Lecture 15 - Drug Action in the central nervous system - antidepressants Flashcards
What is depression?
- affective/mental disorder
- Unipolar depression - mood swings always in the same direction: reactive (75%) endogenous (25%)
- Dipolar disorder - depression alternates with mania characterized by excessive exuberance, enthusiasm, self-confidence may be combined with irritability, impatience, aggression
What other conditions are associated with depression?
- anxiety
- eating disorders
- drug addition
What is reactive depression associated with?
a stressful life and accompanied with anxiety and agitation
What is endogenous depression associated with?
unrelated to external stresses
Are reactive and endogenous depression treated in a different way?
Both treated in the same way
What causes bipolar?
Bipolar hereditary but no genes identified - episodes last several weeks
What brain region is involved in depression?
No single brain region involved in depression, prefrontal cortex, amygdala and hippocampus all implicated
What are typical symptoms of depression?
- low mood (anhedonia), negative thoughts, misery, pessimism irritability
- Apathy - loss of interest in daily activities
- severe loss or gain in weight/appetite
- low self-esteem, feeling of worthlessness or guilt
- sleep disturbance: insomnia or excessive sleeping
- loss of appetite & libido
- diminished ability to think/concentrate
What is subjective about depression diagnosis?
Subjective - qualitative: patients exhibit depressed behaviour for >2 weeks & symptoms disrupt normal social and occupational function
Describe depression risk
- stressful life events (personal loss, financial, or professional crisis)
- Genetic risk - 40%
- Secondary to illness (e.g. Cushing’s) side effect of a drug
How is the subgenual cingulate cortex or the nucleus accumbens (NAc) may be implicated in the pathophysiology of depression?
Deep brain stimulation of the subgenul cingulate cortex or the nucleus accumbens has an anti-depressent effect on individuals who have treatment-resistant depression. This effect is thought to be mediated through inhibiting the activity of these regions either by depolarization blockade or by stimulation of passing axonal fibres
What occurs following increased activity-dependent release of brain-derived neurotrophic factor (BDNF)?
Increased activity-dependent release of brain-derived neurotrophic factor (BDNF) within the mesolimbic dopamine circuit (dopamine-producing ventral tegmental area (VTA) to dopamine-sensitive NAc) mediates susceptibility to social stress, probably occuring in part through activation of the transcription factor CREB (cyclic-AMP-response-element-binding protein) by phosphorylation
What does neuroimaging studies strongly implicate?
It strongly implicates the amygdala as an important limbic node for processing emotionally salient stimuli, such as fearful faces.
What effect does stress have?
Stress decreases the concentrations of neurotrophins (such as BDNF), the extent of neurogenesis and the complex of neuronal processes in the hippocampus (HP), effects that are mediated in part through increased cortisol (released from adrenal cortex) and decreased CREB activity
What produces mood-related changes?
peripherally released metabolic hormones, in addition to cortisol, such as ghrelin and leptin, produce mood-related changes through their effects on the hypothalamus (HYP) and several limbic regions (e.g. the hippocampus, VTA and NAc)
What is postnatal depression?
usually occurs 2-8 weeks after delivery and in some cases stays even a year after the birth of the baby. Babies brain waves can become altered if the mother is depressed.
epigenetic changes can contribute to depression
Describe depression as an illness
- treatment is important
- many depressed people don’t get help
- counseling in combination with antidepressants is recommended
- antidepressants are important because depression can cause changes in brain chemistry that can only be reversed by these drugs. Even if the reason for the depression is gone, people will stay depressed due to the biochemical changes at synapses
What do animal models of depression-acute (instant) stress measure?
- ‘coping behaviour, despair’
Classic model for antidepressant efficacy: rodents are placed in an inescapable container of water on 2 occasions. On the 2nd occasion, antidepressant drugs increase the escape behaviour. Good assessment of efficacy of monoaminergic antidepressant drugs. Effects seen acutely (immediately) in animal, unlike delayed effects seen in humans
What do chronic (mild) stress models show?
- structural, transcriptional and epigenetic changes in several brain regions
- mirror therapeutic delay of 4-6 weeks seen when treating humans.
What are the neurotransmitters involved in depression?
