Depression (wk 6) Flashcards
delusion
A belief that is clearly false and indicates an abnormality in content of thought
False belief cannot be explained by the person’s cultural or religious background or intelligence level
Belief is held despite being presented with evidence against it (“fixed” – firmly maintained)
Patient is convinced the delusion is real
causes of delusion
Can be due to: mental disorder, neurological or medical disorder
Examples: schizophrenic, substance abuse, bipolar disorder, major depressive disorder (MDD), delirium and dementia
hallucination
“A sensory perception in the absence of a corresponding external or somatic stimulus and described according to the sensory domain in which it occurs”
Not under voluntary control
Vivid, clear, full force and impact of normal perceptions
Visual, auditory, tactile, olfactory, gustatory, nociceptive, thermoceptive, proprioceptive, equilibrioceptive
Formed (i.e. voice making a command) or unformed (i.e. non- specific sound)
With insight – px is aware that its not real only hallucination OR without insight – px is unaware and accepts the experience as reality
hallucination vs delusion vs psychosis
hallucination: “A sensory perception in the absence of a corresponding external or somatic stimulus and described according to the sensory domain in which it occurs”
delusion: A belief that is clearly false and indicates an abnormality in content of thought
psychosis: Hallucination (without insight), delusion OR hallucination (without insight) and delusion
psychosis
Hallucination (without insight), delusion OR hallucination (without insight) and delusion
Loss of contact with external reality
Central component: Impaired reality testing
Can occur in psychiatric and neurological disorders Additionally:
Disorganized thoughts and impairment in cognitive function (i.e. reduced verbal fluency)
Mood changes
Reduced attention and concentration Sleep disturbances
what is the central component in psychosis?
impaired reality testing
delirium
Acute, fluctuating change in attention (reduced) and consciousness including disorganized thoughts
Altered consciousness: hypervigilant, unresponsive, near-coma, severe agitation
May include: psychosis; delusions and hallucinations, altered mood
how long does delirium last and what is it triggered by
Can vary in duration: days (typically) or months
Triggered by: change in medication, infection, surgery, trauma, stroke, withdrawal, very extensive list
depressive episode
Experience of low or depressed mood Loss of interest in most activities Additional possible symptoms:
Fatigue
Changes in appetite (and weight)
Feelings of worthlessness
Recurrent thoughts of death
Unexplained physical ailments unresponsive to treatment (i.e. digestive problems, pain)
can be seen in MDD< anxiety, bipolar, schizo, post stroke..
mania
Characteristics: increased talkativeness, rapid speech, decreased need for sleep, racing thoughts, distractibility, increase in goal-direct activity, psychomotor agitation
May include: elevated mood, mood lability, impulsivity, irritability, grandiosity
seen in bipolar, meds or substance, brain tumor
how long must mania last vs hypomania
Duration: 1 week or more OR if severity of symptoms warrants hospitalization
hypomania is 4 days
main dif between mania and hypomania
Differentiating factors from mania:
Duration: at least 4 days (rather than at least 1 week)
Does NOT cause major deficit in social or occupational functioning
Conditions: bipolar disorder, substances, neurological causes (i.e. encephalitis, dementia, lupus)
MDD risk factors
trauma, chronic pain or chronic disorders, low income, family history
mood physical and cognitive symptoms of MDD
Mood Symptoms
Physical Sx
Cognitive Sx
Feeling sad/ low
Lack of energy / tired
Slow thinking
Lack of interest in general
Difficulty sleeping; waking early
Difficulty concentrating
Anhedonia
Restless/ agitated
Slow movement
Low self-esteem
Weight loss
Forgetfulness
Lacking confidence
Low libido
Difficulty planning
Feelings of guilt or worthlessness
Low appetite/ overeating
Difficulty making decisions
Suicidal thoughts
which 2 components must be included in MDD
Depressed mood (subject report of observations of others) Anhedonia – loss of interest/ pleasure in almost all activities
These 2 sx must be present most of day, every day for at least 2 weeks in a row
how many symptoms for MDD total
at least 5ot
components of MDD
Category A – must include the first two components and a total of 5 or more components:
Depressed mood (subject report of observations of others) Anhedonia – loss of interest/ pleasure in almost all activities
