What are the emotional symptoms of major depression?
Misery, apathy, pessimism
Low self-esteem, feelings of guilt or inadequacy, or suicidal thoughts
Indecisiveness, loss of motivation
What are the biological symptoms of major depression?
Disturbances of appetite, sleep, energy, libido, and psychomotor function
What important factors contribute to major depression?
Abuse or neglect in childhood
Prolonged excessive stress or traumatic events
Adverse social circumstances
General medical conditions (hypercortisolemia, and hypothyroidism)
Substances (Corticosteroids, interferons, and alcohol)
How common is depression?
20% of people experience it at least once in their lifetimes.
More women than men. (50% rate of recurrence following a single episode)
What percentage of depressed people experience suicidal thoughts?
10 - 15%
What percentage of people treated with antidepressants resond well?
2/3rds are treated adequately
What is mania?
Episodes of pathologically elevated or irritable mood of at least a week.
What are the symptoms of mania?
Associated characteristic symptoms and behavioural changes include decreased need to sleep, excitable speech and behaviour, grandiose ideas, disinhibition and poor judgement.
Which neurotransmitters influence mood and cause mood disorders?
serotonin, noradrenaline, dopamine, acetylcholine, glutamate, and GABA.
Which neurotransmitters are manipulated pharmacologically for treatment of depression?
Serotonin (5-HT) and noradrenaline
Why are NA and 5-HT targetted pharmacologically?
5-HT neurons from raphe nuclei and NA from locus ceruleus innervate many areas of the brain to control mood, alertness, appetite, sleep, pain perception, and other functions
What are the main antidepressant drugs being used?
SSRIs (sertraline, citalopram, escitalopram, etc)
Noradrenaline Reuptake Inhibitors (reboxetine)
Serotonin and NA reuptake inhibitors aka SNRIs (venlafaxine, duloxetine)
Moclobemide: Reversible inhibitor of monoamine oxidase A (RIMA)
Mirtazapine: noradrenergic and specific serotonergic antidepressant (NaSSA)
Buppropion: Noradrenaline dopamine reuptake inhibitor (NDRI)
Tricyclic antidepressants (TCAs): desipramine, nortiptyline, amitriptyline, imipramine
Monoamine oxidase inhibitors (MAOIs)
SNSMMBTM (pneumonic: Stay North; Sadness May Mean Bad Times, Mate)
Name some SSRIs:
sertraline, citalopram, escitalopram, paroxetine, fluoxetine, fluvoxamine
Name some NRIs:
Name some SNRIs:
Name some TCAs:
desipramine, nortriptyline, amitriptyline, imipramine
Which of the antidepressants are frontline? Which drugs are used if they don’t work?
SSRIs, SNRIs, mirtazapine (NaSSAs)
Used in a more niche targetted fashion: RIMAs, , NDRIs, NRIs
They are used before TCAs and MAOIs
Which front line drugs are used in a more niche targetted fashion?
Moclobemide (RIMA), Bupropion (NDRIs), NRIs
What do NA receptors do?
they activate alpha and beta receptors
What does alpha1 do to IP3 and DAG?
It increases their concentration
What does alpha2 do to cAMP?
It decreases it
What do beta receptors do to cAMP?
They increase it
What do 5-HT1A, B, D, E, F, and 5-HT5a do?
They decrease cAMP
What does 5-HT2A, B, C do?
They increase IP3 and DAG
What does 5-HT3 do?
activates ligand gated ion channels (stimulating action)
What do 5-HT4,6,7 do?
What do 5-HT1A and B do to serotonin nerve activity?
5-HT1A inhibit serotonin nerve activity by decreasing the firing of serotonin
5-HT1B inhibit serotonin nerve activity by inhibiting release of serotonin
What do TCAs do?
They block reuptake of NA, serotonin, and dopamine by binding to monoamine transporter at allosteric site decreasing its affinity for neurotransmitter
Why are TCAs not front-line therapy?
They produce toxic side effects and are difficult to use
How do TCA antidepressants alleviate depression?
They do it over a few weeks of action. They increase synaptic levels of NA and 5-HT which results in complex adaptive changes in receptors and signalling.
These changes increase CREB transcription factors (cAMP Response Element Binding protein) and BDNF (Brain Derived Neurotrophic Factor) in the hippocampus and frontal cortex resulting in increased neurogenesis and enhancement of neuronal connectivity and improving information processing and alleviation of depression.
How do other antidepressants differ from TCAs?
They only differ in initial action but both still elevate CREB and BDNF in the hippocampus and frontal cortex
What do SNRIs do?
Reversible, negative allosteric modulation of the 5-HT transporter and NA transporter on axon nerve terminals and dendrites
What do SSRIs do?
Selective reversible negative allosteric modulation of SERT
What does Bupropion (NDRI) do?
Weakly inhibits both noradrenaline (NET) and dopamine transporter (DAT)
What do MAOIs like phenelzine do?
Irreversible inhibition of monoamine oxidases (MAOa and MAOb) resulting in decrease intraneuronal breakdown of NA, 5-HT and dopamine
How do NRIs work?
Selective reversible negative allosteric modulation of NET
What does moclobemide do?
Reversible selective inhibition of MAOa resulting in decrease intraneuronal breakdown of NA and 5-HT
What does mirtazapine do?
Serotonin and noradrenaline are inhibited when alpha 2 receptors are activated presynaptically. Mirtazapine acts as an antagonist to these alpha 2 receptors thus increasing production of serotonin and noradrenaline.
