Chapter 12 Mood Disorders and Depression From Diseases of the Nervous System. Copyright © 2015 Elsevier Inc. All rights reserved.

Figure 1 Neurotransmitter systems that regulate mood and happiness include particularly dopamine released from the amygdala and ventral tegmental area (VTA) as well as serotonin released by the raphe nucleus. Image was modified using 3D brain, Cold Spring Harbor DNA Learning Center. From Diseases of the Nervous System. Copyright © 2015 Elsevier Inc. All rights reserved. 2

Reproduced with permission from Ref. 10. Figure 2 Signaling cascades important for understanding depression. Blockade of serotonin (5-HT) reuptake by selective serotonin reuptake inhibitors (SSRIs) causes activation of G-protein-coupled receptors leading to enhanced cAMP signaling, which in turns leads to transcriptional changes via the cAMP–protein kinase A (PKA)–cAMP response element binding (CREB) pathway. Chronic use of SSRIs alters expression of the transcription factor CREB and the Ca2+ binding protein p11. As a result, a number of genes are transcribed, including neurotropic factors such as BDNF. Rapid responses act via Glu receptors and Ca2+-dependent signaling mechanisms such as the Ca2+ calmodulin-dependent protein kinase (CAMK). Reproduced with permission from Ref. 10. From Diseases of the Nervous System. Copyright © 2015 Elsevier Inc. All rights reserved. 3

Figure 3 The trisynaptic hippocampal network, comprised of dentate gyrus, CA3, and CA1 pyramidal cells, in depression and as the site of action for mood stabilizing drugs. (A) The schematized trisynaptic circuit encompasses the dentate gyrus (DG, blue) that also contains the germinal subgranular zone (SGZ). DG cells (green) project excitatory terminals onto CA3 pyramidal cells and GABAergic interneurons. The output from the CA3 pyramidal cells forms the Schaffer collaterals that innervate the CA1 pyramidal neurons. (B) CA1 pyramidal cells provide the major output of the hippocampus to the medial prefrontal cortex (mPFC), amygdala, striatum, and hypothalamus. (C) Synaptic strength may be altered through pre- or postsyanptic changes involving neurotropic factors such as BDNF. (D) Mood-stabilizing drugs may restore the retraction of dendrites that occurs with stress, or (E) by promoting adult neurogenesis. Reproduced with permission from Ref. 11. From Diseases of the Nervous System. Copyright © 2015 Elsevier Inc. All rights reserved. 4

Reproduced with permission from Ref. 11. Figure 4 The hypothalamic-pituitary-adrenal (HPA) axis in depression. The hippocampus, along with the limbic system, controls the release of corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP), which are secreted into the blood stream. They cause the release of adrenocorticotropic hormone (ACTH) from the pituitary, which in turn stimulates the production and release of cortisol from the adrenal gland. Cortisol feeds back as the stress hormone acting via glucocorticoid receptor (GR) and melanocortin receptors (MR) throughout the body and brain. Reproduced with permission from Ref. 11. From Diseases of the Nervous System. Copyright © 2015 Elsevier Inc. All rights reserved. 5

Reproduced with permission from Ref. 17. Figure 5 Epigenetic regulation of depression. Experiences can alter the accessibility of DNA for transcription by changes in the association of DNA with histones (A) or by methylation of the promoter sites on DNA (B). Both can be modulated using drugs that change the methyl groups that silence DNA or ethyl groups that activate it (C). Reproduced with permission from Ref. 17. From Diseases of the Nervous System. Copyright © 2015 Elsevier Inc. All rights reserved. 6

Figure 6 Targets of available drugs to treat depression Figure 6 Targets of available drugs to treat depression. Monoamine oxidase inhibitors (MAOIs) inhibit the breakdown of monoamine transmitter by inhibiting the enzyme monoamine oxidase. Lithium inhibits presynaptic transmitter release as well as postsynaptic signaling cascades. The various transporter inhibitors such as selective serotonin reuptake inhibitors prolong the activity of the transmitter at the synapse. Abbreviations used: TCAs, tricyclic antidepressants; SNRIs, selective norepinephrine reuptake inhibitors; SSRIs, selective serotonin reuptake inhibitors; VMAT, vesicular monoamine transporter; IP3, inositol trisphosphate. Modified after Ref. 19. From Diseases of the Nervous System. Copyright © 2015 Elsevier Inc. All rights reserved. 7

Reproduced with permission from Ref. 10. Figure 7 Glycogen-serine kinase 3 (GSK3), the target of lithium and its signaling pathways implicated in depressive disorders. Reproduced with permission from Ref. 10. From Diseases of the Nervous System. Copyright © 2015 Elsevier Inc. All rights reserved. 8

Reproduced with permission from Ref. 24. Figure 8 18Fluorodeoxyglucose positron emission tomography (PET) imaging in a volunteer using ketamine shows enhanced glucose utilization (indicated by red color) in frontal, temporal and parietal cortex. Reproduced with permission from Ref. 24. From Diseases of the Nervous System. Copyright © 2015 Elsevier Inc. All rights reserved. 9

Reproduced with permission from Ref. 21. Figure 9 Hypothesized action of ketamine explaining how a glutamate receptor antagonist may still cause a paradoxical increase in glutamate tone. In the treatment of depression, low concentrations of ketamine predominantly affect NMDA-Rs on GABAergic interneurons. These in turn reduce their inhibitory activity on the prefrontal cortex, resulting in a net increase in gluatamatergic tone. Reproduced with permission from Ref. 21. From Diseases of the Nervous System. Copyright © 2015 Elsevier Inc. All rights reserved. 10

Table 1 Nine Criteria Used to Diagnose Major Depressive Disorder, of Which Five or More Must Be Present for a Positive Diagnosis From Diseases of the Nervous System. Copyright © 2015 Elsevier Inc. All rights reserved. 11

Table 2 Currently Used Pharmacological Treatments for Depressive Disorders From Diseases of the Nervous System. Copyright © 2015 Elsevier Inc. All rights reserved. 12