Updated Depression Lecture PDF

Pathology 3.06 - Depression Major Depression and Bipolar Disorders Dr. Albert Iarz, ND, RMT BMS 150 Week 6 Overview Overview of psychiatry Definitions of common psychiatric presentations Major Depressive Disorder Epidemiology Major clinical feature...

Pathology 3.06 - Depression Major Depression and Bipolar Disorders Dr. Albert Iarz, ND, RMT BMS 150 Week 6 Overview Overview of psychiatry Definitions of common psychiatric presentations Major Depressive Disorder Epidemiology Major clinical feature Diagnostic Criteria Neurochemistry/ Neuropathology Bipolar 1 and 2 Epidemiology Major clinical feature Diagnostic Criteria Neurochemistry/ Neuropathology Mechanism of action of antidepressant and antimanic medication Learning Objectives Describe the role of psychiatry in health care Define common psychiatric presentations including psychosis, delusion, hallucination, depressive disorder, mania, hypomania, delirium Describe the epidemiology, major clinical features and diagnostic criteria major depressive disorder (MDD) and bipolar disorders 1 and 2 Describe the neurochemistry and neuropathology contributing to the disorders of MDD including role of circadian rhythm abnormalities, excitotoxicity, inflammatory hypothesis, monoamine hypothesis and neurotrophic hypothesis Describe the neuropathology and biochemistry of bipolar disorders, particularly the role of increase glycolysis and reduced oxidative phosphorylate in metabolic imbalance associated with these pathologies Describe mechanism of action of selected common antidepressant and anti- manic agents, such as SSRI, MAO inhibitors, and others Overview of Psychiatry Branch of medicine which focuses on the prevention, assessment and treatment of mental, emotional and behavioural disorders Disorders include substance abuse/ addictions, mood, anxiety, eating disorders, personality disorders and psychotic disorders Treatments can include medications, psychotherapy, electroconvulsive therapy, and other forms of medicine Common Psychiatric Presentations Definition for Delusion Delusion A belief that is clearly false and indicates an abnormality in content of thought False belief cannot be explained by the person’s cultural or religious background or intelligence level Belief is held despite being presented with evidence against it (“fixed” – firmly maintained) Patient is convinced the delusion is real Can be due to: mental disorder, neurological or medical disorder Examples: schizophrenic, substance abuse, bipolar disorder, major depressive disorder (MDD), delirium and dementia Definition for Hallucination Hallucination “A sensory perception in the absence of a corresponding external or somatic stimulus and described according to the sensory domain in which it occurs” Not under voluntary control Vivid, clear, full force and impact of normal perceptions Visual, auditory, tactile, olfactory, gustatory, nociceptive, thermoceptive, proprioceptive, equilibrioceptive Formed (i.e. voice making a command) or unformed (i.e. non- specific sound) With insight – px is aware that its not real only hallucination OR without insight – px is unaware and accepts the experience as reality Can occur in illness and in health (i.e. grief) Can be due to: psychiatric disorder, neurological or medical disorder Definitions for Psychosis Psychosis Hallucination (without insight), delusion OR hallucination (without insight) and delusion Loss of contact with external reality Central component: Impaired reality testing Can occur in psychiatric and neurological disorders Additionally: Disorganized thoughts and impairment in cognitive function (i.e. reduced verbal fluency) Mood changes Reduced attention and concentration Sleep disturbances Definition for Delirium Delirium Acute, fluctuating change in attention (reduced) and consciousness including disorganized thoughts Altered consciousness: hypervigilant, unresponsive, near-coma, severe agitation May include: psychosis; delusions and hallucinations, altered mood Can vary in duration: days (typically) or months Triggered by: change in medication, infection, surgery, trauma, stroke, withdrawal, very extensive list Definition for Depressive Episode Depressive Episode Experience of low or depressed mood Loss of interest in most activities Additional possible symptoms: Fatigue Changes in appetite (and weight) Feelings of worthlessness Recurrent thoughts of death Unexplained physical ailments unresponsive to treatment (i.e. digestive problems, pain) Conditions include: MDD, anxiety disorder, bipolar, schizophrenia, post-stroke, bereavement, and others