Antidepressants Flashcards
What are some of the feelings in depression?
Anhedonia - ability to feel pleasure Grief and guilt Self-harm Psychomotor retardation Vegetative symptoms (Sleep, appetite, stress hormones)
What are some symptoms of depression?
- Persistent sad, anxious, or ‘empty’ mood.
- Feelings of hopelessness, pessimism.
- Feelings of guilt, worthlessness, helplessness.
- Loss of interest or pleasure in hobbies and activities that were once enjoyed.
- Thoughts of death or suicide.
Decreased energy, fatigue, being ‘slowed down’
Restlessness, irritability
Insomnia, early-morning awakening or oversleeping,
Appetite and/or weight loss or overeating and weight gain.
Persistent physical symptoms that do not respond to treatment such as headaches, digestive disorders and chronic pain
What is MAO?
Monoamine Oxidase Inhibitors
How was MAO found as a drug for depression?
Discovered by chance when Iproniazid when being used to treat tuberculosis. They saw greater vitality (Healey, 1999)
What kind of drug is Iproniazid?
A monoamine agonist
What does a monomaine agonist (like Iproniazid) do?
Increases the levels of monoamines by inhibiting the activity of the enzyme monoaminoxidase (MAO)
What are monoamines?
Noradrenaline, dopmaine and serotonin
What happens when a drug effects the enzymatic process?
It increases the availability of neurotransmitters in synaptic gap, so then they can bind to post synaptic receptors again.
What serious side effects are associated with MAO?
Cause liver damage
Dysfunction in blood pressure controls
How does MAO affect blood pressure?
Noradrenaline is involved in blood pressure control so an increase in noradrenaline will raise blood pressure.
Nonspecific MAO blockers influence MOA-A centrally and in periphery, leading to increase in noradrenaline, increase in blood pressure.
What is dietary tyramine?
An indirect noradrenaline agonist found in foods, such as mature cheese, red wine, pickled herring and yeast like marmite.
These indirectly increase the availability of noradrenaline so if the enzyme is inhibited then there is an increase in blood pressure and a hypertensive crisis.
What are tricyclic antidepressants?
Drugs that block the reuptake of both serotonin and noradrenaline, thus increasing their levels in the brain.
How were tricyclic antidepressants found to help depression?
Patients diagnosed with depressive psychosis showed marked improvement in their general state within a few weeks (1957).
What are some side effects of tricyclic antidepressants?
Dry mouth (salivary gland activation) Impaired muscular control in the eye (blurred vision) Tachycardia (irregular heartbeat), constipation etc.
What is Ashcroft & Eccleston’s (1960) take on the monoamine hypothesis?
First theory that serotonin low in depression
Low concentration of serotonin, 5HT or its main metabolite, 5-HIAA were found in autopsy.
Studied brains of suicide victims and cerebrospinall fluid in depressed patients
What is Axelrod’s (1961) take on the monoamine hypothesis?
Discovered monoamine reuptake by pre-synaptic neurons and tricyclic antidepressants block this mechanism
Dismissed 5HT as unimportant.
What is Schildkraut’s (1965) take on the monoamine hypothesis?
The catecholamine hypothesis of affective disorders
The noradrenaline hypothesis of depression was the leading idea that guided research.
What is the evidence that depression is associated with monoamine neurotransmitter deficiency?
Certain drugs that depleted these neurotransmitters could induce depression (reserpin)
Known antidepressants at the time boosted these neurotransmitters and alleviated depression.
What are the main serotonin pathways in depression?
Transmission from both the caudal raphe nuclei and rostal raphe nuclei is reduced in patients with depression.
How can serotonin pathways alleviate depression?
Increasing levels of serotonin in these pathways, and reducing reuptake and thus increasing serotonin function.
what are the behavioural functions of serotonergic projection from the raphe to the frontal cortex?
Regulating mood
what are the behavioural functions of serotonergic projection from the raphe to the basal ganglia?
Help control movements as well as obsession and compulsion.
what are the behavioural functions of serotonergic projection from the raphe to the limbic areas?
Anxiety and panic
what are the behavioural functions of serotonergic projection from the raphe to the hypothalamus?
