NEUROENDOCRINOLOGY OF DEPRESSION

1. NEUROENDOCRINOLOGY OF DEPRESSION "A STRESSFUL STORY” Presented By Janet Menzie

2. WHAT IS DEPRESSION ? • Generally: A negative disturbance of ones mood Affective mood disorder Normal and expected negative mood change

3. WHAT IS DEPRESSION ? • “In grief one feels an aching loss, whereas in depression the mood is colorless...it has been described as painful anesthesia - painful because the patient remembers that life used to be pleasurable,…anesthesia because of the general numbness” (Wender and Klein 1981:45) • “the intensity and quality of the mood is such that it pervades the individual, in such a way that incapacitates the individual and that the person does not respond to comfort and reassurance” (Whybrow et al. 1984:15) • “Mood seems to have a life of its own persisting autonomously” (Whybrow et al. 1984:15)

4. GENERAL SYMPTOMS OF DEPRESSION • Feeling sad, hopeless and despairing • A loss of interest and pleasure in normal activities • Loss of appetite or weight • Loss of sex drive • Sleeping problems, such as an inability to get to sleep or early waking • Feeling physically tired all the time • Concentration difficulties • Feeling guilty and worthless • Feeling that life isn't worth living.

5. TYPES OF DEPRESSION • Bipolar disorder (Manic-Depression) Individual cycles between two extremes phases of emotion; one of euphoria and the other of paralyzing despair (contemplating suicide) • Major depression Depressive symptoms impacts on their daily life; extremely low energy level, no motivation (even to perform the simplest task), feeling despair and hopeless, hypertensive, low self-esteem, suicidal thoughts • Cyclothymic disorder Mild mood swings from high to low with each mood lasting for a long time, such as months, with tendency to develop bipolar disorder

6. TYPES OF DEPRESSION Dysthymic disorder Affects the persons quality of life such as sleeping and eating habits, but not their ability to work and interact with family and friends. Express difficulty in concentration and memory • Postpartum depression (PPD) Depression occurs from anywhere between four weeks to one year after childbirth. Express severe anxiety attack, loss of energy, feeling of worthlessness. Abnormal maternal behavior such as infant neglect; fearful of being alone with the child • Seasonal affective disorder (SAD). Depression occur during a particular season of the year, generally in the fall or winter months and remits in spring; Winter SAD.

7. MAJOR DEPRESSION • Other names: Major depressive disorder (MDD), Severe depression, Unipolar depression • Epidemiology: Onset is commonly in 20’s and 30’s 2:1 ratio of women:men

8. MAJOR DEPRESSION • Criteria: Five or more of these symptoms should be shown most of the day, everyday, for 2 weeks (DSM lV : Diagnostic and Statistical Manual of Mental Disorder - American Psychiatric Association) 1. Depressed mood 2. Diminished interest or pleasure in most activity 3. Significant weight loss or gain 4. Insomnia or hypersomnia 5. Fatigue or loss of energy 6. Feelings of worthlessness or excessive and inappropriate guilt 7. Poor ability to think or concentrate 8. Recurrent thoughts of suicide NB: The presence of any of these symptoms should not be due to drug abuse, medication, medical condition (hyperthyroidism) or psychiatric illness (Parkinson’s Disease or Schizophrenia)

9. MAJOR DEPRESSION • Etiology: Genetic;Seen in generation after generation Psychological; Consistent low self-esteem, persistent pessimistic view Environmental;Associated with an unpleasant change in one’s life Stress: anything that stimulates the secretion of ACTH and corticosterone/cortisol

10. A QUICK NEUROANATOMICAL LOOK • The Limbic Connection Structures: Hippocampus, Parahippocampus, mamillary body (hypothalamic structure) Amygdala, cingulate gyrus, anterior thalamic nucleus Others: Prefrontal cortex, Hypothalamus Hippocampal connection: Afferent fibers - entorhinal area, cholinergic fibers from septal area, basal forebrain nuclei (Nucleus Accumbens), dopaminergic fibers from VTA (ventral tegmental Area), Noradrenergic from locus coeruleus and serotonergic from raphe nuclei Amygdalal connection: afferent from temporal prefrontal cortex