- Monoamine hypothesis (1965) functional deficit in noradrenaline & serotonin –> long term trophic effects (development of organs)
- BDNF/TrkB reduced neurogenesis
- Glutamatergic (NMDA) neurodegeneration is also implicated
- Depletion of monoamine transmitters cause depression
What is evidence in support of monoamine hypotheses of depression?
Iproniazid - the first specific antidepressant, is an MAO (monoamine oxidase) inhibitor
Reserpine - which produces depression and parkinsonism depletes stores of monoamine transmitters
Tricyclic AD (anti-depressants) - (originally synthesized in an attempted to develop new antipsychotics) inhibit re-uptake of 5-HT and/or noradrenaline
How do monoamine projections significantly modulate brain areas, from the midbrain and brainstem nuclei?
Dopamine - from the ventral tegmental area
Serotonin - from dorsal raphe in the periaqueductal grey area
Noradrenaline - locus coeruleus (control alertness, awareness & emotion)
Observations with drugs gave rise to monoamine hypothesis of depression
What does Iproniazid do?
Increase central Noradrenergic and serotonergic transmission
What does evidence suggest about the monoamine hypothesis of depression?
OVERSIMPLICATION - drugs affecting monoamines work immediately on raising levels, but therapeutic takes weeks
Monoamine depletion in healthy (as opposed to Parkinson’s patients) patients doesn’t cause depression. In animals, increased dopamine and noradrenaline can have negative effects in stress-related disorders by strengthening memories of aversive life events
Acute (instant) effects produce secondary neuroplastic changes that take longer, at transcriptional and translational level, produce changes in molecular and cellular plasticity
Describe features of anti-depressants
- Monoamine oxidase inhibitors (MAOI e.g. Phenylzine moclobemide)
- Classical Tricyclic antidepressants (TCA e.g. imipramine)
- Selective serotonin (5-HT) reuptake inhibitors (SSRIs e.g. fluoxetine)
- Monoamine Receptor Antagonist
Drugs with varied selectivity for noradrenaline and 5HT uptake inhibitors also used.
What is the difference between MAOIs and TCAs?
Monoamine oxidase inhibitors - inhibits monoamine oxidase (enzyme) which degrades monoamines
Tricyclic anti-depressants - prevents monoamine reuptake
Describe the principles of monoamine oxidase inhibitors as anti-depressants
- MAOIs, inhibition of MOA type A produces anti-depressant effect (type B inhibitors useful in Parkinson’s). Produce rapid & sustained increase 5-HT –> noradrenaline (NA) –> dopamine e.g. Phenelzine, irreversible non-competitive inhibitor, long duration of action
- They have a MAJOR SIDE EFFECT (noradrenaline depletion in sympathetic terminals cause postural hypotension - condition where a person experiences a sudden drop in blood pressure when they stand up from a sitting position
- When combined with dietary sources of tyramine get hypertension cheese effect avoided in the new reversible, selective MAO-A inhibitor - moclobemide
What do MAO usually breakdown?
Monoamines (neurotransmitters) & the amine compound tyramine (found in high concentrations in cheese)
What are the principle actions of TCAs (Tricyclic Anti-Depressants) as anti-depressants?
TCAs inhibit neuronal reuptake of 5-HT and NA
- side effects associated with anticholinergic (mACh, dry mouth, blurred vision, constipation) adrenergic (a2 block, postural hypotension) and histaminergic (H1 block, sedation) effects.
- Dangerous in overdose - confusion & mania, cardiac dysrhythmias
SSRIs specifically inhibit 5-HT reuptake less side effects & toxicity
Describe selectivity found in TCAs
SNRIs - NA selective
TCAs - non-selective
SSRIs - 5-HT selective
Describe the noradrenergic pathways in the CNS
- Functions - arousal/attention, mood, blood pressure regulation, pain
- NA role in regulating sensory processing relates it to withdrawal - increased sleep and anorexia
- Deficiency in central noradrenergic transmission contributes to depression
- Inhibition of NA re-uptake (NARIs) in frontal complex improves mood
What do TCAs & MAOIs affect?