These 2 sx must be present most of day, every day for at least 2 weeks in a row
Unintentional weight loss or gain (>5% in 1 mo) or significant change in appetite
Sleep disturbance (insomnia/ hypersomnia)
Psychomotor changes (agitations/ retardation)
Fatigue, low energy, decreased efficiency with routine tasks
Sense of worthlessness or excessive/ inappropriate guilt (i.e. guilt about being sick)
Impaired ability to think/ concentrate/ make decisions Recurrent thoughts of death, suicide ideation or attempts
Additional diagnostic requirements:
These sx must cause significant distress OR impair social, occupational or other important areas of function
Sx are not due to direct physiological effects of a substance (i.e. meds, drug abuse) OR medical condition (i.e. hypothyroidism)
Px has never experienced a manic or hypomanic episode
This condition is not better explained by schizophrenia spectrum or other psychotic disorders
leading theories of MDD
Monoamine hypothesis
Stress-induced depression hypothesis
Neurotrophic / Neuroplasticity hypothesis
Cytokine hypothesis/ Neuroinflammation hypothesis Circadian hypothesis of depression GABA-glutamate-mediated depression hypothesis
monoamine hypothesis of depression
what is it based on
Altered levels of monoamine neurotransmitters, specifically serotonin and noradrenaline, and/or dopamine cause depression
Based on antidepressant therapies that increase the presence/ function of one or more neurotransmitter resulting in reduced depression
Critiqued in that abruptly decreasing serotonin and/or dopamine doesn’t cause depression in a healthy person
Other neurochemicals are implicated in depression beyond these
Probable causes: genetics, environment, stress
stress induced depression hypothesis
which system on the body is impacted
HPA axis
stress induced depression hypothesis
Chronic stress leads to dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis
Prolonged, moderate stress is the problems, versus minor daily stresses OR one strong stressor
Examples: maternal stress, maternal smoking, early grave loss, child abuse
Early trauma may have more sig impact than in adult life (impact how HPA is developed in utero)
Chronic HPA activation leading to: excess cortisol secretion and pro-inflammatory agents that damage glia and neurons, interfere with neurogenesis and reduce glutamate and GABA
Clinical studies support this in some patients with severe depression: measurable increase in cortisol which is not reduced through negative feedback (also increased CRH)
Resistance of the glucocorticoid receptor (GR)
Antidepressants appear to restore the functioning of the GR and thus improve negative feedback and normalize cortisol levels
Critique: hypercortisolism is not a feature of all MDD cases AND not clear what causes HPA dysregulation (i.e. loss of GR sensitivity)
what does chronic HPA acitvation cause
excess cortisol secretion and pro-inflammatory agents that damage glia and neurons, interfere with neurogenesis and reduce glutamate and GABA
which receptor does cortisol bind to
glucocorticoid receptor –> for stress induced depression hypothesis and HPA dysregulation
what factor promotes neurogenesis
BDNFn
neurotrophic and neuroplasticity hypothesis of depression
Brain-derived neurotrophic factor (BDNF) promotes neurogenesis, regulates differentiation and growth of neurons
Neurogenesis may offer resilience against stress by enhancing the negative feedback loop with HPA
Observations:
Decreased BDNF gene expression, decreased BDNF levels and receptors in MDD patients
Increased cortisol can inhibit BDNF
Same triggers that elevated cortisol appear to block neurogenesis
Antidepressants
Have been demonstrated to stimulate neurogenesis in adult hippocampus (animal studies) – takes 4 weeks
Correlates with the 3-4 week expectation of achieve improvement in mood
which pro inflammatory markers are increased in MDD
TNFalpha, IL6, IL1, CRP, macrophage /monocyte activation
cytokine and neuroinflammation hypothesis
MDD px have increased levels of pro-inflammatory markers: TNFalpha, IL-1, IL-6, C-reactive protein (CRP) vs healthy px, as well as increased level of macrophage/monocyte activation
Frequent correlation b/w MDD and inflammatory conditions such as asthma, diabetes, arthritis, obesity, CAD
Animal studies: injecting pro-inflammatory cytokines induces depressive sx
Some antidepressants have anti-inflammatory properties
Earlier case reports observed improvement in mood in patients with treatment resistant MDD treated with anti- inflammatory medications, particularly in context of other inflammatory conditions (like IBD)