Definition for Mania Mania Characteristics: increased talkativeness, rapid speech, decreased need for sleep, racing thoughts, distractibility, increase in goal-direct activity, psychomotor agitation May include: elevated mood, mood lability, impulsivity, irritability, grandiosity Duration: 1 week or more OR if severity of symptoms warrants hospitalization Conditions: bipolar disorder, certain medications and substances may cause sx of mania, neurological causes can include stroke, brain tumor or injury Definition for Hypomania Hypomania Differentiating factors from mania: Duration: at least 4 days (rather than at least 1 week) Does NOT cause major deficit in social or occupational functioning Conditions: bipolar disorder, substances, neurological causes (i.e. encephalitis, dementia, lupus) Major Depressive Disorder (MDD) Epidemiology Major clinical feature Diagnostic Criteria Neurochemistry/ Neuropathology Major Depressive Disorder (MDD) Epidemiology Predicted to be the 2nd leading cause of disability world wide by 2030 (according to WHO) Canada: 4.7-5.4% of population experience MDD, higher rates in at-risk groups Risk Factors: Exposure to traumatic life events (death, abuse, parental psychopathology…) Chronic pain and chronic disorders (cancer, stroke, MS, others) and physical health Low income, increased caregiver burden, lack of social support Family history (first degree relative 3x risk of developing MDD) MDD: Clinical Features Mood Symptoms Physical Sx Cognitive Sx Feeling sad/ low Lack of energy / tired Slow thinking Lack of interest in Difficulty sleeping; Difficulty general waking early concentrating Anhedonia Restless/ agitated Slow movement Low self-esteem Weight loss Forgetfulness Lacking confidence Low libido Difficulty planning Feelings of guilt or Low appetite/ Difficulty making worthlessness overeating decisions Suicidal thoughts MDD: Diagnostic Criteria DSM-5 Category A – must include the first two components and a total of 5 or more components: Depressed mood (subject report of observations of others) Anhedonia – loss of interest/ pleasure in almost all activities These 2 sx must be present most of day, every day for at least 2 weeks in a row Unintentional weight loss or gain (>5% in 1 mo) or significant change in appetite Sleep disturbance (insomnia/ hypersomnia) Psychomotor changes (agitations/ retardation) Fatigue, low energy, decreased efficiency with routine tasks Sense of worthlessness or excessive/ inappropriate guilt (i.e. guilt about being sick) Impaired ability to think/ concentrate/ make decisions Recurrent thoughts of death, suicide ideation or attempts MDD: Diagnostic Criteria DSM-5 Additional diagnostic requirements: These sx must cause significant distress OR impair social, occupational or other important areas of function Sx are not due to direct physiological effects of a substance (i.e. meds, drug abuse) OR medical condition (i.e. hypothyroidism) Px has never experienced a manic or hypomanic episode This condition is not better explained by schizophrenia spectrum or other psychotic disorders MDD: Neuropathology and Neurochemistry Multifactorial disease with various causes and triggers Psychosocial causes Genetics Nutritional deficiencies Pollution/ environment Gut-brain axis Leading biomedical theories Monoamine hypothesis Stress-induced depression hypothesis Neurotrophic / Neuroplasticity hypothesis Cytokine hypothesis/ Neuroinflammation hypothesis Circadian hypothesis of depression GABA-glutamate-mediated depression hypothesis Monoamine Hypothesis Altered levels of monoamine neurotransmitters, specifically serotonin and noradrenaline, and/or dopamine cause depression Based on antidepressant therapies that increase the presence/ function of one or more neurotransmitter resulting in reduced depression Critiqued in that abruptly decreasing serotonin and/or dopamine doesn’t cause depression in a healthy person Other neurochemicals are implicated in depression beyond these Probable causes: genetics, environment, stress Stress-induced depression hypothesis Chronic stress leads to dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis Prolonged, moderate stress is the problems, versus minor daily stresses OR one strong stressor Examples: maternal stress, maternal smoking, early grave loss, child abuse Early trauma may have more sig impact than in adult life (impact how HPA is developed in utero) Chronic HPA activation leading to: excess cortisol secretion and pro-inflammatory agents that damage glia and neurons, interfere with neurogenesis and reduce glutamate and GABA Stress-induced depression hypothesis