnostic Statistical Manual (DSM I,II, III, IV and since 2013 V). World Health Organization: International Statistical Classification of Diseases and Related Health Problems (ICD 1-10), Primary indicators 1.Persistent sadness or low mood 2. Loss of interests or pleasure 3.Fatigue or low energy most days most of the time Persistence of behaviour For at least 2 weeks if present probe. Associated Symptoms 4.Disturbed sleep 5. Poor concentration or indecisiveness 6.Low self-confidence 7.Poor or increased appetite 8. Suicidal thoughts or acts. 9. Agitation or slowing of movements 10. Guilt or self-blame. Primary indicators + persistence + associated symptoms= diagnosis of disease not depressed (fewer than four symptoms) mild depression (four symptoms) moderate depression (five to six symptoms) severe depression (seven or more symptoms, with or without psychotic symptoms) symptoms should be present for a month or more and every symptom should be present for most of every day. Biological basis for the multiple dysfunction in depression What causes depression. Genetics. Environment. Sex differences. Defined Environment-Genetic interaction.  Stress pathway inputs into to aetiology and potentially treatment 1.Stress is a prima facta in triggering depressions. Principle stress pathway 2.Dysregulation of the feed back inhibition elevating Corticotrophin Releasing Factor (CRF) and glucocorticoids in depressed patients and animal models of depression. 3. i. Elevated glucocorticoids kill cells, and cause synapse loss. ii. Glucocorticoids inhibitory to synaptogenesis and neurogenesis in brain (hippocampus). 4. Additionally, CRF1 and CRF2 receptors exist in outside hypothalamic-pituitary axis (e.g. Amygdala). 5.Changes in CRF receptor levels in post mortem brains of depressed patients. ACTH (adrenocorticotropic hormone) 6.Antagonists against CRF receptors have some good indications in treatment of depression.  Monoamine Theory of Depression Elevating the levels of the Neurotransmitter Available for Signalling improves Mood.  Monoamine theory of depression 1960’s two serendipitous observations put monoamines (noradrenalin, serotonin (5-HT), dopamine) at the forefront of depression research. Tricyclic antidepressant Iproniazid was in trials for TB and patients Imipramine in trials as antipsychotic reported an elevation in mood. drugs indication to improve mood. Major target was inhibition of monoamine Elevated levels of monoamines oxidase, mitochondrial enzyme Adrenalin >serotonin>dopamine metabolizes neuroactive form of By blocking reuptake of released monoamines. Inhibition increased bio- Transmitter (monoamine) into cells. availability of neuroactive monoamine. Inside MAO-A metabolizes serotonin ,noradrenalin and dopamine. MAO-B metabolize selectively dopamine. CHO MAO-A MA NA NA aldehyde Outside The monoamine hypothesis in a neurobiological context. Elevated synaptic monoamines (noradrenalin, dopamine, serotonin) Monoamine neuron Inhibited Monoamine neuron MA (monoamine) 1. Blocking re-uptake or 2. inhibiting catabolic breakdown by MAO increases 3. the amount of MA available to activate 4. MA receptors Thus hypothesis implies increased signalling Mitochondria Mitochondria Nerve terminal MA-oxidase MA-oxidase MA 2. MA MA-ad MA Reuptake transporters 1. 3. MA receptor Post Synaptic Cell MA receptor Evidence in favour of the of the monoamine hypothesis. Pharmacological-drugs that increase content (see above) or synthesis (tryptophan-Horlicks) or sensitivity to monoamines are antidepressant. Drug that deplete storage (reserpine) or synthesis (alpha-methyltyrosine) of monoamines act as mood depressors. Measuring major metabolites in the CSF or urine equivocal. Levels of 3-methoxy-4-hydroxyphenylglycol (MHPG) and 5-hydroxy indoleacetic acid are elevated in the manic phase of bipolar but are much more varied in CSF plasma, urine of unipolar depressed patients. Measurable but not major alterations in a number of monoamine receptors in particular 5HT 2A in the post mortem tissue of patients. Some genetic mutations associated with deficient serotonin synthesis predispose to depressive episodes (e.g. Serotonergic transporters).  