Depression Flashcards
What are depressive disorders?
the presence of sad, empty, or irritable mood, accompanied by somatic and cognitive changes that significantly affect the individual’s capacity to function
largest economic burden of illness
What is disruptive mood dysregulation disorder?
children (6-18)
chronic and severe irritability and angry outburst out of proportion to situation and developmental level of child
prevalence 2-5%, higher in males and school-age than females and adolescents
What is persistent depressive disorder (dysthymia)?
persistent depressed mood (most of the day, most days) for at least 2 years without remission (<2 months)
presence of hypo- or hyperphagia, insomnia or hypersomnia, fatigue, etc.
prevalence of 1.5-2%
What are premenstrual dysphoric disorder?
affective lability, irritability, anger, depression or anxiety in the week preceding menses
symptoms leading to clinical distress or interference with normal occupational and social functioning
prevalence 1.8 - 5.8% of women
heritability of 30-80%
What is the DSM-5 criteria for major depressive disorder?
five or more symptoms during the same 2 week period that marks a change from prior functioning
these occur most of each day, most days
symptoms cause clinically significant distress or interfere with normal social or occupational functioning
What are the symptoms for major depressive disorder outlined in the DSM-5?
depressed mood, (feelings of sadness, hopelessness) or irritable mood in children/adolescents (subjective/objective)
marked decrease in interest or enjoyment of daily activities (subjective/objective)
significant weight loss/gain or increased/decreased appetite (outside of dieting)
insomnia or hypersomnia
psychomotor agitation or retardation (observable by others)
fatigue or loss of energy
feeling of worthlessness, inappropriate guilt
diminished ability to think or concentrate, indecisiveness
recurrent thought of death, suicidal ideation, suicide attempt or planning
What are correlates of MDD?
lifestyle, sociodemographic, and other factors that correlate with risk of MDD
women, homemakers, unemployed/disabled, never married, previously married
less than 12 years of education
living in or near poverty
What are common comorbidities of MDD?
medical or psychiatric conditions found at increased rates i populations with MDD
72.1% with MDD meet criteria for another DSM-5 disorder
anxiety disorder, substance use disorder, impulse control disorder
What are medical comorbidities of MDD?
cardiovascular disease (congestive heart failure, myocardial infarct, and stroke)
diabetes
cancer
dementia
many risks are bidirectional: stroke or diabetes increases risk of MDD, and MDD increases risk of stroke or diabetes
What is the incidence and progression of MDD?
onset typically after puberty
incidence peaks in 20s
MDD is episodic in most people with spontaneous recovery starting at 3 months to 1 year (in 4/5 patients)
remission is any 2 month period symptom-free
length of remission and severity of the previous episode impact risk of recurrence
What are the temperamental risk factors for MDD?
neuroticism (negative affectivity)
What are the environmental risk factors for MDD?
adverse childhood experiences (abuse, neglect, trauma)
stressful life events
What are the genetic risk factors for MDD?
2-4 fold increased risk in first-degree family members
up to 40% heritability
What are the functional consequences of MDD?
impact highly variable
increased pain and physical illness
decreased social and occupational functioning: depression is the leading cause of disability in Canada
decreased cognitive functioning
elevated risk of suicide
can lead to incapacity, muteness, or catatonia
What is the cognitive affective bias (CAB) in depression?
interaction of emotional and cognitive processes
highly relevant to cognition in depression
depressed patients are more likely to remember negative emotion information, interpret ambiguous social signals negatively
correlated with increased risk of relapse
What is the psychodynamic perspective on depression?
focus on loss as an initiator
Freud: depression represents inward projection of anger following actual or threatened loss (person, object, or personal failure)
self-focus/self-examination, fixation on subject of loss or failure
excess rumination without reconciliation
What is the learning perspective on depression?
depression arises from insufficient reinforcement or reciprocal interactions
partner or peers alter interactions with a depression-prone person further reducing opportunities for positive interactions
What is the cognitive perspective on depression?
depression resulting from a negative view of self, environment, or the future
negative attention bias / pessimistic world view leads to depression
What is the learned helplessness perspective on depression?
depression results from a perceived inability to control their environment or change for the better
cyclic or self-reinforcing - depressive behaviors lead to further helplessness
What factors cause an individual to develop affective bias?
most psychological models address the onset, progression, or recurrence of depression but none address causal agents
some posit features of depression (e.g., excess rumination, negative bias) as causal agents
How are the neurobiological changes in depression assessed?