Clinical studies support this in some patients with severe depression: measurable increase in cortisol which is not reduced through negative feedback (also increased CRH) Resistance of the glucocorticoid receptor (GR) Antidepressants appear to restore the functioning of the GR and thus improve negative feedback and normalize cortisol levels Critique: hypercortisolism is not a feature of all MDD cases AND not clear what causes HPA dysregulation (i.e. loss of GR sensitivity) Neurotrophic and neuroplasticity hypothesis Brain-derived neurotrophic factor (BDNF) promotes neurogenesis, regulates differentiation and growth of neurons Neurogenesis may offer resilience against stress by enhancing the negative feedback loop with HPA Observations: Decreased BDNF gene expression, decreased BDNF levels and receptors in MDD patients Increased cortisol can inhibit BDNF Same triggers that elevated cortisol appear to block neurogenesis Antidepressants Have been demonstrated to stimulate neurogenesis in adult hippocampus (animal studies) – takes 4 weeks Correlates with the 3-4 week expectation of achieve improvement in mood Cytokine and Neuroinflammation hypothesis Observation: MDD px have increased levels of pro-inflammatory markers: TNFalpha, IL-1, IL-6, C-reactive protein (CRP) vs healthy px, as well as increased level of macrophage/monocyte activation Frequent correlation b/w MDD and inflammatory conditions such as asthma, diabetes, arthritis, obesity, CAD Animal studies: injecting pro-inflammatory cytokines induces depressive sx Some antidepressants have anti-inflammatory properties Earlier case reports observed improvement in mood in patients with treatment resistant MDD treated with anti- inflammatory medications, particularly in context of other inflammatory conditions (like IBD) However, several clinical trial failed to reproduce these results Circadian Physiology Healthy state: Light inhibits pineal gland from producing melatonin (by activating neurons with suprachiasmatic nucleus (SNC) of the hypothalamus) SCN regulates production of melatonin throughout the body Melatonin production increases at night during conditions of dark Circadian Hypothesis Stressful events lead to changes in diurnal molecular rhythms in cells that in vulnerable px triggers MDD Bidirectional link with sleep disturbance and depression Insomnia is a predisposing factor Sleep deprivation therapy – reduces MDD sx (may reset the circadian clock) Genes controlling circadian rhythms in anterior cingulate cortex are dysregulated in depression Phase advance in cortisol rhythm and reduced amount of melatonin production seen in some patients with MDD Altered circadian rhythms can also affect reward systems, particularly social interaction Same 5-HT receptors have been implicated in both sleep rhythms and depression; serotonin is involved in phosphorylation of CLOCK protein, which regulate suprachiasmatic circadian rhythms Sleep disturbances have also been correlated with pro-inflammatory cytokines Excitatory Neurotransmitters Hypothesis Glutamate may cause excitotoxicity resulting in neuronal atrophy and reduced synaptic connectivity Stress induced changes may be accelerated in the presence of elevated Glu Reduced GABA in CSF of MDD px – may be d/t change in serotonin which modulates GABA, which in turn modulates glutamate Reduced GABA and glutamate within glial cells and neurons of the prefrontal cortex (PFC) Astrocytes recycle glutamate and transport to presynaptic neurons Elevated metabolism of glucose within same areas of PFC, and reduction of the gray matter in this region Ketamine – modulates glutamate transmission Approved for tx of treatment resistant MDD Glutamate Excitotoxicity Excessive accumulation of glutamate within synaptic cleft results in over stimulation of postsynaptic glutamate receptors Via NMDA receptor glutamate promotes calcium influx Review: how does increased cytosolic Ca2+ result in necrosis? Bipolar Disorders Epidemiology Canada 1.5% of pop experience bipolar disorder Clinical Features Mania Hypomania Depression (most of time spent in depressive state) Cyclical changes between these states a common to be part of the disorder Manic psychosis, which may include delirium Bipolar 1 At least 1 manic episode and usually depressive episodes Bipolar 2 Major depressive episodes with at least 1 hypomanic episode Bipolar Disorders - DDX Bipolar Disorder 1: Exclusion of hyperthyroidism (TSH and T4) Exclusion of stimulant drug abuse (blood/urine) Clinical based on DSM-5: At least 1 episode of mania/hypomania lasting for at least 4 consecutive days AND be present most