Biospych of Depression PDF

Monoamine Oxidase Inhibitor- MAOI e.g. Iproniazid...

Monoamine Oxidase Inhibitor- MAOI e.g. Iproniazid - MAO- enzyme involved in the degradation (breakdown) of monoamines in the synapse ^ so this drug reduces/stops/inhibits the degradation action of monoamines, leads to: - increase cerebral levels of NA and 5-HT ^ enhances chemical communication in synapse Can take 2-6 weeks to start showing Tricyclic Antidepressants- TCA effects e.g. Imipramine 5-HT2A Postsynaptic Receptors ^ although increases - if serotonin levels are low in depressed patients- postsynaptic corresponding - inhibits the reuptake of monoamines ^ leads to more monoamines in synapse receptors may become hypersensitive neurotransmitter concentrations SSRIs ^ leads to more chance for chemical transmission ^ as there isn't much to receive and therefore quickly uptake within hours? - work by inhibiting serotonin reuptake (SERT- - inhibits the reuptake of both NA and 5-HT but to ^ so, should desensitisation help this?: the serotonin transporter) different extents - Antidepressants result in the down-regulation of 5-HT2A & 5- Efficacy Comparisons- in lab conditions HT2C receptor subtypes (Van Oekelen et al., 2003) ^ increases levels of serotonin ^ desipramine is more effective on NA - when comparing TCAs and SSRIs, no difference in efficacy was found - Chronic MAOIs and TCAs use = down-regulate 5-HT2A receptors - specifically targets these receptors ^ amitriptyline is more effective on 5-HT ^ but TCAs had higher drop-out rate than SSRIs- suggesting better - Animal studies suggest 5-HT2A antagonists possess Examples: - also blocks alpha receptors and muscarine receptors- tolerance of SSRIs, and more negative side effects of TCAs antidepressant effects fluoxetine (prozac), citalopram, fluvoxamine, thought to be responsible for additional side effects ^ overall efficacy is greater with lower drop-out rates (undurraga & - 5-HT2A antagonist enhanced the antidepressant like behavioural baldessarini 2017) paroxetine, sertraline effects of fluoxetine (Marek et al., 2005) - when comparing SSRIs and SNRIs, there is a limited difference Administration of pindolol a 5-HT1A antagonist and b- ^ this blockade may affect the function of the prefrontal- ^ may be some slight advantage of SNRI but this may not be large Drug Development adrenoceptor antagonist accelerated the action of SSRIs subcortical circuits, an effect that probably underlies the beneficial enough to be clinically relevant (papakostas et al., 2007) - selective-serotonin reuptake inhibitors (SSRIs): fluoxetine etc Early Antidepressants (Aritgas et al 1994) an effect attributed to the 5-HT1A action effects of the addition of atypical antipsychotic drugs (which are 5- - noradrenaline reuptake inhibitors (NARIs): maprotiline etc - non-specific action- interacts with all monoamines HT2a receptor antagonists) - serotonin-noradrenaline reuptake inhibitors (SNRI): venlafaxine etc ^ result in many side effects, drug-drug and drug-food Depression Imaging Studies: ^ especially useful for SSRIs treatment-resistant patients - Atypical antidepressants: mianserin, trazodone etc interactions/possible overdose (serotonin syndrome) - elderly patients with depression show enlarged lateral ^ often used if others don't work ^ e.g. in food- aged food has tylenine which is a chemical, The desensitisation of 5-HT1A auto-receptors can ventricles (Beyer & krishnan, 2002) ^ mianserin- antagonist mainly at 5-HT2 and alpha presynaptic and and when taking these drugs, prevents the breakdown of this accelerate or augment the antidepressant effect ^ associated with corticol atrophy somatodendritic auto- and hetero-receptors chemical- dangerous ^ want to slow the auto-receptors process down Tryptophan Depletion - reduced cortical thickness in orbitofrontal cortex, anterior ^ trazdone- antagonist of 5-HT-2A receptor, H1 receptor, and ^ have reduced compliance and led to further development - in a study, artificially created hypersensitive auto- ^ the body uses tryptophan (get from food)to help make and posterior cingulate, insula and temporal lobes in alpha-1 adrenergic receptors receptors by increasing the levels of auto-receptors in melatonin and serotonin depression (schmaal et al 2017) a mouse ^ melatonin helps regulate the sleep-wake cycle ^ Mice with higher 5-HT1A auto-receptor levels ^ serotonin helps regulate appetite, sleep, mood and pain Postmortem Studies showed blunted response to acute stress, increased ^ liver can also use tryptophan to produce niacin (vitamin Depression and Brain Structure - reduced density of layer III neurones in the behavioural despair and no behavioural response to B3)- needed