Mood Disorders

etiology of mood disorders

-genetic vulnerabilities

-altered gene expression

-environmental stress

-dysregulated neurotransmission

-abnormal neuroplasticity

major depressive disorder

chronic mood disorder characterized by lethargy/tiredness, feelings of worthlessness, and loss of interest in family/friends and activities with symptoms lasting more than 2 weeks

bipolar disorder

mood disorder characterized by severe bouts of cycling between mania and depression; high genetic susceptibility, high rates of relapse, and diminished quality of life due to lingering residual symptoms and cognitive impairments

HPA axis

hypothalamus is stimulated to release CRF in response to stress, which stimulates pituitary gland to release ACTH, which stimulates the adrenal cortex to release cortisol in primates and corticosterone in rodents to activate the fight-or-flight response

neurobiological changes in mood disorders

-decreased activity in areas involved in controlling behavior (PFC, insula, ACC, and NAc) and in serotonergic and monoaminergic systems

-dysregulated HPA axis (lower glucocorticoid receptor levels, increased sensitivity to and levels of glucocorticoids)

-decreased gray matter in hippocampus and PFC (mitochondrial disturbances and oxidative stress increase apoptosis)

physiological factors that contribute to increased incidence of mood disorders in women

-lower body weight and organ size

-high body fat %

-lower glomerular filtration rate

-different gastric motility

-presence of ovarian hormones

typical antidepressants

antidepressants that increase the release of one or more neurotransmitters; includes MAOIs, TCAs, and SSRIs

MAOIs (monoamine oxidase inhibitors)

drugs that inhibit monoamine oxidase to increase presynaptic NE and 5-HT levels, allowing for more monoamines to be released

TCAs (tricyclic antidepressants)

drugs that inhibit the reuptake of norepinephrine and serotonin, but have many off-target effects

SSRIs (selective serotonin reuptake inhibitors)

allosteric inhibitors of SERT, preventing 5-HT reuptake to enhance 5-HT and NE signaling by forcing them to stay in the synapse

atypical antidepressants

antidepressants that act in ways other than by increasing neurotransmitter levels; includes 5-HT2 receptor antagonists that result in release of serotonin and presynaptic α2-adrenergic receptor antagonists

TMS (transcranial magnetic stimulation)

treatment for depression that involves direct stimulation of brain areas that have decreased activity or volume; only adverse effects are headache and scalp discomfort

ECT (electroconvulsive therapy)

treatment primarily used for treatment-resistant bipolar disorder that involves delivering electric shock to the brain; short term side effects include memory loss and disorientation

lithium

primary pharmacotherapeutic for bipolar disorder that has multiple targets including GSK-3 inhibition, which is thought to increase BDNF and produce neurotrophic effects; most efficacious for treating acute mania

valproic acid

an anti-epileptic drug used to treat bipolar disorder that blocks Na+ channels to reduce neuron excitability, inhibits GABA release, and decreases AMPA receptors

lamotrigine

anti-epileptic used for bipolar disorder maintenance treatment, especially prevention of depression relapse; inhibits voltage-gated Na+ channels, glutamate release, and postsynaptic AMPAR-induced currents

emerging therapies for mood disorders

-increasing neurogenesis to attenuate reduction in gray matter seen in affective disorder patients

-ketamine inhibition of NMDARs results in enhanced glutamatergic signaling via AMPARs to produce a rapid, robust, and sustained antidepressant effect

-deep brain stimulation (invasive or non-invasive stimulation of limbic-cortical circuit to increase functioning)

-psychedelics induce neural plasticity to correct certain aberrant functional connections in mood disorders; adverse effects include altered consciousness that can lead to panic

construct validity

animal models of mood disorders should be based on and recreate genetic and environmental (etiological) processes that cause mood disorders in humans and replicate neural and behavioral features of the illness

face validity

animal models of mood disorders should have endophenotypes that match features/symptoms of human mood disorders (neuroanatomical, biochemical, or behavioral phenotypes)

endophenotype

a group of neurophysiological, biochemical, endocrine, neuroanatomical, cognitive, or neuropsychological characteristics that accompany an inherited susceptibility to a particular disorder

predictive validity

animal models of mood disorders should be able to predict outcomes in human mood disorders and pharmacological treatments that attenuate endophenotypes seen in animal models of mood disorders should predict effectiveness of those treatments for mood disorders in humans

models of depression

-chronic mild/unpredictable stress produces anhedonia that can be treated with chronic antidepressants

-chronic social defeat stress produces anhedonia and social withdrawal that can be reversed with chronic antidepressants

-maternal separation produces behavioral and neuroendocrine abnormalities, some of which can be reversed with antidepressants

-social isolation produces anhedonia that can be treated with chronic antidepressants

tests of depression

-learned helplessness (forced swim and tail suspension tests)

-measures of anhedonia (sucrose preference, ICSS reward thresholds, engaging in social behavior)

-measures of apathy (deficits in goal-oriented behavior such as nest building, self-grooming, maternal care, or novel object interest)

-measures of irritability/social aversion (resident-intruder test)

-measures of cognitive impairment (memory deficits, learning difficulties, or deficits in attention such as in novel object/social recognition, Morris water maze, etc.)

models of bipolar disorder

-repeated psychostimulant administration produces locomotor sensitization that can be blunted by lithium and valproic acid; however, the mechanisms underlying this sensitization are not the same as the pathophysiology of mania

-GSK3-β overexpression or Clock gene (controls circadian rhythm) knockout produces some endophenotypes similar to symptoms of bipolar disorder (hypophagia, hyperlocomotion, less immobility in forced swim test, and more "risk-taking" behavior)