of the day, almost every day 3 or more symptoms (representing sig change from norm) of mania Cause significant impairment or necessitates hospitalization Mania Symptoms 3 or more symptoms (representing sig change from norm) of mania: Inflated self-esteem or grandiosity Decreased need for sleep (feels rested after 3 hours of sleep) More talkative than usual or pressure to keep talking Flight of ideas or subjective experience that thoughts are racing Distractibility (i.e. attention too easily drawn to unimportant / external stimuli) Increase in goal-directed activity (purposeful) or psychomotor agitation (purposeless) Excessive involvement in activities that have a high potential for painful consequences (i.e. foolish business investments, unrestrained buying sprees) Bipolar Disorders - DDX Bipolar Disorder 2: No/never experienced episode of mania Exclusion of/ not better explained by: schizophrenia, delusional or psychotic disorder or unspecified schizophrenia spectrum Clinically significant distress from symptoms Hypomania episode Hypomania Episode (DSM-5) Elevated, expansive or irritable mood with persistently increased activity or energy; 4+ days, most of the day, nearly every day 3 or more additional mania symptoms Episode is different from px regular non symptomatic experience Observers can note change in mood and function Not severe enough to impair functioning or necessitate hospitalization (no psychotic features) Episode is not triggered by substance (drug, medication, other treatment) Pathophysiology of Bipolar Disorders Circadian Rhythm Dysfunction Metabolic Dysfunction Mitochondria Dysfunction Glutamate Excitotoxicity Circadian Rhythm Dysfunction During mania there is a reduced need for sleep Observations in patients with bipolar disorders: Changes in melatonin levels Changes in melatonin receptor expression with CNS Changes in cortisol profiles (patterns of release) Sleep deprivation as well as light therapy have been effective as adjunct in some cases of bipolar disorder Correlation between polymorphism in CLOCK genes as well as positive response to lithium therapy (common drug used in bipolar management) Metabolic Dysfunction Various metabolic abnormalities have been found in patients with bipolar disorder such as: Increased risk of obesity, type 2 diabetes, and reduced longevity due to increased cardiovascular problems Increased amount of leptin secreted in obese patients with bipolar compared to obesity alone Leptin regulated appetite AND sleep duration A hypothesis suggests that the body is forced to compensate for the high metabolic demand of the brain during manic states: Reduced appetite Reduced sleep Increased energy expenditure Mitochondria Dysfunction Impairment in mitochondrial function resulting brain metabolism shifting towards glycolysis Observations: Polymorphisms within mitochondrial DNA linked to BD Reduced levels of phosphocreatine within frontal cortex. Phosphocreatine is a reserve for ATP and this implied chronic deficiency in ATP synthesis Evidence of impaired oxidative phosphorylation Increased amounts of alpha-ketoglutarate and pyruvate – review: how do these substrates relate to ATP production? Reduced expression of genes coding for various complexes of the electron transport chain in hippocampus Glutamate Excitotoxicity Observation: increased glutamate in frontal cortex of px with BD Mood stabilizers appear to return glutamate levels to normal Increased levels of excitatory glutamate appear to result an increased energy demand on the neuron Increased glucose consumption in areas of high glutamate synaptic activity Hypothesis: increased shift to glycolysis may be due to increased glutamate stimulation Antidepressants Pharmacology Dr. Heisel BMS150 Objectives Provide a potential mechanism for antidepressants that addresses their delayed therapeutic effects Discuss the demographics of antidepressant-related suicide risk Provide the therapeutic mechanism of action for SNRI’s, SSRI’s, MAOI’s, trazodone and bupropion Describe the adverse effects (including OD effects) of antidepressants, including a mechanism where applicable Describe the causes, symptoms and treatment for serotonin syndrome Mechanism Overview Review: select theories of depression Overall: NT ▪ Potentially related to low levels of NT’s, such as? levels too low, Low levels of NT’s lead to receptor receptor levels upregulation too high Possible mechanisms of antidepressant action ▪ Reuptake inhibitors Immediate: increase levels of NT’s (ex serotonin) NT reuptake  Mechanism Overview Possible mechanisms of antidepressant action ▪ Reuptake