for energy metabolism and DNA production - depressive symptoms are seen in people with stroke, dorsolateral prefrontal cortex an antidepressant whereas mice with lower levels - reducing availability of the amino acid precursor for traumatic brain injury or brain tumour, particularly those ^ neurones project to other cortical regions and 5-HT1A autoreceptor display a robust response to fluoxetine after 5-HT, tryptophan, was related to significant worsening of affecting the frontal lobe and basal ganglia within the PFC ^ on the pre-synaptic neurone administration (Richardson-Jones et al 2010) mood in SSRI-related, remitted depressed patients - when activated- inhibits release of 5-HT (Delgado et al 1990, spillman et al 2001) - MDD hypersensitive auto-receptors = Reserpine Medial Temporal Lobe leads to low levels of 5-HT release Biomarkers - blood pressure drug - hippocampus volume reductions have been reported in people Stress and MDD Noradrenaline and Depression ^ too quick at detecting and therefore - 5-HT metabolite is 5-hydroxyindoleacetic acid (5-HIAA) ^ peripheral nerve cells use monoamine neurotransmitters to with recurrent depression (schmaal et al 2016) - animal studies- show early life stress produces persistent - similar explanations are offered inhibiting 5-TH release stimulate heart rate and vascular contraction - increased connectivity and heightened activation of the amygdala increases in corticotrophin releasing hormone (CRH)- Meaney, 2001 to explain the role of noradrenaline - NA metabolite is 3-Methoxy-4-hydroxyphenylglycol (MHPG) - Both reduced in cerebrospinal fluid (CSF) of depressed - reduces storage of noradrenaline (NA) and serotonin (5-HT) - hippocampus and amygdala have an action in emotion regulation - clinical studies- sexual or physical abuse in childhood can show in depression patients compared to controls - depletes neuronal stores (vesicles) of NA and 5-HT by causing - one model has implicated hippocampal damage due to stress in enhanced activity of the hypothalamic-pituitary-adrenal axis (HPA ^ the presynaptic auto-receptor is metabolite= a substance made or used when the body breaks leakage from the vesicles that store these transmitters the brain to depression axis) when exposed to standardised psychosocial stressors or the a2 receptor down food, drugs or chemicals (or own tissue e.g. muscle shown to: ^ linked to changes in neurotrophic signalling cascades- following endocrine tests that attempt to suppress HPA activity ^ the postsynaptic receptor are b- tissue)- used in the process of metabolism, makes energy ^ induce depressive symptoms in healthy people particularly through brain-derived neurotrophic factor (BDNF) (stetler&miller 2011) receptors and the materials needed for growth, reproduction and ^ precipitate depression in remitted patients protein which may be partly reversed by antidepressant treatment ^ glucocorticoid receptor function is reduced in these individuals - in depression- both are maintaining health - suggesting depletion of NA and 5-HT is related to depressive ^ neurotrophins- prominent regulators of neuronal survival, growth (glucocorticoid resistance)- supported by evidence indicating same hypersensitive and the therapeutic symptoms and differentiation during development individuals also show increased activation of the inflammatory effect of NA-active antidepressants ^ BDNF in particular- important role of neuronal survival and system (which is inhibited by cortisol) involve receptor desensitisation of growth, serves as a neurotransmitter modulator, and participates in ^ this receptor (GR/GCR, aka NR3C1) is the receptor which cortisol a2 followed by b-receptors Therapeutic Delay and Serotonin Monoamine Theory neuronal plasticity, which is essential for learning and memory (and other glucocorticoids) bind - MDD is thought to result from the dysfunction of various ^ widely expressed in the CNS, gut and other tissues ^ glucocorticoid resistance, HPA axis hyperactivity and neurotransmitter or metabolic systems increased inflammation are all evidence in MDD - monoamines- make up a neurotransmitter class that is Acts to assure a response to stress Biochemistry and Biological Mechanism of Depression characterised by the shape of its chemical structure e.g. dopamine, serotonin, norepinephrine/noradrenaline Hypothalamic-Pituitary-Adrenal Axis (HPA axis) (sugar & fat mobilisation & metabolism), and act in a negative feedback loop to Pharmacology of Depression Genetics - occurs in the synapse between neurones- in between the axon/ decrease production and release of CRH pre-synaptic terminal and the dendrite/post-synaptic terminal - family studies- earlier age of onset (