11. NEUROANATOMIC CIRCUITS • Interconnection between the limbic system and cortex • Indirect evidence indicates the circuit to be the limbic cortical-striatal-pallidal-thalamic circuit (Wayne et al., 1992) • Atrophy of the prefrontal cortex, the hippocampus (Marek and Duman, :155)

12. THE STRESS FACTOR- HPA AXIS

13. THE STRESS FACTOR- HPA AXIS Distribution of the CRH receptors

14. DYSREGULATION OF HPA AXIS • Hyperactivity of the HPA axis Increased circulation of CRH, ACTH and cortisol (Kalin et al., 1982) Hypercortisolism changes over time; a process-oriented perspective - Acute Depression: increased state of all hormones in the HPA axis -Chronic Depression: increased CRH, cortisol but low ACTH

15. TWO COMPLEMENTARY HYPOTHESIS IN CHRONIC DEPRESSION

16. A MODEL OF HYPERCORTISOLISM • Adrenal response changes with respect to separation (psychogenic stressor) Parker et al., 2003

17. A MODEL OF HYPERCORTISOLISM • Feedback mechanism

18. NEUROTRANSMITTERS

19. NEUROTRANSMITTERS Neurotransmitters underlying affective disorders • Norepinephrine (NE) • Serotonin (5-HT) • Acetylcholine (Ach) • Dopamine (DA)

20. NE • NE & its metabolites in CSF & urine are decreased in depressed patients • Treatment with antidepressant leads to down regulation of beta-adrenergic receptors in CNS. This down regulation parallels with the time course of improvement in depressive symptoms

21. 5-HT • Deficient of 5-HT neurotransmission has been implicated in patients with major depression • Serotonin uptake-inhibiting drugs are most often used as antidepressant

22. ACh • Physostigmine = cholinesterase inhibitor • Physostigmine increases ACh in CNS and produces a depression-like state

23. DA • Hypofunction of mesocorticolimbic dopaminergic system (functions as rewarding pathway) might result in loss of interest & lack of motivation which are part of the core symptoms of major depression • Decreases in DA metabolite (HVA) concentration in CSF of depressed patients

24. CHANGES IN A LIMBIC STRUCTURE - HIPPOCAMPUS Post mortem hippocampus was collected from 19 MDD and 21 control human subjects. Stockmeier et al., 2004

25. CHANGES IN A LIMBIC STRUCTURE - HIPPOCAMPUS Stockmeier et al., 2004

26. CHANGES IN A LIMBIC STRUCTURE - HIPPOCAMPUS Reduced pyramidal soma size with an increase in its density and similar increase in glial density result in reduced hippocampus volume Such changes contributes to dysfunctional neuronal circuits Stockmeier et al., 2004

27. Intracellular pathways contribute to actions of stress Stress induces high level of glucocorticoid Glucocorticoid decreases level of glucose transporter in the membrane results in reduced glucose uptake and decreases energy capacity

28. Intracellular pathways contribute to actions of stress • Stress increases the release of glutamate in hippocampus which could result in sustained activation of NMDA receptors and elevation of intracellular Ca2+ --> hyperactivation of Ca2+ dependent enzymes and generation of oxygen free radicals. These factors are known to cause damage to cells

29. Intracellular pathways contribute to actions of stress • Stress decreases the expression of BDNF in hippocampus. How this is done, is not known • This could result in reduced trophic support for CA3 pyramidal and dentate gyrus granule neurons

30. WHAT ABOUT THE GR RECEPTORS ? GR has both negative and positive regulation of gene transcription: A & B = negative regulation C & D = positive regulation Therapeutic potential of GR antagonists in depression requires further studies

31. SEXUAL DIFFERENCE OF MDD Benedetta et. al., 2004