inhibitors continued Delayed: down-regulation of NT receptors ▪ Could explain time needed to see antidepressant effects ▪ The 5HT1a receptors are autoreceptors – they inhibit release of NT from presynaptic terminals If they’re down-regulated ! increased NT release ▪ Sustained antidepressant therapy is also associated with increased production of BDNF, which is likely linked to efficacy ▪ FYI: Reuptake enhancers Approved in Europe, have opposite mechanism: lead to decreased NT levels  Mechanism Overview Depression and anxiety disorders are complex, multifactorial illnesses and research is still developing re: how pharmacotherapies actually work Theories that attempt to explain the MOA of SSRIs or SNRIs need to account for the delayed onset of action ▪ Weeks before clinically-relevant effects in mood are seen  Antidepressant Suicide Risk Take home: increased suicide risk in children, adolescents and young adults upto 24 years of age when taking antidepressants. https://online.epocrates.com/noFrame/monographPrint? activeTab=0&activeDrugId=135&activeSectionId=11&activeFormulary=-1 Main Classes of Antidepressants SNRI’s: Serotonin & Norepinephrine Reuptake Inhibitors ▪ Examples: Know generic names, brand names are FYI only* TCA’s (tricyclic antidepressants) such as amitriptyline (Elavil®) ▪ “-triptyline” suffix = TCA (but not all TCA’s are “-triptylines”) Venlafaxine (Effexor®) SSRI’s: Selective Serotonin Reuptake Inhibitors ▪ Example: fluoxetine (Prozac®) “-oxetine” suffix = SSRI (but not all SSRI’s are “-oxetines”) Other ▪ MAOI’s: monoamine oxidase inhibitors ▪ Trazodone (Desyrel®) ▪ Bupropion (Wellbutrin®, Zyban®)* * Need to recognize these two brand names SNRI’s: TCA’s One of first types of antidepressants discovered ▪ Therapeutic mechanism? ▪ Adverse effects Many are due to non-therapeutic block of M, alpha 1 and H1 receptors ▪ M and alpha 1 receptor review: Where are each found? What main NT binds and activates each? Does their activation typically lead to parasympathetic or sympathetic effects? M, H1, and alpha 1 receptor review: Muscarinic (M) Receptors Muscarinic receptors are a type of acetylcholine receptor and are part of the G protein-coupled receptor (GPCR) family They play a significant role in the parasympathetic nervous system M, H1, and alpha 1 receptor review: Alpha-1 Adrenergic Receptors Alpha-1 adrenergic receptors are another type of GPCR that primarily respond to the catecholamines norepinephrine and epinephrine. These receptors are predominantly involved in the sympathetic nervous system, which is responsible for the "fight or flight" response. M, H1, and alpha 1 receptor review: H1 Receptor a type of histamine receptor, which is a member of the G protein-coupled receptor (GPCR) family. These receptors play a crucial role in the body's response to allergens and inflammatory processes. They are predominantly involved in mediating the effects of histamine in allergic reactions and are distributed throughout various tissues in the body.  AUTONOMIC NERVOUS SYSTEM Review Sp. Cd. Sympathetic α,β, : Heart, ACH N NE Sm. mus. Glands ACH N → E, → Ad. M. NE Brainstem Parasympathetic or Sp. Cd. M: Heart, ACH N ACH Sm. mus. Glands Receptor Review M-receptors ▪ What adverse effect would result from blocking M-receptors on the following: Salivary glands Intestines Bladder Pupil Alpha 1-receptors ▪ What adverse effect would result from blocking alpha-1 receptors on blood vessels? Receptor Review M-receptors ▪ What adverse effect would result from blocking M-receptors on the following: Gastrointestinal: Dry mouth (xerostomia) due to reduced salivary secretion. Constipation due to reduced gastrointestinal motility. Genitourinary: Urinary retention due to relaxation of bladder smooth muscle. Ocular: Blurred vision due to cycloplegia. Sensitivity to light (photophobia) due to pupil dilation. Alpha 1-receptors ▪ What adverse effect would result from blocking alpha-1 receptors on blood vessels? - Orthostatic Hypotension, Dizziness and Headache, Nasal Congestion, Fatigue and weakness, Reflex tachycardia Receptor Review H1-receptors ▪ Review: Found in the CNS and mediate what? Can also inhibit feeding ▪ What two adverse effects are therefore expected from block of H1? Receptor Review H1-receptors Help to control ▪ Appetite and Thermoregulation ▪ Wakefulness and Arousal  TCA: Common Receptor-block Adverse Effects M-block Alpha 1-block H1-block ▪ Dry mouth Orthostatic Weight gain ▪ Constipation hypotension Sedation/ ▪ Urinary retention Sedation drowsiness ▪ Mydriasis Sexual dysfunction ▪ Blurred vision ▪ Confusion TCA: Other Adverse Effects Adverse