Brain & Behavior
bipolar type I vs. bipolar type II
* bipolar I disorder requires at least one full manic episode * bipolar II disorder requires only hypomania, which does not need to be functionally impairing, but does require a full depressive episode
main (DSM IV) mood disorders we covered
* bipolar disorder * major depressive disorder * cyclothymia * dysthymic disorder * other mood disorders:
which is more disabling: bipolar disorder or major depression? which has a better 10-year remission rate? which has a greater risk of completed suicide?
* bipolar disorder is more debilitating than major depression * MDD has a better 10 year remission rate (63%) than bipolar disorder (41%) * bipolar disorder has a greater risk of completed suicide (10-19% of bipolar I disorder patients ultimately die by suicide)
what is the biggest problem with mis-diagnosing bipolar disorder as unipolar depression?
* bipolar disorder needs to be treated with mood stabilizers * however, depression is treated with antidepressants, which can EXACERBATE manic episodes
in what parts of the CNS is serotonin (5-HT) synthesized?
* caudal cell body groups: medulla, central pons, spinal cord * rostral cell body groups: rostral pons, mesencephalon, cortex, basal ganglia, thalamus, hypothalamus, limbic system
what are some of the major side effects of prednisone?
* depression * delirium * panic * paranoia * hypomania/mania
what are some of the structures in the brain implicated in major depressive disorder?
* Anterior Cingulate Cortex (ACC) * Amygdala * Prefrontal Cortex (PFC) * somatosensory cortex * insular cortex * hippocampus * cerebellum
in what locations in the body is serotonin (5-HT) made? in what proportions?
* GI tract (duodenum): 95% * CNS: 5%
how do PTSD and major depression differ with respect to glucocorticoid levels?
* PTSD: suppression of basal HPA tone causes decreased cortisol levels * depression: increased HPA activity causes elevated cortisol levels
what effect do addictive behaviors have on HPA activity?
* addictive substances/activities suppress HPA activity (lower cortisol levels) * withdrawal from the addictive substance/activity leads to elevated HPA activity (and heightened cortisol levels)
how does the body prevent cortisol from binding to mineralocorticoid receptors in certain organs of the body?
* aldosterone-responsive cells that contain 11-beta-hydroxy steroid dehydrogenase in organs (like placenta, colon) can convert cortisol to cortisone, which can bind only to glucocorticoid receptors (GR)
what are some common comorbidities associated with bipolar I disorder?
* anxiety (93%) * substance abuse (71%) * conduct disorders (59%) * antisocial behavior (29%)
what comorbidities are often seen with depression?
* anxiety disorders * substance abuse disorders
what are the relationships between depression and other medical illnesses?
* depression often coexists with one or more medical conditions, and it can worsen disease outcomes (e.g. increased post-MI mortality, decreased survival in nursing home patients) * depression and cardiovascular disease are closely linked
how do glucocorticoids function in signaling?
* glucocorticoids affect gene transcription by binding to intracellular receptors, which activate, dimerize and translocate to the nucleus where they promote transcription of certain genes
how does hippocampal atrophy affect the HPA axis in patients with depression?
* hippocampal activity provides negative feedback to the hypothalamus * therefore, when hippocampal atrophy occurs, HPA activity increases, leading to increased cortisol levels
what important effects of glucocorticoids are important for survival in response to stress?
* increased glucose availability * increased fat storage * increased emotional learning/memory (amygdala) but decreased episodic memory (hippocampus) * inhibit non-essential systems: decreased immunity, sex hormones, bone mass
what is the "kindling" phenomenon in depression?
* kindling: with increased depressive episodes... a) the risk of developing depression increases, and b) those periods of depression become less and less associated with environmental stressors
where are the 5-HT5-7 receptors located? what are their functions?
* located in CNS * functions: less well characterized
where is the 5-HT2 receptor located? what is its function?
* located in CNS * subtypes: A-C * function: Gq coupled receptors (increase [IP3], [DAG] & intracellular [Ca++])
where is the 5-HT1 receptor located? what is its function?