what produces melatonin and what regulated melatonin and what inhibits the production of melatonin
Light inhibits pineal gland from producing melatonin (by activating neurons with suprachiasmatic nucleus (SNC) of the hypothalamus)
SCN regulates production of melatonin throughout the body
Melatonin production increases at night during conditions of dark
circadian hypothesis of MDD
Stressful events lead to changes in diurnal molecular rhythms in cells that in vulnerable px triggers MDD
Bidirectional link with sleep disturbance and depression
Insomnia is a predisposing factor
Sleep deprivation therapy – reduces MDD sx (may resent the circadian clock)
Genes controlling circadian rhythms in anterior cingulate cortex are dysregulated in depression
Phase advance in cortisol rhythm and reduced amount of melatonin production seen in some patients with MDD
Altered circadian rhythms can also affect reward systems, particularly social interaction
Same 5-HT receptors have been implicated in both sleep rhythms and depression; serotonin is involved in phosphorylation of CLOCK protein, which regulate suprachiasmatic circadian rhythms
Sleep disturbances have also been correlated with pro- inflammatory cytokines
what excitatory neurotransmitter has a hypothesis for MDD
glutamate
excitatory neurotransmitter hypothesis of MDD
Glutamate may cause excitotoxicity resulting in neuronal atrophy and reduced synaptic connectivity
Stress induced changes may be accelerated in the presence of elevated Glu
Reduced GABA in CSF of MDD px – may be d/t change in serotonin which modulates GABA, which in turn modulates glutamate
Reduced GABA and glutamate within glial cells and neurons of the prefrontal cortex (PFC)
Astrocytes recycle glutamate and transport to presynaptic neurons
Elevated metabolism of glucose within same areas of PFC, and reduction of the gray matter in this region
Ketamine – modulates glutamate transmission Approved for tx of treatment resistant MDD
what drug modulate glutamate
ketamine
too much glutamate…..
fries the brain circuitry
glutamate hypotheiss
Excessive accumulation of glutamate within synaptic cleft results in over stimulation of postsynaptic glutamate receptors
Via NMDA receptor glutamate promotes calcium influx
increased calcium in the cytosol can cause necrosis via NOS, ROS, pore in mitochondria so cant make ATP
clinical features of bipolar
Mania
Hypomania
Depression (most of time spent in depressive state)
Cyclical changes between these states a common to be part of the disorder
Manic psychosis, which may include delirium
bipolar 1 vs bipolar 2
Bipolar 1
At least 1 manic episode and usually depressive episodes
Bipolar 2
Major depressive episodes with at least 1 hypomanic episode
what’s more severe bipolar 1 or 2
1 (mania)
what must you exclude when diagnosis bipolar
Exclusion of hyperthyroidism (TSH and T4)
Exclusion of stimulant drug abuse (blood/urine)
how many mania symptoms does bipolar 1
3+
DSM5 of bipolar
At least 1 episode of mania/hypomania lasting for at least 4 consecutive days AND be present most of the day, almost every day
3 or more symptoms (representing sig change from norm) of mania
Cause significant impairment or necessitates hospitalization
symptoms of mania
Inflated self-esteem or grandiosity
Decreased need for sleep (feels rested after 3 hours of sleep)
More talkative than usual or pressure to keep talking
Flight of ideas or subjective experience that thoughts are racing
Distractibility (i.e. attention too easily drawn to unimportant / external stimuli)
Increase in goal-directed activity (purposeful) or psychomotor agitation (purposeless)
Excessive involvement in activities that have a high potential for painful consequences (i.e. foolish business investments, unrestrained buying sprees)
bipolar 2
No/never experienced episode of mania
Exclusion of/ not better explained by: schizophrenia, delusional or psychotic disorder or unspecified schizophrenia spectrum
Clinically significant distress from symptoms
Hypomania episode
hypomania episode DSM5
Elevated, expansive or irritable mood with persistently increased activity or energy; 4+ days, most of the day, nearly every day
3 or more additional mania symptoms
Episode is different from px regular non symptomatic experience
Observes can note change in mood and function
Not severe enough to impair functioning or necessitate hospitalization (no psychotic features)
Episode is not triggered by substance (drug, medication, other treatment)
4 theories of bipolar
Circadian Rhythm Dysfunction Metabolic Dysfunction Mitochondria Dysfunction Glutamate Excitotoxicity
bipolar disorder; what changes in sleep hormones and genes that are related to circadian rhythm?