Appetite and eating behaviour
what are the behavioural functions of serotonergic projection from the raphe to serotonergic neurons in the brain stem?
Sleep centres regulate sleep
what are the behavioural functions of serotonergic projection from the raphe to serotonergic neurons descending down the spinal cord?
Responsible for controlling certain spinal reflexes that are part of the sexual response, such as orgasam and ejaculation.
What role do the noradrenergic pathways have?
Mediating behaviour and other functions, such as cognition, mood, emotions and movement.
Where are most of the cell bodies for noradrenergic neurons in the brain located?
In the brain stem, an area known as locus, coeruleus.
What role do noradrenergic pathways have in depression?
Transmission of noradrenaline is reduced from both the principle noradrenergic centres- the locus coerleus and the caudal raphe nuclei.
An increase in noradrenaline in frontal/prefrontal cortex modulated tha action of selective noradrenaline transmission to other areas of the frontal cortex modulated attention.
What is noradrenaline destroyed by?
Enzymes in the NA neurons.
Principle destructive enzyme is MAO
Catechol-O-methyl-transferase (COMT) can also destroy enzymes
What post synaptic receptors regulate noradrenaline?
Alpha 1, Alpha 2
Beta 1, Beta 2
What presynaptic receptors regulate noradrenaline?
Alpha 2 autoreceptor
What the alpha 2 presynaptic autoreceptors do at the terminal?
Stop noradrenergic release
What the alpha 2 presynaptic autoreceptors do at the dendrites?
Decrease noradrenergic release
What do the noradrenergic receptors that regulate serotonin on the presynaptic receptors do?
Act as an accelerator (alpha 1 receptor)
Act as a break (alpha 2 hetero receptor)
of serotonergic transmission
what are the behavioural functions of noradrenergic projection from the locus coeruleus to frontal cortex thought to be responsible for?
Actions of NA on mood
and
mediate effects of NA on attention, concentrating and other cognitive functions, such as working memory and speed of information processing.
what are the behavioural functions of noradrenergic projection beta 1 postsynaptic receptors thought to be responsible for?
Transducing noradrenergic signals regulating mood in postsynaptic targets.
what are the behavioural functions of noradrenergic projection from the locus coeruleus to limbic cortex thought to be responsible for?
Mediate emotion and energy, fatigue and psychomotor agitation/retardation.
what are the behavioural functions of noradrenergic projection from the locus coeruleus to cerebellum thought to be responsible for?
Mediating motor movements, especially tremor.
what are the behavioural functions of noradrenergic projection from the brain ste, thought to be responsible for?
Blood pressure
what are the behavioural functions of noradrenergic projection from sympathetic neurons thought to be responsible for?
Heart
What are the symptoms of noradrenaline deficiency?
7
Impaired attention
Problems concentrating
Deficiencies in working memory
Slow information processing
Depressed mood
Psychomotor retardation
Fatigue
What are the symptoms of serotonin deficiency? (6)
Depressed Mood
Anxiety
Panic
Phobia
Obsession and compulsions
Food craving; bulimia
What was Schildkraut’s Catecholamine theory (1965)?
Inhibition of noradrenaline reuptake common denominator
What did Kielholz (1960) suggest?
Different antidepressants do different things and it is important to select the right antidepressant for the right patient.
What effect do MAOIs have?
Drive enhancing
What effect does Trimipramine have?
Sedative effects
What effect does Clomipramine have?
effect on mood and emotion
When was the first SSRI?
Late 60s by Clarson, called Zelmid
What appeared to be an effect of Zelmid?
In rare cases causes a serious neurological disorder calles Guillain-Barre Syndrome which is a potentially fatal disorder and this led to the immediate removal of the drug.
What do SSRIs do?
Inhibit the reuptake of serotonin into the presynaptic neurone –> overall effect is to enhance serotonergic activity.
What are the names of the most famous SSRIs?
Fluoxetine or Prozac
What are the side effects of Prozac SSRIs
Generally mild
- Nausea
- Sexual dysfunctin
Who were SSRIs initially approved for?
Adults with symptoms of clinical depression
What is the monoamine theory of depression?
The MAO-inhibitor blocks the enzyme from destroying monoamine neurotransmitter and the reuptake pump is blocked by the neurotransmitter.