* located in CNS * subtypes: A-F * function: Gi coupled receptors (decrease [cAMP])
where is the 5-HT4 receptor located? what is its function?
* located mainly in GI tract (enteric nervous system) * function: Gs coupled receptor (increase [cAMP])
where is the 5-HT3 receptor located? what is its function?
* located mainly in periphery; GI tract; chemoreceptor trigger zone (CTZ) in brain * unlike other 5-HT receptors, it is an ion channel
4 important physiological effects of the HPA axis and the sympathetic nervous system
* metabolic mobilization * increased: HR, BP & RR * redistribution of blood flow * suppression of immune & digestive functions
what changes to the hippocampus are seen in patients with depression? what might this signify?
* patients with depression might have dysfunctional hippocampi * because the hippocampus has cortisol receptors and is important in regulatory feedback to the HPA axis, dysfunction might be responsible for the inappropriate emotional responses seen in patients with depression
what changes to the amygdala are seen in patients with depression? what might this signify?
* patients with depression often have hyperactive amygdalas, * the amygdala is involved in emotional learning and memory, which indicates that it might be involved with the ruminative negative thought processes characteristic of depression
what are some of the pathological effects of long-term increased levels of glucocorticoids?
* sleep disturbances * disruptions in attention * impaired episodic memory (hippocampus) * enhanced emotional memory (amygdala, PTSD) * hypertension, cardiovascular disease, coagulation * susceptibility to infection * sexual disorders
which parts of the brain receive increased blood flow in patients with depression?
* the amygdala * the ventrolateral prefrontal cortex (vlPFC)
what are the members of the CRF family of neuropeptides? which receptors can they activate?
1) CRF (activates CRF-R1) 2) Urocortin I (activates CRF-R1 AND CRF-R2) 3) Urocortin II (activates CRF-R2) 4) Urocortin III (activates CRF-R2)
what are the 2 receptors for CRF neuropeptides? which CRF neuropeptides activate each? what is each of their functions?
1) CRF-R1 (activated by CRF & Urocortin I) --> anxiogenesis 2) CRF-R2 (activated by Urocortins II & III) --> anxiolysis
4 types of mood-stabilizer trea
1) lithium salts (mainly lithium carbonate) 2) divalproex 3) carbamazapine 4) antipsychotics (1st & 2nd generation)
which enzymes degrade serotonin (5-HT) to 5-hydroxyindoleacetic acid?
1) monoamine oxidase A (MAO A) 2) aldehyde dehydrogenase
what 3 mechanisms terminate the actions of serotonin (5-HT)?
1) reuptake into nerve terminals the serotonin transporter (SERT) 2) metabolic transformation/catabolism (by MAO A & aldehyde dehydrogenase) 3) diffusion out of synaptic cleft
what are 2 main physiological responses to stressors?
1) the hypothalamic-pituitary-adrenal (HPA) axis 2) the sympathetic nervous system (SNS)
what is the average age of onset in bipolar disorder?
17.5 years old (very young compared to major depressive disorder, which normally occurs ~30 years old)
which enzyme converts serotonin to N-acetyl serotonin? where does this occur?
5-HT N-acetyl-transferase, which is in the pineal gland
what is the relationship between 5-HT transporter genes and depression?
5-HTT polymorphisms: long (wild type) & short (less functional) * slight correlation between 5-HTT genotype and vulnerability to depression (when exposed to stressful life events) * risk: s/s > s/l > l/l
7 clinically important subforms of major depressive disorder
7 subtypes of MDD: 1) "neurotic" (externally-caused) depression 2) melancholia (endogenous) depression 3) "atypical" depression 4) seasonal depression 5) psychotic depression 6) chronic depression 7) post-partum depression
what are the 3 main types of bipolar disorder?
