Affective Disorders Neurobiology and Treatment (AC)_2022_new.pptx

Module 202 2022/23 23 Nov 2022 Affective Disorders Neurobiology and Treatment Dr Alessandro Colasanti, MD, MSc, PhD, Senior Clinical Lecturer in Psychiatry, Department of Clinical Neuroscience and Neuroimaging, Brighton and Sussex Medical School Consultant Psychiatrist at OpCourage TILS Veterans se...

Module 202 2022/23 23 Nov 2022 Affective Disorders Neurobiology and Treatment Dr Alessandro Colasanti, MD, MSc, PhD, Senior Clinical Lecturer in Psychiatry, Department of Clinical Neuroscience and Neuroimaging, Brighton and Sussex Medical School Consultant Psychiatrist at OpCourage TILS Veterans service & Complex Mood disorder services and Immunopsychiatry Research clinic - Sussex Partnership NHS Foundation Trust Learning outcomes students should be able to • describe the most important neurobiological mechanisms underlying the pathogenesis of mood disorders • list the major classes of medications used for treatment of mood disorders • describe mechanism of action of common antidepressant drugs • describe the side effects of common drugs used in mood disorders Aetiology of depression • Multifactorial • Incompletely understood • Interactions of: genetic factors, personality, early environment, childhood adversities, life events, psychological predisposition and biological factors Mood Disorders Historical classification : endogenous vs reactive depression However, the current classification systems do not contain categories of reactive or endogenous depression. “every illness is a product of two factors—of the environment working on the organism— whether the constitutional factor is the determining influence or the environmental one ... is never a question to be dealt with as either/or.” Lewis, 1934 when considering the aetiology of individual cases of depression, the relative contributions of the various aetiological factors must be considered  5HT and NA function Depressive syndromes Adverse childhood experience Current Stress Genetic factors  5HT and NA function Depressive syndromes Adverse childhood experience Current Stress HPA Axis function Cortisol Genetic factors  5HT and NA function (neuro)inflammatio n neuroplasticity Depressive syndromes Genetic causes of depression The risk of depression in 1st relatives of a proband is approx. 3-fold increased The heritability of major depression has been estimated at 37%, less than that of bipolar disorder or schizophrenia No convincing loci identified by genome wide association studies, due to large genetic and clinical heterogeneity of depression polygenic inheritance : Genetic liability to depression results from combined action of multiple genes of small effect in a context of gene– enviroment interaction Gene-environment interactions From Caspi et al., 2003, Science Neurobiology of depression 1. Abnormal monoamine activity 2. Gaba and Glutamate 3. HPA Axis and Glucocorticoids 4. Neuroplasticity and Neuronal Atrophy 5. Immune dysfunction Serotonin (5-HT) and Noradrenaline (NA) Pathways in the Human Brain Limbic System Prefrontal Cortex Amygdala Raphe Nuclei (5-HT source) Hippocampus Locus Coeruleus (NA source) Descending 5-HT pathways Descending NA pathways Cooper JR, et al. The Biochemical Basis of Neuropharmacology. 8th ed. New York: Oxford University Press; 2003. Neural systems involved in Depression Kupfer et al, 2012 Serotonin (5HT) dysfunction in Depression All traditional antidepressants affect 5-HT/NA systems Clinical relapse after experimental reduced 5-HT concentrations (acute tryptophan depletion) Reduced 5-HT Transporter in post-mortem suicide studies Reduced brain 5-HT release in depressed patients HPA dysfunction in Depression Neuroplasticity alterations and subcortical atrophy GABA and glutamate Chronic stress/depression: Decreased GABA & Glutamate Ketamine : NMDAR blocker single dose has rapid and striking antidepressant effects But transient stimulates synaptogenesis reverses stress/depression Gaba&Glutamate deficits Depression treatment – types and phases Psychotherapy