effects not fully explained by M-, alpha 1 -and H1-blocks are: ▪ Sexual dysfunction Caused by serotonin acting at 5-HT2a receptors ▪ Antidepressant effect of serotonin is via 5-HT1a receptors ▪ Weight gain Could also be due to remission of depression and/or direct stimulation of appetite TCA: Overdose TCA OD can lead to life-threatening cardiac arrhythmias ▪ FYI: Main mechanism is block of Na+ channels in myocardial cells, slowing propagation of the action potential ▪ What else can make TCA’s “hard on the heart”? Hint: Think about their mechanism of action and their receptor blockades SNRI’s: Venlafaxine Venlafaxine is also an SNRI It differs from TCA’s in the following ways: ▪ Also weakly inhibits dopamine reuptake ▪ No significant alpha 1, H1 or M-block Less likely to cause related adverse effects, including sexual dysfunction and weight gain (may cause weight loss) SSRI’s Most commonly prescribed antidepressant class Therapeutic mechanism? Adverse effects often related to M, α1, H1-block ▪ Receptor blocks less potent than with TCA’s, related adverse effects typically more mild Exception: sexual dysfunction is typically worse ▪ What is the role of serotonin? ▪ Additional NO (vasodilator) synthesis block Weight disturbances can include weight loss ▪ Transient, followed by potential long-term weight gain Does not have the same cardiotoxicity as TCA’s ▪ Does have the potential for serotonin syndrome SSRI’s: Serotonin Syndrome Serotonin syndrome can occur in response to increased serotonin levels ▪ Often caused by a combo of two drugs (such as?) Can also be caused by a “high-normal” dose in a sensitive individual ▪ Triad of symptoms (examples on next slide) Altered mental status Autonomic hyperactivity Neuromuscular abnormalities SSRI’s: Serotonin Syndrome Triad of symptoms (know bolded examples) ▪ Altered mental status Ex: Anxiety, agitation, disorientation ▪ Autonomic hyperactivity Diaphoresis, mydriasis, tachycardia, hyperthermia, hypertension, dramatic swings in pulse & bp, vomiting, and diarrhea ▪ Patient is often hot and sweating with a fast heart rate and high blood pressure that goes up and down ▪ Neuromuscular abnormalities Tremor, clonus, muscle rigidity, hyperreflexia, bilateral Babinski sign ▪ Hyperreflexia and clonus are particularly common and are more often pronounced in the lower extremities SSRI’s: Serotonin Syndrome How might you treat serotonin syndrome? ▪ Remove the causative agent Most cases typically resolve 24 hrs after ▪ Interfere with serotonin action Cyproheptadine can be given – what do you think its therapeutic mechanism might be? ▪ Symptomatic treatment Treat the agitation with benzodiazepines (BDZ) ▪ More on BDZ coming up soon! MAOI’s Historical use, some patients may still take them Therapeutic mechanism ▪ Block monoamine oxidase, the enzyme that metabolizes NE, resulting in higher NE levels Can induce a hypertensive crisis when combined with foods containing tyramine ▪ Tyramine has synergistic effect on NE levels How do high NE levels precipitate a hypertensive crisis? Other: Trazodone Trazodone ▪ Inhibits serotonin reuptake, but not considered an SSRI Also acts directly as an antagonist at serotonin 5-HT2A receptors ▪ What is the benefit of this antagonist action? ▪ Adverse effects H1-block and potent alpha 1 block effects ▪ Strong sedative effects May be useful for patients with anxiety, or for helping with sleep patterns of depressed patients Weight gain tends to be minimal Other: Bupropion Need to know brand names to distinguish therapeutic uses: ▪ Wellbutrin® = antidepressant ▪ Zyban® = smoking cessation therapy Mechanism of action: ▪ Relatively weak inhibition of NE and dopamine reuptake Important adverse effect: ▪ Dose-related seizure risk Suspected OD should lead to hospitalization Contraindication? Study Guiding Questions 1. Create a compare and contrast table for the definitions 2. Create a flow chart or alternative schematic linking the different neuropathology hypothesis of depression into a unified theory (where possible) 3. How does the neuropathology of bipolar disorders differ from the hypotheses of major depressive disorders? References ▪ Filatova E, et al. Major depression: one brain, one disease, one set of intertwined processes. Cells. 2021; 10(6): 1283 ▪ Kiran C, et al. Understanding deluisions. Ind Psychiatry J. 2009; 18(1): 3-18 ▪ Kim Y, et al. Molecular mechanisms of bipolar disorder: progress made and future challenges. Front Cell Neurosci. 2017; 11:30 ▪ Beckett C, et al. The role of immunomodulators in treatment-resistant depression: case studies. Cell Death Discovery. 2022; 8(367)