Noradrenaline transmission in the BRAIN - excessive central stimulation leading to tremors, excitement, insomnia and on overdoses; convulsions
What are side effects of TCAs and MAOIs?
increased appetite - weight gain
Describe the 5-HT (5-hydroytamine)/serotonergic pathways in the CNS
Functions:
- Hallucinations
- Sleep
- Wakefulness
- Mood
- Emotion
- Feeding behaviour
- Sensory pathways
- Nociception
- Body temperature
- Vomiting
5-HT role in regulating limbic-processing relates it to anhedonia - the inability to gain pleasure from normally pleasurable experiences
Drugs acting on 5-HT transmission are used to treat DEPRESSION, anxiety, migraine, anti-emetic (chemotherapy), antipsychotic
What is tryptophan?
A precursor to 5HT. Protein rich foods - rich in tryptophan
How many subfamilies of receptors for 5HT known?
7
Describe the different subfamilies of 5HT subfamilies
5HT3 is the only ligand-gated one, the rest are GPCRs, 5HT1 and 5 couple to Gi/Go, 5HT2 is Gq coupled, 5HT2 is Gq coupled, 5HT4,6,7 are Gs coupled. Implicated in huge list of behaviours.
What is LSD (psychedelics)?
5-HT1A, 5-HT2A, 5-HT2C, 5-HT5A, 5-HT5, 5-HT6 agonist
What do serotonin receptors influence?
Influence various biological and neurological processes such as aggression, anxiety, appetite, cognition, learning, memory, mood, nausea, sleep and thermoregulation
Serotonin receptors are the target of a variety of pharmaceutical drugs, including many anti-depressants, antipsychotics, anorectics, antiemetics (vomiting), gastroprokinetic agents (help move food and digestive contents through the stomach and intestines more quickly), antimigraine agents, hallucinations and entactogens (make people feel more connected or in touch with their emotions)
How does the slow mechanism of action of SSRIs work?
need to desensitize somatodendritic 5HT1A receptors
Several antidepresants drugs, including SSRI citalopram known to also bind to P-glycoprotein, molecule in BBB transports drugs back into bloodstream. Human polymorphisms in gene encoding P-glycoprotein alter efficacy of antidepressants - pharmacogenetics
The serotonin receptors modulate the release of many neurotransmitters, including glutamate, GABA, dopamine, epinephrine/norepinephrine and acetylcholine, as well as many hormones, including oxytocin, prolactin, vasopressin, cortisol, corticotropin, and substrate P, among others
What are biochemical effects of antidepressants?
- while anti-depressants have an immediate biochemical effect, their clinical effect may take 3-4 weeks to emerge.
- This time lag suggests that regulatory mechanisms - e.g. receptors are involved
- effect of chronic antidepressant treatments is a downregulation of 5-HT auto-receptors e.g. somatodendritic 5-HT1A receptors on raphe neurons, or alpha 2 auto- and heteroreceptors and NA and 5-HT terminals
What is the neurotrophins in depression BDNF (brain-derived neurotropic factor) hypothesis?
- increased activity-dependent release of BDNF in mesolimbic areas may also contribute to slow biological actions of anti-depressants
Changes in brain volume may be associated with decrease in neurotrophic factors. BDNF expression abundant in adult limbic structures.
Chronic stress, decrease in BDNF in hippocampus
Chronic treatment with antidepressants increase BDNF singalling
HOWEVER recent studies show situation is more complex - as in male mice conditional knock out of BDNF or receptors in forebrain doesn’t show evidence of depression
How does stress affect BDNF levels?
Stress lowers BDNF in the hippocampus (a brain area for memory and emotions).
How does anti-depressants affect BDNF levels?
Antidepressants increase BDNF activity to help improve mood.
What does BDNF do?
stabilizes synaptic connections
What are some other approaches to treating depression?
- anti-epileptic drugs and atypical antipsychotics are also used as ‘mood stabilizers’
- electroconvulsive shock therapy (ECT), electromagnetic therapy, deep brain stimulation & vagus stimulation
What are features of bipolar disorders?
- lithium narrow therapeutic window, plasma levels need monitoring
- permeates voltage-gated Na channels, inhibit inositol monophosphatase, AKT signalling & glycogen synthase kinase 3 (GSK3 - involved in apoptosis) signalling
Summarise anti-depressants
- depression greatly affects society so treatment is essential
- there are 3 main types of antidepressants - TCAs, MAOIs and SSRIs
- Prozac and other antidepressants appear to work by reducing receptor expression and stimulating cell growth factors (e.g BDNF)
- A combination of both anti-depressant treatment and counselling is needed to best treat depression.
What is brain-derived neurotrophic factor?
cell growth factors