Bipolar disorders: * Bipolar Type I (at least 1 manic episode) * Bipolar Type II (hypomania & depression) * Bipolar Not-Otherwise-Specified (not I or II)
what are the main functions of: a) the dorsal ACC? b) the rostral ACC? c) the ventral ACC?
A) dorsal ACC: decision-making, sustained attention, control of behavior B) rostral ACC: interface between dorsal and ventral parts of ACC C) ventral ACC: visceral/affective behavior
which parts of the paraventricular nucleus of the hypothalamus secrete CRF? what are the effects?
A) median eminence --> CRF --> stimulates ACTH secretion by pituitary B) autonomic --> CRF --> modulates autonomic pathways
what is the main function of the anterior cingulate cortex (ACC)? what are the different parts of the ACC?
ACC: a) main function: emotional and cognitive integration b) components: * dorsal ACC * rostral ACC * ventral (subcalosal/sebgenual) ACC
what is BDNF? how is it affected by depression?
BDNF = brain-derived neurotrophic factor * BDNF is crucial for the survival and functioning of neurons * in depression, increased cortisol levels cause a down-regulation of BDNF, which leads to atrophy and death of neurons
increase in what hormone is associated with increased HPA function in major depression?
CRF (corticotropin-releasing factor), which leads to increased levels of cortisol
what is CRF?
CRF = corticotrophin releasing factor, a polypeptide hormone and neurotransmitter involved in the stress response; it's main function is the stimulation of the pituitary synthesis of ACTH
which isozyme of monoamine oxidase degrades serotonin (5-HT)?
MAO-A degrades: serotonin (5-HT), NE & tryptamine
which parts of the diurnal rhythm are mediated by mineralocorticoid receptors (MRs)? what about glucocorticoid receptors (GRs)?
MRs: basal corticosterone levels, during day and while sleeping GRs: peak in morning (wake up time!)
depression is predominant in which sex?
females
what is the primary mineralocorticoid in humans? what receptors can it bind to?
aldosterone: can bind to mineralocorticoid receptors (MR), but NOT glucocorticoid receptors
what effect do SSRIs and other antidepressants have on BDNF?
antidepressants help to increase BDNF levels in the brain, helping to reverse some of the neuronal atrophy/dysfunction caused by major depressive disorder
what is bipolar disorder?
any of several mood disorders characterized usually by alternating episodes of depression and mania or by episodes of depression alternating with mild nonpsychotic excitement—called also bipolar affective disorder, bipolar illness, manic depression, manic-depressive illness, manic-depressive psychosis
which enzyme catalyzes the conversion of 5-hydroxytryptophan to serotonin (5-HT)?
aromatic amino acid decarboxylase (L-AAD), the same enzyme that converts dopa to dopamine
what is "atypical depression"?
atypical depression: * "atypical" = misnomer * milder type of depression with the opposite of vegetative features seen in more severe depression (i.e. overeating/oversleeping) * often chronic * female predominant * common in bipolar illness
how many medications is the average patient with treated bipolar disorder on?
average patient with bipolar disorder is on 3+ medications
what are some common mis-diagnoses of bipolar disorder?
bipolar disorder often mis-diagnosed as: * unipolar depression * personality disorders * anxiety disorders *** 35% of people with bipolar disorder go for more than 10 years without being correctly diagnosed! ***
what disorders are related to bipolar disorder?
bipolar-esque disorders * cyclothymic disorder * schizoaffective disorder * mania secondary to medication or illness
how is the likelihood of depression related to a) stressful experiences and b) 5-HTT genotype?
both a short 5-HTT polymorphism and stress predispose a person to depression
what is chronic depression?
chronic depression: * defined by major depressive episodes/sx for at least tow years OR by the superimposition of a major depressive episode on antecedent dysthymia
what is the primary glucocorticoid in humans? what receptors can it bind to?
cortisol: can bind to both glucocorticoid receptors (GR) and mineralocorticoid receptors (MR)
what is cyclothymic disorder?