What happens when you elevate Monoamines? Widespread increase in key transmitters across brain regions Ventral Locus coerelus Dorasal Raphe Tegmentum Substantia Nigra Transmitters can potentially act on a broad number of receptors. Modifying the potency at sites responsible for the increase in transmitter levels Tricyclic antidepressant Selective serotonin reuptake inhibitor Imipramine (Tofranil) Fluoxetine (Prozac) Kd approx 50nM Kd approx 1nM  Fluoxitine Serotonin Extracellular Intracellular Secondary transporters co-transport Na+ and Cl- into cell with the substrate. Substrate binds within in Transmembrane domains (TM). Uptake inhibitors occupy substrate binding site and prevent translocation of monoamine into cytoplasm. Some evidence for more than one SSRI binding site (e.g. citalopram)  Billion Dollar Baby $10 Billion expenditure on SSRI’s in 2011 Allosteric Detailed molecular picture (additional site) Substrate Competitive Binding site (SB) Binding at SB Coleman, J.A., Green, E.M. and Gouaux, E (2016) Nature 532 334-339. News and views Caron, M and Gether,U (2016) 532 320-321. Change the way in which you achieve elevation of monoamine and/or the receptors that the signalling is being carried by. Noradrenalin serotonin selective antidepressant KD approx. 10-1000nm depending on target Noradrenalin Serotonin Selective Antidepressants (NaSSA) Selective increase in Noradrenalin by autoreceptor block Selective increase in Serotonin by heteroreceptor block Additional blocking or activating on sub-classes of receptor  The therapeutic use of Antidepressant activity. Success of antidepressants in treatment of disorder is good certainly heavily prescribed. Offer good efficacy in 40-50% (full recovery) with some efficacy in up 80%. Note the affective nature of the disorder means they can often have to work against drug interactions (bipolar treatment requires AD and mood stabilizer, co-illness heart disease and depression and individual variation (may include genetic background will determine drug of choice). Example Mechanism of action Side effects risks/notes Ipronazid Irreversible inhibition Long duration of action and many side effects (see below) (blocks MAO-A and B) inhibitors Phenelzine Non–Selective but Cheese reaction tyramine containing foods; insomnia weight MAO irreversible. gain, liver damage. MOA-selective and short Safer than other MAO but still Moclobemide acting exhibit drug interactions with opiods and sympathomimetic drugs Imipramine Block reuptake of monoamines Anticholinergic (e.g. dry mouthed relatively non-specifically. First and dizziness). Hypertension. TCA Clomipramine generation reuptake inhibitors. Seizure. Impotence interaction with CNS depressants, alcohol. Risk of overdose in dysrythmias of heart. Fluoxitine Relatively selective for serotonin Nausea, Diarrhoea, Insomnia. Uptake. Considered 2nd Inhibit other drug metabolism by generation reuptake inhibitors. P450 risk of interactions. Rather improved tolerance with Reuptake serotonin Selective Fluovoxime Reduced nausea inhibitor respect to side effects (e.g. heart) compared MAO and TCA compared to other SSRI drugs. Mirtasepine Blocks alpha 2, H1, 5HT2 and Dry mouthed and sedation. NaSSA muscarinic receptors. Elevate Faster acting than other monoamines by preventing inhibition of release. antidepressants. (NaSSA) noradrenergic and specific serotonergic antidepressant  Antidepressant paradox Drug administration rapid effect on the levels of Monoamine in the CNS. In general consistent with an inhibition of monoamine degradation (MAO) or inhibition of monoamine uptake. However it takes 2-6 weeks of drug treatment to see an effect on clinical signs of depression. This paradox predicts a long term change in brain structure function in response to drug treatment. Drug treatment Full efficacy Probably not a one step process. Short term Medium Term Longer term  Brain structure function that may square the circle of antidepressant paradox. Cell body Short-term firing or release to inhibit e.g. 5HT activate Autoreceptors Inhibit uptake monoamine (e.g. serotonin) impacts increased signalling. Measured by microdialysis as increased in Raphe nucleus, locus coeruleus and cortex Locally this can inhibit neuronal firing (cell body) and release (nerve terminals) by activating negative autoreceptors ( e.g.5HT1A) that Inhibit firing or release. Nerve terminal Medium term Prolonged treatment leads to down regulation of auto receptors reduced feedback Inhibition leading to increase neuron firing and chemical transmission (release). of negative signalling Down regulation Other noted changes include Down regulation 2 postsynaptic receptors Down regulation of 2 auto receptors Down regulation of 5HT2 receptors. Overall sense of a homeostatic response of pathways returns to signalling to pre-treatment levels. Long- term Above indicative of an adaptive response after treatment and serotonin (monoamine signalling) has been implicated in longer term an possibly more sustained changes supported by GROWTH FACTOR EXPRESSION (e.g. BDNF). This is associated with synaptic plasticity neurogenesis and synaptogenesis. Sustained rewiring of circuits associated with mood. Neurogenesis (New neurons) Synaptogenesis (New or replacing lost synapses) 5HT Neuronal progenitor Normal Depressed Treated or stem cell  An excitation of a serotonin mechanism that acts in depression. Excitation of a discrete subset of prefrontal cortical projection neurons regulates (executes) a motivated state (anti-depressant). Warden et al., (2012) Nature 492. 