Exam 2 Lecture 21, Antidepressant I Flashcards
Monopolar Mood disorders (depression)
Continuous depression: Become and stay depressed
Recurrent depression: Bounce between depression and “normal”
Bipolar Mood Disorder (manic-depressive illness)
Cycle of depression and mania: Bounce between elation and depression
Major Depressive Disorder (MDD)
denotes 1 type of mood disorder, unipolar depression
Symptoms maybe secondary to adverse, distressing events in patients life (reactive) or may have no clear precipitating cause (endogenous)
lifetime prevalence in US is 17%, one of most common psych disorders
Associated with other med conditions; high co-morbidity with heart disease, diabetes, chronic pain and anxiety disorders
Economic cost $70 Billion
3.4% commit suicide
Bipolar disorder
applied to recurrent cyclic episodes of mania and depression, used to be called “manic-depressive illness”
Form of psychotic disorder distinct from schizophrenia
1-3% prevalence in adult pop
Trends in antidepressant use
Percentage of people using antidepressant has increased
Females tend to take more then men
DSM-V criteria MDD
5 or more symptoms should have been present during at least a 2 week period and represent a change from previous functioning
Symptoms of MDD
severely depressed mood for most of day
Anhedonia
Loss of interest or pleasure in normally enjoyable things
Feelings of extreme sadness, hopelessness, etc
Lost of self esteem; self depreciation
change in appetite with weight gain or loss
Suicidal thoughts
fatigue, decreased energy
early waking with trouble sleeping
DSM-V criteria Biopolar disorder
3 or more of the following symptoms for >1 week and interfering with job or relationships
Symptoms of Bipolar Disorder
inflated self-esteem and grandiosity
Extreme elation, tinged with dysphoria and irritability
Marked insomnia
Increased verbal and motor activity, increased goal-directed activities
Poor judgment
Mania alternates with depression, transition or “switch” can occur over a period of minutes to hours to days
2 types of Bipolar disorder
Bipolar I disorder: at least 1 episode of mania
Bipolar II disorder: at least 1 episode of hypomania and 1 episode of depression
Pathophysiology Depressive symptoms
symptoms traditionally sought to be associated with deficiencies of CNS monamine transmitters, specifically NE and/or 5HT.
Maybe disruption in linkage between the NE and 5HT systems
Pathophysiology Manic symptoms
In bipolar disorder, were thought to be due to excessive monoaminergic transmission….especially by NE and DA
Monoamine theory is…
Controversial, not all evidence fits
Current drug therapies based on this theory
Definition Monoamine theory
Depression due to deficiency of monamine transmission by NE or 5-HT or both
Mania is due to an excess of monoamine neurotransmission
Evidence supporting Monoamine theory
Reserpine (which depletes catecholamines) causes depression
MAO inhibitors (which prevent catecholamine and serotonin metabolism) are antidepressants
Drugs that block NE and 5HT reuptake (TCA and SSRIs) are antidepressants
Depressed patients excrete less catecholamine metabolites in urine, suggesting lower CNS catecholamine neuronal activity
Theory is based on mechanism of action of 1st effective antidepressant drugs….MAO inhibitors and TCA
Where is 5HT produced
Rostral raphe nuclei and Caudal raphe nuclei
Where is NE produced
Locus cerulean and Lateral tegmental NA cell system
Issues with Monoamine theory
Some effective antidepressants do not block either NE or 5HT uptake by nerve terminals
Some drugs that do block catecholamine and serotonin uptake (blow and amphetamine) are poor antidepressants clinically
There is poor temporal correlation between the onset of the clinical antidepressants effect (3-4 weeks) and the blockade of re-uptake or MAO inhibition in brain (immediate)
“Newer” evidence depression
suggests depression maybe due to loss of brain-derived neurotrophic factor (BDNF) in critical brain areas such as hippocampus and frontal cortex
BDNF normally promotes neurogenesis (birth of new neurons) in these regions, and BDNF deficiency is associated with fewer new neurons
Stress and pain = decrease BDNF levels, MDD patient have decreased hippocampal volume
Neurotrophic hypothesis overview
BDNF critical for neural plasticity, exert neural growth via RTK B, Hippocampus to HPA (hypothalamus, pituitary, adrenal) axis, anterior cingulate, orbitofrontal cortex.