cyclothymic disorder: a mild form of bipolar disorder (manic depressive illness) in which a person has mood swings over a period of years that go from mild depression to euphoria and excitement
are CRF levels elevated or depressed in major depression?
depression: CRF levels = elevated
what exactly is 'mania'?
diagnostic criteria for mania: * a distinct period of abnormally elated or irritable mood (dx criteria: must be at least 7 days long for first episode) * at least 3 of the following: grandiosity, decreased need for sleep, pressured speech, flight of ideas, racing thoughts, distractibility, increased goal-directed activity, agitation, poor judgment/risky behaviors * impairment in occupation and/or social functioning * not attributed to other illness or medication/drug
what is the most consistent neuroanatomical abnormality found in depression?
dysfunction of the anterior cingulate cortex (ACC)
what effect does the administration of exogenous GR/MR agonist (prednisone) have on the HPA axis?
exogenous GR/MR agonist (prednisone) suppresses HPA activity, decreasing endogenous cortisol production and blocking ultradian cortisol pulses,
what effect does the level of maternal contact have on: a) ACTH/cortisol levels in plasma b) GR in hippocampus c) CRF levels in brain d) anxiogenic behavior
high maternal contact: :) a) ACTH/cortisol levels in plasma: decreased b) GR in hippocampus: increased c) CRF levels in brain: decreased d) anxiogenic behavior: decreased separation from mother: :( a) ACTH/cortisol levels in plasma: increased b) GR in hippocampus: decreased c) CRF levels in brain: increased d) anxiogenic behavior: increased
what is the definition of homeostasis (according to Walter B Cannon)?
homeostasis: "The coordinated physiological processes which maintain most of the steady states in the organism are so complex and so peculiar to living beings -- involving the brain, nerves, the heart, lungs, kidneys, and spleen, all working cooperatively -- that I have suggested a special designation for these states, homeostasis." - Walter B. Cannon
homeostasis vs. allostasis
homeostasis: the maintenance of an internal steady state allostasis: maintenance of stability in the face of changes/stressors via compensatory mechanisms
how does the level of metabolism in the amygdala relate to cortisol levels in depressed patients?
in depressed patients, increased amygdala metabolism has been shown to be associated with elevated cortisol levels
what happens to the hippocampus in patients with untreated depression?
in patients with untreated depression, the hippocampus atrophies
what effects does increased cortisol levels have on neurons in a) the amygdala and b) the hippocampus?
increased cortisol levels: a) increased neuronal growth in basolateral amygdala b) decreased neuronal growth in hippocampus
in bipolar disorders, what phase of mood is dominant? causes illness?
it's the depression that both is dominant (in terms of time) and causes illness
in addition to history of stress/maltreatment, 5-HTT genes and BDNF genes, what is a major risk factor for developing depression?
lack of social support (friends/family)
what is the spectrum of sadness & mood disorders?
least severe to most severe: * normal sadness * adjustment disorder w/depressed mood * grief (big gap) * major depressive episode * major depressive episode, severe w/melancholy * major depressive episode, severe w/psychosis
which aspects of bipolar disorder responds more quickly to mood-stabilizing medications: mania or depression?
mania responds more quickly than does depression
mania vs. hypomania
mania: causes impairment, often psychotic (i.e. includes mood-congruent delusions) hypomania: does not cause impairment, not psychotic
what is "melancholia"?
melancholia: * used to be called "endogenous depression" (to distinguish it from "neurotic depression") * this is the classical presentation of severe, recurrent depression in mid-to-late life
what is 'mood'?
mood =m a conscious state of mind or predominant emotion : affective state, * composite state of well being, including cognitive, emotional and behavioral components
what is a 'mood disorder'?
mood disorder: any of a group of psychiatric disorders, including depression and bipolar disorder, characterized by a pervasive disturbance of mood that is not caused by an organic abnormality. Also called affective disorder.
what is the ultimate goal of treatment in bipolar disorder?
mood stabilization
what are "mood stabilizers"?