Can also be alone or as adjunctive therapy Pharmacotherapy Effective for Major Depression and Persistent MDD How effective in mild depression? Primary care supportive Counselling Important 1st MAOi. Generation Antidepressants Monoamine oxidase inhibitors (Phenelzine, Tranylcypromine) Nonselectively inhibit enzymes involved in the breakdown of monoamines, including serotonin, dopamine, and norepinephrine Tryciclic antidepressants (Amytryptiline, Clomipramine)… Nonselectively inhibit the reuptake of monoamines, including serotonin, dopamine, and norepinephrine 2nd generation antidepressants SSRI: Selective serotonin reuptake inhibitors [Sertraline, Citalopram, Escitalopram, Fluoxetine, Vortioxetine ] SNRI: Serotonin-noradrenaline reuptake inhibitors [Venlafaxine, Duloxetine] Others: eg, alpha2 and 5-HT2Cantagonist, that modulate 5HT and NA release [ Mirtazapine ] Efficacy and tolerability of SSRIs Advantages Efficacy equal to tryciclics in outpatients Large spectrum of action (OCD, PTSD, Panic, GAD, social anxiety) Low toxicity and safe in overdose Side effects initial treatment phase most delicate, due to more side effects vs benefits gastro-intestinal symptoms (nausea, diarrhea) headache, Irritability, Anxiety reduction of libido and sexual dysfunction Gradual suspension to avoid withdrawal symptoms (worst with venlafaxine and paroxetine due to short half-ife) Neurobiology of Bipolar Disorder Bipolar Disorder: Genetic causes Familial aggregation (10 times higher risk in 1st degree relatives) Up to 85 % heritability estimate Polgyenic inheritance (thousands of genes of small effect ) GWAS association w)ith CACNA1C (encoding a subunit of the L-type calcium channel replicated GWAS finding • Overlap in risk alleles identified in GWAS studies between Bipolar and schizophrenia. More than overlap between Bipolar and Depression • • • • Bipolar Disorder: Role of environment • Monozygotic twins concordance rate around 60%  environmental factors likely to be important • Stressful live events can trigger episodes • Life trauma increase risk to develop Bipolar (as any other psychiatric disorder), ie seems non-specific for Bipolar Neurobiology of Bipolar Disorder 1. Neurochemistry (excessive dopamine in mania, and 5HT abnormalities in depression) 2. HPA Axis and cortisol 3. Neuroprogression and neurodegeneration in some patients 4. Neurometabolic and mitochondrial abnormalities Bipolar Disorder treatment Overview of drug categories Lithium 2nd gen Antipsychotics Anticonvulsants Antidepressants Bipolar Disorder Treatment phases Short-term treatment to reduce the severity and shorten the duration of the acute episode and achieve remission of symptoms Long-term treatment prevention of new episodes and to achieve adequate inter-episode control of residual or chronic mood symptoms Bipolar Disorder treatment Overview of drug categories Lithium (acute mania, prevention of mania and depression) 2nd gen Antipsychotics (acute mania, acute depression, prevention of mania and depression) Anticonvulsants: Valproate ( acute mania, prevention of mania) Lamotrigine (prevention of depression ) Antidepressants: acute depression, prevention of depression Adverse effects of pharmacological treatments for BPAD Lithium toxicity  n arrow therapeutic index (requires therapeutic drug monitoring of plasma levels) Kidney and Thyroid dysfunction (poorly regulated Lithium) Weight gain and metabolic syndrome (many 2nd gen antipsychotics and anticonvulsants, ie Olanzapine and to a lesser extent Quetiapine) Liver damage (e.g. Valproate) Hyperprolactinemia (any Dopamine antagonist) Tardive dyskinesia (much reduced risk with 2nd generation antipsychotic agents) Other disadvantages of pharmacological treatments for BPAD stopping lithium abruptly might exacerbate manic relapses antidepressant drugs risk to induce mania Often poor adherence and long-term compliance without interventions around psychoeducation and enhancing self-management of patients Valproate during pregnancy is cause of neurodevelopmental defects Thanks for your attention Any questions?