428-32. Forced swim test When move they are motivated When float given up (model despair).  Significant problem with a clear solution? 350 million depressed people world wide. Cost major economies money $210 billion in US £25 billion in UK Health Burden for afflicted and family Anti-depressants market is $15 billion per year. 15 % of major western countries on AD  Novel old approaches to depression treatment. Murrough et al., 2013 Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial. Am J Psychiatry. 170:1134-42. Clinical trial comparing Ketamine with midazolam showing efficacy of former. Clinical depression in refractory to licensed therapies. Preferred monoamine modulation therapies Recognized as an issue in 20-30% take time. Can be limiting in severe of diagnosis. depression. Possible misdiagnosis. Lead cohort to sustained depression that self harm or suicide. Many reason for non-responders (ranging from non compliance to Genuine need to speed up therapeutic genetic background). potential Not helped by limited insight into mechanisms.  Ketamine: repurposing drugs? Dose dependent impacts on behaviours producing distinct behavioural states Anaesthesia Dissociative symptoms Anti-depressant. About 3mg/kg about 1 mg/kg (2mg/kg K-hole) 0.5 mg/kg Inhibits thalamic regions Limits subcortical inhibition Basis of effect?  Comparison of ketamine (0.5mg/kg) with midazolam (0.045 mg/kg) a sedative benzodiazepine. Recruited; flushed of existing medication and assigned to either treatment. Given a baseline rating of depression. nfused with drug and then assessed after 1 day for antidepressant activity. Some follow up based on time that patients remained responders. 1. Antidepressant effect with 50% reduction of the MADRS. Supported self reporting scor 2. Hints at longer term effect based on relapse below 50% reduction (note fall out). 3. Adverse effects (e.g. dizziness nausea for both groups and 15% reported dissociative symptoms for ketamine only).  Interesting biological explanation of ketamine activity. Forced swim test where motility is a measure of depression Ketamine CPP NMDA Competitive MK-801 NMDA channel block inhibitor NMDA channel block Ketamine selectively induces acute and allows a sustained (1 week) antidepressant activity PLASTICITY  BDNF knock out animals do not show ketamine induced antidepressant activity Ketamine activity requires the acute induction of BDNF protein that depends on translational (protein synthesis) but not transcriptional (new gene expression) control. Confirmed or reinforced by experiments showing that translation inhibitors (anisomycin) but not transcriptional inhibitors prevent ketamine effects. cuit level explanation: NMDA receptors and glutamate work in hways that control excitation. And the excitation of inhibition. Simple to cell reciprocal circuit. Negatively regulated Excited relative to above Still a change in state of the circuit but mediated by a selective targeting of the inhibitory component that drives the system.  Ketamine’s potential. Fast tracked for FDA approval in the US of A. Nasal formulation being developed based on esketamaine (S-isomer which has increased potency). Will this will be revisited based on recent results. Delayed prescription in the UK. Cautionary notes suggest study of long term physical impacts (kidney). Long term impacts in terms of psychological impact (reflect on Benzodiazepine in 70’ and 80’s) Long term efficacy in terms of its therapeutic potential. Route for “novel” approaches to rising and intractable problem (HNK model suggests a new mode of action).  Slow increase in Anti-Depression Armoury Drug Target Side Effect Wider impact effects/comments MAO-Inhibitors Enzyme that break Extensive Elevate bioactive Time dependent down bioactive monoamines plasticity. monoamines. TCA/SSRI Monoamine Varied and Elevate synaptic Time dependent Transporters TCA>SSRI monoamines plasticity NASSA Auto/hetero- Strong side effects. Elevate synaptic Short term and receptors increase But success in 5HT and NA. time dependent release and intractable plasticity signalling depression Ketamine Glutamate Kidney toxicity Signalling and Acute and signalling Social stigma circuit level. sustained plasticity Psilocybin 5HT receptor Relatively low Allosteric increase Acute and signalling. Social stigma in serotonin synaptic plasticity signalling. Deep brain Targeted Major surgery. Increase circuit Acute and brain stimulation stimulation off target activity. re-organization of brain regions. stimulation. Behavioural Brain function Efficacy and Neurochemical Behavioural Therapy assisted by drugs changes and recovery brain structure