mood stabilizers: * treat acute mania and/or depression * prevent future recurrence of mania/depression * doesn't increase risk of mania/depression
what is "neurotic depression"?
neurotic depression: * no longer called 'neurotic' * historically significant b/c it was the counterpart to endogenous depression * associated with life events, anxiety comorbidity and hx of trauma
what are the 3 parts of the paraventricular nucleus of the hypothalamus?
paraventricular nucleus of hypothalamus: 1) median eminence (red) 2) posterior pituitary (green) 3) autonomic (blue)
what is post-partum depression?
post-partum depression: * major depressive disorder with onset within weeks of childbirth
what is psychotic depression?
psychotic depression: * most severe form of MDD * characterized by delusions and occasionally hallucinations
what is the rate-limiting step in the synthesis of serotonin?
rate limiting step: tryptophan → 5-hydroxytryptophan, which is catalyzed by tryptophan hydroxylase
what are the DSM IV criteria for major depressive disorder?
sad, low or blue mood, most days for 2 weeks OR pervasive loss of interest and anhedonia, along with at least 4 of the following: * fatigue, low energy * insomnia or hypersomnia * loss of appetite/weight or increased appetite/weight * psychomotor retardation or agitation * poor concentration * suicidal ideation * pathological guilt
differences between sadness and clinical depression
sadness: a normal human emotion that accompanies loss or defeat * transient/short-lived * understandable in context * does not cause significant impairment * is generally relieved by engaging/enjoyable activities clinical depression: a mood disorder marked especially by sadness, inactivity, difficulty with thinking and concentration, a significant increase or decrease in appetite and time spent sleeping, feelings of dejection and hopelessness, and sometimes suicidal thoughts or an attempt to commit suicide * long-lasting, pervasive * causes functional impairment * is not relieved by engaging/enjoyable activities
what is schizoaffective disorder?
schizoaffective disorder: a mental disorder characterized by recurring episodes of elevated or depressed mood, or of simultaneously elevated and depressed mood, that alternate with, or occur together with, distortions in perception
what is seasonal depression?
seasonal depression: * recurrent depression with a recurrent fall-winter onset * often "atypical" (milder), linked to bipolar disorder * therapy w/bright white light
what system seems to be chronically activated in people with major depression?
the stress response system, including: * HPA axis hyperactivity * increased cortisol secretion by adrenal cortex * responses: metabolic, electrophyiologic, behavioral
which part of the prefrontal cortex has been shown to be hypometabolic and smaller in depressed patients, as compared to controls?
the subgenual prefrontal cortex
what are some of the physiological functions of serotonin (5-HT)?
serotonin (5-HT): is a key 'modulator' of... * mood * sleep * eating/body weight * sex (arousal/desire) * nociception * GI * body temperature * vascular tone * respiration * learning/memory * behavior inhibition/impulsivity
what are the different types of serotonin receptors?
serotonin receptors: 1-7 (all but 5-HT3 are G-protein-coupled receptors) * 5-HT1 * 5-HT2 * 5-HT3 * 5-HT4 * 5-HT5-7
which enzyme catalyzes the conversion of tryptophan to 5-hydroxytryptophan?
tryptophan hydroxylase
what are the steps in the synthesis of serotonin (5-HT)?
tryptophan → 5-hydroxytryptophan → serotonin (5-HT) → a) 5-hydroxyindoleacetic acid (5-HAA), or b) N-acetyl serotonin → melatonin (in pineal gland)
what protein transports serotonin (5-HT) into vesicles in the presynaptic cell?
vesicular monoamine transporter (VMAT), which also transports catecholamines (DA, NE, E) into vesicles
is bipolar disorder heritable? if so, to what degree?
yes, bipolar disorder is very heritable * MZ concordance rate = ~50-70% * first degree relatives of patient with bipolar disorder have a 10x increased risk of mania and a 2x increased risk of depression
is depression heritable?
yes, very much so
what is the average age of onset for major depression?
~30 years old