lesion-deficit studies
structural imaging: structural MRI, diffusion tensor imaging (DTI tractography)
functional imaging: functional MRI (fMRI), PET, SPECT
What are lesion-deficit studies?
one of the oldest “models” for functional specialization of the brain
has been very widely used historically to correlate changes in cognition, emotion, memory, personality, etc with specific structures of the brain
limited to observational studies (ethics)
What structural differences in MDD are indicated by lesion studies?
develop depression after damage to the frontal lobe, temporal lobe, or basal ganglia
What structures report decreased volume in depressed patients MRI?
hippocampus
anterior cingulate cortex (ACC)
caudate nucleus
putamen
orbitofrontal cortex
What are the structural differences between MDD and neurological conditions?
conditions such as stroke, Alzheimer’s, Parkinson’s, and Huntington’s have high comorbidity with depression and have defined structural defects
high variability in structural differences
volumetric differences are worse in older patients
depression disproportionally affects younger patients
What is positron emission tomography?
uses positron-emitting radiotracers to analyze brain metabolism
tissue uptake of FDG is proportional to glucose uptake and hence activity
What is single photon emission computed tomography?
uses gamma-emitting radiotracers to analyze brain blood flow
tissue uptake of Tc-HMPAO is proportional to blood flow and hence activity
What are the neuropsychological deficits of MDD found through functional imaging?
structural imaging fails to show consistent changes in MDD
functional imaging techniques allow investigation into changes in neural activity or connectivity
functional imaging can be correlated with specific tasks or emotional states
functional abnormalities may however affect connection regions
difficult to identify necessary and sufficient abnormalities
What are the commonly observed areas of increased activity in depression?
frontal, orbital, parahippocampal cortices
ventrolateral prefrontal cortex
subgenual cingulate cortex
(amygdala), striatum, hypothalamus
What are the commonly observed areas of decreased activity in depression?
dorsal medial prefrontal cortex
dorsal anterior cingulate cortex
posterior cingulate cortex
What is the limbic-cortical dysregulation model of MDD?
depression results from dorsal hypoactivity (dmPFC, ACC) and ventral hyperactivity (frontal cortex, subgenual cingulate cortex, insula, hippocampus, hypothalamus)
What structures are involved in the limbic-cortical dysregulation model?
lesion-deficit studies and functional imaging identified changes in limbic, paralimbic, striatal-palladial, and thalamic areas
subgenual cingulate cortex BA25 implicated as a key modulator of depressive circuits
anterior cingulate (BA24a) activity predicts treatment response to antidepressants
What are the two major compartments of change in depression according to the limbic-cortical dysregulation model?
dorsal hypoactivity: dorsal anterior and posterior cingulate, inferior parietal and dorsolateral prefrontal cortex
ventral hyperactivity: subgenual cingulate, ventral frontal cortex, hippocampus, hypothalamus, and insula
What is the monoamine hypothesis of depression?
depression is the result of a functional deficit of the neurotransmitters norepinephrine (NE) and/or serotonin (5-HT) at specific synapses in the CNS
What are monoamines?
monoamines (biogenic amines) are a group of neurotransmitters / hormones that share a common single amino functional group
What is serotonin?
derived from tryptophan in the brain (5-HT cannot pass the blood-brain barrier)
major neurotransmitter in the gut responsible for contraction
What is the synthesis and catabolism of serotonin?
dietary L-tryptophan is transported into the brain where it is converted to 5-HT by tryptophan hydroxylase (the rate limiting enzyme)
5-HT is deaminated by monoamine oxidase to 5-hydroxyindoleacetic acid in the cytoplasm of serotonergic neurons
in contrast to the catecholamines, 5-HT breakdown occurs only through MAO
What are the broad behavioral effects of serotonin?
5-HT is colloquially thought to contribute to happiness, mood, and spirituality
most antidepressants target serotonergic systems and improve mood
5HT receptors (5HT2A) are responsible for the effects of hallucinogenic drugs (e.g. LSD)
diverse effects on behavior make it difficult to ascribe an overall function to serotonergic systems: mood, emesis, migraine propagation, anxiety, attention/alertness
5-HT binding capacity has been suggested to correlate with tendency towards spirituality
What is the bioavailability of tryptophan?
tryptophan is dietary in source and availability of tryptophan can affect 5-HT production
the tryptophan transporter is a competitive amino-acid transporter, thus increased protein intake does not elevate tryptophan bioavailability in the brain
dietary restriction of tryptophan intake can dramatically alter 5-HT levels in the brain and induce depressive symptoms
How does uptake inactive 5-HT signalling?
serotonin transporter (SERT or 5-HTT) regulates synaptic clearance of 5-HT
two polymorphisms of SERT-5-HTT were associated with increased risk of depression
SERT-5-HTT is the primary target of SSRI, SNRI, and TCA antidepressants
How does catabolism by MAO inactive 5-HT signalling?
