Neurotransmitters Amines Quaternary amines Acetylcholine (ACh) Monoamines Catecholamines Epinephrine (EPI) Norepinephrine (NE) Dopamine (DA) Indoleamines Serotonin (5-HT) Melatonin Amino acids Gamma-aminobutyric acid (GABA) Glutamate (GLU) Glycine Histamine (HIST) Neuropeptides Opioid peptides Enkephalins (ENK) Endorphins (END) Peptide Hormones Oxytocin (Oxy) Substance P Cholecystokinin (CCK) Vasopressin (ADH) Neuropeptide Y (NPY) Brain-derived Neurotrophic factor Hypothalamic Releasing Hormones GnRH TRH CRH Lipids Anandamide Gases Nitric Oxide (NO)

5-Hydroxytryptamine (5-HT)

Features of a serotonergic neuron

Serotoninergic (5-HT) System

Serotonergic Receptors 5-HT 1A-F receptors CNS Blood Vessels 5-HT 2A-C receptors CNS PNS Blood Vessels GI Tract 5-HT 3 receptors CNS PNS GI Tract 5-HT 4 receptors CNS PNS GI Tract 5-HT 5A-B receptors CNS 5-HT 6 receptors CNS 5-HT 7 receptors CNS Blood Vessels GI Tract Iontotropic Metabotropic 5-HT 1B receptor

5-HT 1A and 5-HT 2A receptors operate through different signaling mechanisms

Serotonergic Drugs

Mood Disorders Unipolar Disorder (2 wks to 9 mos) Major Depressive Disorder, Single Episode (MDDSE) rare Major Depressive Disorder, Recurrent (MDDR) family history is common Dysthymic Disorder (DD) milder symptoms chronic occurrence (2-30yrs) Double Depression combination or MDDR and DD Bipolar Disorder (2 wks to 9 mos) Bipolar I Disorder Bipolar II Disorder (hypomania) Dysphoric Mania manic episodes with simultaneous depression Cyclothymic Disorder (mild bipolar)

Major Depressive Episode Characteristics Onset is in early to mid 20’s but not age specific Onset age has been dropping 16% of population experience MDD in their lifetime 2:1 women to men ratio 41% occurs just before or just after menstruation

Mood Disorder Genetics

Depression and Stress Hormones cortisol steroid hormone

HPA Axis Hypothalamus CRF/CRH Pituitary ACTH Adrenals Cortisol

Stress Diathesis Model Existing Correlations: Adult Depression : Elevated Cortisol levels Childhood Abuse : Adult Depression Stress Diathesis Model: Genetic Predisposition plus Early Abuse/Neglect leads to Adult Depression Animal Model shows: More CRF neurons Larger CRF neurons More sensitive CRF neurons Early abuse permanently alters the stress response increasing the risk of depression

Cortisol Abnormalities

Sleep Abnormalities

Monoamine Hypothesis Originated with observation of Reserpine action: Inhibits vesicular uptake Allowing MAO degradation Reduces levels of DA, NE, and 5-HT Induces depression-like symptoms MAOi suppresses depression-like symptoms

Serotonin Hypothesis Acute Effects: Transporters blocked Autoreceptors activated Cancelling effect Chronic Effects: Transporters blocked Autoreceptors down regulated Increased 5-HT in synapse

Serotonin Hypothesis Metabolite of 5-HT: 5-HIAA Increased levels found in people who committed suicide

5-HT Receptors Less sensitive Sensitivity restored with use of antidepressants 5 HT 2 Receptors Increased density Due to low 5-HT levels? Chronic use of antidepressants down regulated 5-HT 2 receptors Serotonin Hypothesis

Serotonin-Norepinephrine Hypothesis down-regulation of β- receptors with chronic antidepressant treatment. takes 7 to 21 days of treatment, a lag that parallels the onset of therapeutic response in depressed patients. Similar results occur with many different antidepressants. But not all antidepressants reduce β -receptors. There are anatomical and functional interactions between NE neurons originating in the locus coeruleus and the 5-HT neurons in the raphe nuclei. Each system is capable of modulating the other.

Glucocorticoid Hypothesis focuses on the stress-related neuroendocrine abnormalities of depression. Depressed patients have abnormally high CRF secretion. The hypothalamic CRF neurons are normally controlled by other areas: the amygdala stimulates and the hippocampus has inhibitory control. When stress is prolonged and intense, glucocorticoid levels remain high, hippocampal neurons are damaged and no longer respond. Damage includes decreased dendritic branches and spines in the PFC and hippocampus. Formation of new hippocampal cells is inhibited Cell loss in the hippocampus means reduced response to cortisol levels and loss of feedback inhibition of the HPA axis. Antidepressant drugs reduce levels of CRF and reverse loss of hippocampal dendrites in animal studies Cell loss in the hippocampus means reduced response to cortisol levels and loss of feedback inhibition of the HPA axis. Antidepressant drugs reduce levels of CRF and reverse loss of hippocampal dendrites in animal studies..

Neurotrophic Hypothesis Low BDNF (brain-derived neurotrophic factor) may be responsible for the loss of dendritic branches and spines in the hippocampus and PFC and for reduced neurogenesis in the hippocampus. Antidepressants may prevent decrease of BDNF Supporting evidence: Chronic stress reduces BDNF in the hippocampus in rats. Chronic but not acute antidepressant treatment increases BDNF in animals and humans. Antidepressants prevent stress- induced reduction in BDNF and neuronal atrophy.

Neurotrophic Hypothesis Early life stress can lead to epigenetic changes that enhance CRF expression in the amygdala and hypothalamus and decreased glucocorticoid receptors in the hippocampus. The gene for BDNF can be modified by chromatin remodeling (epigenetic changes) that affect levels of gene expression.

Depression: Treatment Medical Chemical Electroconvulsive Shock Therapy Psychotherapy Cognitive Behavioral Therapy Interpersonal Therapy

Chemical Treatment Tricyclic Antidepressants imipramine (Tofranil) prevents monoamine reuptake 64% respond well many side effects Monoamine Oxidase Inhibitors (MAOi) phenelzine (Nardil) blocks MAO enzyme which breaks down monoamines <64% respond well several lethal side effects Selective Serotonin Reuptake Inhibitors (SSRIs) fluoxetine (Prozac) blocks reuptake of serotonin minor side effects

Treatment Strategies

Cognitive Behavioral Therapy make patient examine thought process and recognize errors arbitrary interference overgeneralization try to correct cognitive errors concentrate on less depressive thoughts - be more realistic target negative cognitive schemes use journals to identify faulty thinking do hypothesis testing put fun back into the patients life increase exercise takes about sessions