melatonin, cortisol, CLOCK genes
circadian rhythm dysfunction in bipolar
During mania there is a reduced need for sleep
Observations in patients with bipolar disorders:
Changes in melatonin levels
Changes in melatonin receptor expression with CNS
Changes in cortisol profiles (patterns of release)
Sleep deprivation as well as light therapy have been effective as adjunct in some cases of bipolar disorder
Correlation between polymorphism in CLOCK genes as well as positive response to lithium therapy (common drug used in bipolar management)
what metabolic dysfunction can be sen in bipolar? which hormonee increases?
leptin;
obesity, T2D
metabolic dysfunction in bipolar dirsoder
Various metabolic abnormalities have been found in patients with bipolar disorder such as:
Increased risk of obesity, type 2 diabetes, and reduced longevity due to increased cardiovascular problems
Increased amount of leptin secreted in obese patients with bipolar compared to obesity alone
Leptin regulated appetite AND sleep duration
A hypothesis suggests that the body is forced to compensate for the high metabolic demand of the brain during manic states:
Reduced appetite
Reduced sleep
Increased energy expenditur
in bipolar disorder which metabolic pathway gets shifted to due to mitochondrial dysfunction
glycolysis
mitochondria uses ETC and Krebs cycles to make lots of ATP
but then glycolysis makes way less ATP
mitochondrial dysfunction in bipolar disorder
Impairment in mitochondrial function resulting brain metabolism shifting towards glycolysis
Observations:
Polymorphisms within mitochondrial DNA linked to BD
Reduced levels of phosphocreatine within frontal cortex. Phosphocreatine is a reserve for ATP and this implied chronic deficiency in ATP synthesis
Evidence of impaired oxidative phosphorylation Increased amounts of alpha-ketoglutarate and pyruvate –review: how do these substrates relate to ATP production?
Reduced expression of genes coding for various complexes of the electron transport chain in hippocampus
what excitatory neurotransmitter can be increased in bipolar and in which region of the brain
glutamate in frontal cortex
glutamate excitotoxicity in bipolar
Observation: increased glutamate in frontal cortex of px with BD
Mood stabilizers appear to return glutamate levels to normal
Increased levels of excitatory glutamate appear to result an increased energy demand on the neuron
Increased glucose consumption in areas of high glutamate synaptic activity
Hypothesis: increased shift to glycolysis may be due to increased glutamate stimulation
what do neutotramsitters do in depression
low levels of neurotransmitters lead to receptor upregulation
what is an antidepressetn action
reuptake inhibitor; increase levels of neurotransmitters at the synapse
what is a delayed effect on antidepressants
down regulation of neurotransmitter receptors
§ Could explain time needed to see antidepressant effects
§ The 5HT1a receptors are autoreceptors – they inhibit release of NT from presynaptic terminals
* If they’re down-regulatedàincreased NT release
§ Sustained antidepressant therapy is also associated with increased production of BDNF, which is likely linked to efficacy
antidepressant suciide risk
increased suicide risk in children, adolescents and young adults upto 24 years of age when taking antidepressants.