MAO breaks down 5-HT, NE, and DA in the brain and 5-HT in gut
primary target of MAOI antidepressants
How is the raphe nuclei involved in depression?
serotonergic projections from the raphe nuclei project to many regions implicated in depression
limbic, frontal, temporal cortex (including BA25)
thalamus
basal ganglia
hippocampus
What is the monoamine hypothesis?
depression is a result of a functional deficit of the neurotransmitters norepinephrine and serotonin (5-HT) at specific synapses in the CNS
What is the pharmacology of the monoamine hypothesis?
first antidepressant was a monoamine oxidase inhibitor (MAOI), iproniazid, ad anti-tuberculosis drug (1952)
MAOI cause elevation of monoamines by inhibiting their breakdown
elevated monoamines leads to increases in monoaminergic neurotransmission (dopamine, norepinephrine, serotonin)
phenelzine was the most common MAOI in use clinically but discontinued due to the cheese effect
What are some examples of MAO inhibitor drugs?
phenelzine
tranylcypromine
moclobemide
What are MAO inhibitors?
increased presynaptic monoamine levels presumed to lead to enhanced monoamine release
MAOI such as phenelzine and tranylcypromine irreversibly inhibit both MAO-A and MAO-B
MAO-A and -B are present in the CNS
MAO-A is also found in the gut where it breaks down tyramine in food
What is the cheese effect of MAOIs?
tyramine is degraded in the gut by MAO-A and thus not taken up systematically
tyramine-rich foods (cheese, red wine) lead to elevations in tyramine in the presence of MAOI (drug interaction)
tyramine acts to release NE from nerve terminals where (due to MAO inhibition) it persists
elevated NE symptoms range from headaches to hypertensive crisis (can be fatal)
MAO inhibitors are currently used as a last resort therapeutic
What are examples of tricyclic antidepressant drugs?
imipramine
amitriptyline
desipramine
nortriptyline
What are tricyclic antidepressants (TCA)?
developed in the 1950’s from chlorpromazine analogues
imipramine is an inhibitor of both norepinephrine transporters (NET) and 5-HT transporters (SERT)
impaired reuptake leads to elevated synaptic NE-5-HT
sustained NE/5-HT levels lead to prolonged and increased post-synaptic activity
side effects on muscarinic receptors (anti-cholinergic): dry mouth, constipation, urinary retention
poor safety margin - induces mania at higher doses
What are examples of selective reuptake inhibitor drugs?
citalopram
fluoxetine (Prozac)
venlafaxine
What are SSRIs?
selective serotonin reuptake inhibitors
second generation antidepressants - targeted drug design
fluoxetine (Prozac) most widely prescribed
selective inhibitors for SERT
5-HT accumulates in the synapse, enhancing post-synaptic activity
What are SNRIs?
serotonin-norepinephrine reuptake inhibitors
second generation antidepressant - replaces TCA
first SNRI was venlafaxine
inhibits both SERT and NET
fewer side effects than TCAs, improved safety margin
How do antidepressant effects compare to placebo effects?
antidepressants have an efficacy of approximately 60%
the placebo response in trials is typically ~75-82% of antidepressant effect
43% of AD trials show a significant benefit of drug over placebo - approximately half of trials go unpublished
AD have been suggested to function as active placebos: all have noticeable side effects, thus in AD trials most patients can guess their trial status, breaking blind
What are the challenges to the monoamine hypothesis?
pharmacologic effects are very rapid (hours-days) but therapeutic effects are slow (weeks-months): monoamines normalize rapidly, but mood normalizes slowly
demonstrated efficacy of drugs that do not affect NA/5-HT reuptake: tianeptine, a selective serotonin reuptake enhancer is equally effective as SSRIs in clinical trials
cocaine (potent NA reuptake inhibitor) does not have antidepressant effects
inconsistent findings in antidepressant effects of amino acid precursors to NA/5-HT (e.g. tyrosine and tryptophan)
model was proposed retrospectively to explain the efficacy of MAOI and TCA class drugs
