Neurobiology of depression

Basics of neurobiology of depression

1. Continuing Medical Education On Neurobiology of Depression and recent updates

2. Neurobiology of Depression and recent updates Dr. Ahsan Aziz Sarkar MD and FCPS Part 2 Trainee Assistant Registrar, NIMH.

3. Etiology of depression

4. Etiology of depression These three factors singly or in combination can make ground for a depressive episode. Presence of genetic predisposition diminishes need for adverse childhood experience and recent life stressors. ( Kendler et al. 2001) Life event is important for 1 st episode but less so for subsequent episodes.

5. Neurobiology in Depression

6. Neurochemical and hormonal abnormalities in depression Substrate Concentration/activity Note Serotonin Neurotransmission Decreased Decrease Tryptophan, 5-HT receptor binding, and receptor uptake site NA Neurotransmission Decreased Blunted NA mediated endocrine response Dopamine Decreased Reward BDNF Decreased Neurogenesis

7. Neurochemical and hormonal abnormalities in depression Serotonin pathway: A versive processing to behavioral inhibition D elay discounting Inhibition of chain of thought leads to negative outcome (Cowen et al. 2015) Eating Behavior Sleep

8. Neurochemical and hormonal abnormalities in depression Role of NA in brain: Alertness, arousal, attention Enhance memory BDNF (Also NGF and FGF-2) Nerve growth, differentiation

9. Neurochemical and hormonal abnormalities in depression Substrate Concentration/activity Note Cortisol and CRH Increased HPA Axis Abnormality Present in 50% of cases Pro-inflammatory Cytokines Increased Acute Phase Proteins IL-6 and TNF-alpha Glutamate, GABA Decreased Glutamate in Ant. Region; GABA in Occipital Cortex

10. Neurochemical and hormonal abnormalities in depression Cortisol on brain: Shrinkage and loss of dendrite. Decreases level of BDNF specially in Hippocampus. Plasminogen activator ( tPA ), lipocalin 2, corticotrophin-releasing factor (CRF), and endocannabinoids . Proteolytic and lipolytic effect.

11. Neurochemical and hormonal abnormalities in depression Cytokines (IL-6 and TNF-alpha): I ncrease tryptophan catabolism thus lower serotonin level. INF treatment can cause depression ( Capuron et al., 2004). Depression that doesn’t respond to anti-depressants has high cytokine level ( Audet et al., 2013). Could have relapse predictive value.

12. Medial, Lateral and Anterior view of PFC

13. DLPFC : 9, 46; VLPFC: 44, 45, 47 VMPFC: 14, 25, 32, 10 OFC: 11, 13, 14 MPFC: 10, 24, 25, 32

14. Brain Regions involved in depression DLPFC: Executive function (working memory, planning, flexibility, decision making), Concrete thinking, Social cognition, Conscious regulation of emotion, inhibition, self-awareness and reflection. VMPFC: Personal and Social decision making, emotional regulation and suppression(automatic), empathy, shame, guilt. OFC: Adaptive learning (expected reinforcer vs. actual reinforcer)

15. Brain regions involved in depression

16. Brain regions involved in depression Limbic system: Motivation, emotion, learning, emotional memory. Amygdala: Fear, conditioned fear, aggression, anxiety, sexual behavior, flight fight response. Hippocampus: Memory, converting short term memory into long term, learning

17. Functional and structural change in brain Region Volume Metabolic Activity Orbital/VMPFC Decreased Increased DLPFC Decreased Decreased Anterior Cingulate Cortex Decreased Decreased Hippocampus Decreased - Amygdala Decreased (?) -

18. Anhedonia Anhedonia : Decrease activity in Nucleus Accumbens Low level of Dopamine (possibly mediated by serotonin) Increase activity in VMPFC and OFC suppresses amygdala emotional processing

19. Appetite and weight change Metabolic cue B lunted by cortisol, IL-6 and TNF-alpha Motivation cue Deficits in activity of nucleus accumbens Low dopamine release Sugar releases dopamine in n ucleus accumbens

20. Insomnia and hypersomnia NREM sleep I ncreased GABA Decreased Histamine REM sleep Decrease Noradrenaline and serotonin Increase acetylcholine

21. Insomnia and hypersomnia Hypersomnia Melatonin dysregulation (Melatonin secretion depends on noradrenaline) O rexin deficiency.

22. Psychomotor retardation or agitation Psychomotor retardation: Decrease activity in DLPFC leads to poor executive functioning and cognitive slowness Psychomotor agitation: Noradrenaline and GABA mediated. Overactive Amygdala.

23. Fatigue and loss of energy Deficits in activity of nucleus accumbens. TNF-alpha acting on hypothalamus. Decrease BDNF concentration in brain.

24. Guilt and worthlessness Self-conscious emotions. Negative mood leads to negative bias. Rumination. Mediated by DLPFC, VMPFC and amygdala.

25. Concentration and decision Impaired attention processing due to low volume of anterior cingulate. Indecisiveness from low volume and metabolic activity of DLPFC.

26. Suicidal idea, thought, attempt Low serotonin level in some cases. Attentional bias indicates cingulate dysfunction. Poor problem solving ability indicates PFC dysfunction.

27. Recent advance in treatment Deep brain stimulation: Subcallosal cingulate V entral striatum and Nucleus accumbens BDNF targeted treatment: Ketamine increases BDNF level. Plant glycoside on trial.

28. Recent advance in treatment Anti-inflammatory approach: Celecoxib Infliximab (TNF-alpha inhibitor) Pioglitazone Minocycline Statins

29. Wrapping the session Winston Churchill : “All great men are products of difficult childhood” Victor Frankl quoted Nietzsche in ‘Man’s search for Meaning’: “He who has a why to live for can bear almost any how”

30. Thank you