In animal models, direct infusion of BDNF alleviates major depression
BDNF in cerebral spinal fluid decreased in human with major depression
Modification of theory addresses temporal discrepancy
chronic administration of antidepressants causes autoreceptor subsensitivity thereby increasing release of NE or 5HT from nerve terminals….
Dumbed down:
When NE reuptake blocked, more NE is in synapse that binds to alpha 2 auto receptors.
These receptors control negative feedback.
Since there is more NE to bind to the alpha 2, they become bound excessively and then they become internalized thereby reducing alpha 2 receptor density at presynaptic end.
Reduced density allows for more NE release since they would usually inhibit it but there are less alpha 2 auto receptors to inhibit release
Reduced contacts at Dendritic spines and dendrites
Due to decreased Monoamines and BDNF acting on CREB dependent transcription, making less BDNF
Also Gluccocorticoids causes reduce in transcription that leads to neural development
Neurotrophic Hypothesis
Chronic stress and/or genetic susceptibility overwhelms normal neuroplasticity and causes a decrease in neurogenesis in the hippocampus
BDNF is up-regulated with antidepressant use (in hippocampus)
BDNF and its receptor (TrkB) are required for antidepressant efficacy and hippocampal neurogenesis
Stress decreases BDNF production and neurogenesis
Inflammation Hypothesis
Depression results from chronic inflammatory event
Increased cytokine levels damage glia and cause tryptophan to turn into the neurotoxin quinolic acid (QUIN) intreat of 5-HT
QUIN causes glutamate receptor activation and glutamate release, leading to excitotoxicity and decreased BDNF production
May explain why glutamate blockers (iu ketamine) have strong antidepressant effects
Integration of all aspects theory of depression
HPA and steroid abnormalities may contribute to the suppression of BDNF gene expression
Binding of stress hormone in hippocampus leads to decreased BDNF synthesis, further results in decreased volume in hippocampus
Chronic activation of monoamine receptors by antidepressants down regulates HPA axis and appress to increase BDNF transcription
Tricyclic structure
7 member ring middle, 2 6 member rings on each side
Tricyclic Mechanism of Action
block reuptake of NE and/or 5HT by presynaptic terminals
Results in transmitters being more available at postsynaptic receptors, potentiating effects of released transmitter.
Reuptake block occurs quickly, within hours
Chronic use required to relieve depressive symptoms
Tricyclic Chronic use
required to relieve depressive symptoms, must be secondary effect with delayed onset
Chronic use causes down-regulation of presynaptic a2 and 5HT autoreceptors on NE and 5HT nerve terminals, increasing release of NE and 5HT.
higher synaptic levels of these transmitters cause post-synaptic B-adrenergic receptor down regulation at about same time that antidepressant efficacy begins
Tricyclic CNS effect
in normal (non-depressed) individuals, feelings of dysphoria, anxiety and sedation, difficult concentrating and thinking
In depressed patients mood is gradually elevated (2-3 weeks required for onset of effect)
Sleep disturbance corrected
Some sedation usually observed
Tricyclic Autonomic effects
Anticholinergic effects: dry mouth, blurred vision, constipation, and urinary retention (due to blockade of muscarinic cholinergic receptors)
Cardiovascular effects: Postural hypotension (due to peripheral a-adrenergic receptor blockade)
Tachycardia (due to cardia muascarinic receptor blockade and inhibitor of norepinephrine reuptake)
tendency to develop arrhythmias
Direct cardiac depressant
Serious cardio toxicity can result in patients with pre-exisitng cardiac disease
Tricyclic other side effects
Excessive sweating
weight gain
risk of transition to manic excitement
Can precipitate glaucoma, especially in elders with narrow angle type
can rarely cause jaundice, agranulocytosis, teratogenic effects
Tricyclic drug interactions
Potentiate effects of…
alcohol and CNS Depressants
MAO inhibitors
Biogenic amines (norepinephrine)
Anticholinergic drugs used in PD treatment, or anticholinergic effects of antipsychotic drugs
Tricyclic absorption, distribution, fate
Well absorbed orally, peak plasma lvl 2-8 hrs
Widespread distribution, highly bound to plasma, long half life
t1/2 = 10 - 20 hrs imipramine, 80 hr protriptyline
due to long 1/2 life, serious toxicity at high plasma level, can be life threatening in those prone to suicide
NEVER DISPENSE MORE THAN A WEEK’S SUPPLY OF A TCA TO ACUTELY DEPRESSED PATIENT