SNRIs examples
- TCAs; amitriptyline
- venlafaxine
“-triptyline” suffix = TCA
SSRI examples
fluoxetine
“-oxetine” suffix = SSRI
other antidepressants
-MAOIs
-trazodone
-bupropion (Wellbutrin and zyban)
why are there adverse effects of TCAs
Many are due to non-therapeutic block of M, alpha 1 and H1 receptors
muscarinin receptors
in brainstem or spinal cord, parasympathetic, bound by acetylcholine
acts on heart, small muscle, glands
alpha 1 receptors
spinal cord, sympathetic, acetylcholine, epinephrin and norepinephrine
act of heart, small muscles, glands
adverse effets of blocking M receptors (via TCAs)
salivary glands= dry mouth
intestine= constipation
bladder= urinary retention
pupil= dilated
advers effects on blocking alpha 1 receptors
vasodilation
H1 receptors role
mediate feeding and part of sleep wake cycle
effects of blocking M, alpha 1, and H1 receptors
- M-block
§ Dry mouth
§ Constipation
§ Urinary retention
§ Mydriasis
§ Blurred vision
§ Confusion
Alpha 1-block
Orthostatic hypotension
Sedation
Sexual dysfunction
H1-block
Weight gain
Sedation/ drowsiness
other adverse effects of TCAs
Adverse effects not fully explained by M-, alpha 1 - and H1-blocks are:
§ Sexual dysfunction
* Caused by serotonin acting at 5-HT2a receptors
§ Antidepressant effect of serotonin is via 5-HT1a receptors
§ Weight gain
* Could also be due to remission of depression and/or direct stimulation of appetite
TCA overdose can lead to?
cardiac arythmias
alpha 1 and muscarinic receptors cause vasodilation
venlafaxine (SNRI) what does it act on
serotonin and norepinephrine
§ Also weakly inhibits dopamine reuptake
§ No significant alpha 1, H1 or M-block
* Less likely to cause related adverse effects, including sexual dysfunction and weight gain (may cause weight loss)
which SNRI has more adverse side effects; TCA or venlafaxine
TCA
SSRI adverse effects
- Adverse effects often related to M, α1, H1-block
§ Receptor blocks less potent than with TCA’s, related adverse
effects typically more mild - Exception: sexual dysfunction is typically worse
§ What is the role of serotonin?
§ Additional NO (vasodilator) synthesis block - Weight disturbances can include weight loss
§ Transient, followed by potential long-term weight gain - Does not have the same cardiotoxicity as TCA’s § Does have the potential for serotonin syndrome
serotonin syndrome
from increased serotonin from SSRIs
agitation
sweat, hot
fast heart rate, high blood pressure
hyperreflexia and clonus
what to give to help with serotonin syndrome
cyproheptadine to interfere with serotonin action
or symptomatic treatment; treat agitation with benzodiazepines
MAOIs mechanism; what neurotransmitter
§ Block monoamine oxidase, the enzyme that metabolizes NE, resulting in higher NE levels
if you combine MAOIs with foods containing tyramine what could happen
hypertensive crisis
tyramine has synergistic effect on NE levels
trazodone acts on which neurotransmitter
and which receptors does it block and can cause adverse effets
serotonin
H1 and Alpha 1 receptors
§ Inhibits serotonin reuptake, but not considered an SSRI
* Also acts directly as an antagonist at serotonin 5-HT2A receptors
§ What is the benefit of this antagonist action? § Adverse effects
* H1-block and potent alpha 1 block effects § Strong sedative effects
* May be useful for patients with anxiety, or for helping with sleep patterns of depressed patients
* Weight gain tends to be minimal
what are the 2 brands of bupropion and their uses
§ Wellbutrin = antidepressant
§ Zyban = smoking cessation therapy
wellbrutin use
antidepressant
zyban use
smoking cessationm
mechanism of action of bupropion
weak inhibition of NE and dopamine reupaake
adverse effects of bupropion
dose related seizure risk