What are TCAs used for?
Treating severe depression resistant to newer and safer antidepressants.
Why are MAOIs not first line?
They have many side effects and drug interactions and are very dangerous in overdose.
What are some drugs that must be avoided when taking MAOIs?
Indirect acting sympathomimetic drugs (leads to hypertension due to increase in NA)
Foods containing tyramine (cheese, vegemite, or salamis) because they interact with MAOb in the gut and result in hypertension
Why are SSRIs used instead of TCAs?
SSRIs lack affinity for muscarinic, alpha1, and H1 receptors.
What drugs should SSRIs not be taken with?
SSRIs should not be combined with other serotonin increasing drugs due to serotonin syndrome
What are the side effects of SSRIs?
GI: Nausea, anorexia, diarrhoea
CNS: Insomnia, anxiety, irritability, restlessness, tremor, headache, fatigue
Sexual: Decreased libido, delayed orgasm, anorgasmia
Other: Weight gain, fever, swearing, bleeding
At the start of treatment in young individuals can cause increase suicidal ideation
What causes SSRI side effects?
Overstimulation of some 5-HT receptors
What conditions are SSRIs used for?
Depression and anxiety disorders primarily.
OCD, social phobia, panic disorders, PTSD, eading disorders.
What drugs must be used before TCAs are tried?
SSRIs -> venlafaxine (an SNRI) -> TCAs
What are the adverse effects of venlafaxine?
Hypertension in some individuals
What causes mirtazapine effects?
Antagonism of presynaptic alpha2 adrenoceptors results in more NA and 5-HT.
Antagonism of 5-HT2A and 5-HT-3 reduces side-effects of insomnia, sexual dysfunction, nausea and diarrhoea.
What causes mertazapine side effects?
antagonism of 5-HT2c and H1 receptors causes weight gain and antagonism of H1 receptors and excessive drowsiness.
What are the advantages of mirtazapine over SSRIs?
Mirtazapine is relatively safe. (It is a weak inhibitor of CYP450 isozymes so it has few interactions with other drugs) [shouldn’t be combined with alcohol and benzodiazepines though]
Less likely to get sexual side effects.
Mirtazapine stimulates appetite
What are the side effects of mirtazapine?
Dizziness, drowsiness, dry mouth, constipation, and weight gain.
What is the half-life of mirtazapine?
Mirtazapine has a half-life of 20 - 40 h
What is Bupropion?
It is a weak noradrenaline and dopamine reuptake inhibitor used for depression and smoking cessation treatment.
What are the side effects of using bupropion?
Nausea, weight loss, insomnia, agitation, dizziness, elevated heart rate, tremours, seizures are most significant but uncommon.
How does lithium work?
Inhibition of glycogen synthase kinase (GSK-3), protein kinase C, and inositol monophosphatase
This results in a more stable mood, neuroprotection and long term neuroplasticity.
Thus it is a good treatment of acute mania and bipolar depression and prevention of suicide.
What condition is lithium used for?
Manic depression (aka bipolar)
How must dose be controlled with lithium?
Theres a range of values they must stay within. (0.5 - 1 mmol/l) anything higher than 1.5mmol/l increases risk of toxicity and anything above 3.5mmol/l is deadly.
What are the side effects of lithium within therapeutic range?
What are the effects of acute overdose?
What considerations must be made with lithium administration?
Usual lithium concentrations may not be tolerated by older patients
Diuretics, NSAIDs, and ACE inhibitors may reduce renal clearance of lithium.
Kidney function should be monitored regularly to avoid tubular damage.
What is the standard treatment for bipolar disorder?
Anticonvulsant mood stabilisers: Carbamazepine, lamotrigine, sodium valproate
Atypical antipsychotics: olanzapine.
What is the standard first line monotherapy and compination therapy for bipolar depression?
First-line monotherapy: lithium, lamotrigine, quetiapine
First-line combination therapy: Olanzapine+fluoxetine, lithium+lamotrigine
Important consideration for lithium and anticonvulsant medication in women:
They can increase chance of foetal malformations
How long must antidepressants be given before deciding whether or not they are effective?
4 - 6 weeks
How long should patients take antidepressant medications?
4 - 9 months and they must be discontinued gradually using maintenance therapy
How must antidepressant treatment be discontinued in people who have had several episodes of recurring depression?
Using maintenance therapy lasting for 2 - 5 years for patients who have had 2 - 3 previous episodes of severe depression. Some patients may require an antidepressant for the rest of their lives
First-line agents for major depression are:
Second-line agents for major depression are:
Agomelatine (melatonin MT11/MT2 agonist and 5HT2c antagonist)
Buprpion (NDRI): for smoking cessation
Third-line agents for major depression: (High toxicity and high efficacy)
MAOIs are reserved for severe depression unresponsive to other antidepressants
What other therapies are available for people in which first and second line therapies don’t work?
Electroconvulsive therapy may be effective in severely depressed patients who are resistant to antidepressant medications
Intravenous ketamine may rapidly and transiently reverse severe depression
What should be done if patient has bipolar disorder, acute psychotic depression, or suicidal?
Refer to psychiatrist
for bipolar: give mood stabilisers, antipsychotics, or a fluoxetine-olanzapine combination.
For depressive psychosis: ECT or a TCA combined with antipsychotic may be effective
How should be patients treated if not much is known about their history of depression?
Start with mood stabiliser then see if antidepressant will be needed.