An introduction to the psychopharmacology of mood disorders Flashcards
What is the function of a modulatory neuron?
Changes the effects of other neurotransmitters or second messenger systems
How do mood disorder drugs act?
Altering brain function:
- change neurotransmitter function
- mimic neurotransmitters (agonist)
- block receptors (antagonist)
What are agonist drugs?
Drugs that mimic neurotransmitters
What are antagonist drugs?
Which block receptors
What is the main excitatory neurotransmitter?
Glutamate
What is the main inhibitory neurotransmitter?
GABA
What are the monoamine neurotransmitters?
- Dopamine
- Serotonin (5-HT)
- Noradrenaline
What are the targets of monoamine drugs in mood disorders?
> Serotonin system
- SSRI and SNRI antidepressants
- second generation antipsychotics -> 5HT receptor actions
> Dopamine system
- second generation antipsychotics - D2 and D3 blockade
> Noradrenaline system
- SNRIs (Venlafaxine, Duloxetine)
What is the target of Ketamine and its action?
- Targets glutamate system
- Blocks NMDA Glu receptor
- Shows promising efficacy in improving mood in patients with depression
What is the target of benzodiazepines and valproate?
GABA system
What is the target of the mood stabilisers lithium, valproate and carbamazepine?
Second messenger systems
What are the main discoveries in the history of the psychopharmacology of mood disorders?
> 1940s: Electroconvulsive therapy
> 1950s: lithium
> 1960s: First generation antidepressants: MAOIs, MARIs
> 1980s: Anticonvulsants (Carbamazepine, Lamotrigine, Valproate)
> 1990s: Second generation anti-depressants
> 2000s: Next-generation antipsychotics (Quetiapine, Olanzapine, Clozapine, Asenapine, Aripiprazole)
Why is serotonin of interest in mood disorders?
> Lowering serotonin levels -> induces depression
> Increasing serotonin levels -> can produce manic symptoms
> SSRI antidepressants and atypical antipsychotics all work in part by changing serotonin systems in brain
How does a normal serotonin system function?
> 5hT cell bodies are located in the caudal raphe nuclei (midbrain)
> Serotonin pathways have projections to the limbic system and subgenual cingulate
What are the important serotonin receptors related to mood disorders?
- 5-HT 2
- 5-HT 1A
What is the action of selective serotonin re-uptake inhibitors (SSRIs) in the synapse?
Inhibit action of 5-HT re-uptake transporter
-> increases synaptic serotonin levels
What are the 5 types of SSRI antidepressants and their usual dosage?
> Citalopram (Cipramil): 20-40mg/day
> Escitalopram: 10-20mg/day
> Sertraline: 50-200mg/day
> Paroxetine: 20-50mg/day
> Fluoxetine (Prozac): 20-60mg/day
What is the action of serotonin-noradrenaline reuptake inhibitors (SNRIs) in the synapse?
Inhibit action of 5-HT re-uptake transporter AND noradrenaline re-uptake transporter
-> increase serotonin and noradrenaline synaptic levels
What are the three types of SNRI antidepressants and their usual dosage?
> Venlafaxine (Effexor): 75-375mg/day
> Duloxetine (Cymbalta): 60mg/day
- may increase dopamine levels in PFC
> Vortioxetine (Brintelix): 10-20mg/day
How may the SNRI antidepressant Vortioxetine (Brintellix) improve cognitive impairment?
- Blocks 5HT2, 5HT7 receptors
- Stimulates 5HT1A receptor
- > may improve cognitive impairment through 5HT7 blockade
Why is dopamine relevant to mood disorders?
> Increasing synaptic dopamine levels can produce effect similar to mania
> Reducing synaptic dopamine levels improves manic symptoms but worsens depression
What is the role of dopamine antagonist antipsychotics?
- Main treatment for mania
- Used as mood stabilisers
What is the role of dopamine in mania?
Mania is a result of increases in dopamine system
- particularly in nigrostriatal and limbic systems
What is the action of dopamine antagonists in the mesolimbic pathway?
- Lowers psychotic symptoms
- Lowers manic symptoms
What is the action of dopamine antagonists in the tuberoinfundibular pathway?
Increase of prolactin secretion (via pituitary gland)
What is the action of dopamine antagonists in the mesocortical pathway?
- Increases negative symptoms
- Increases cognitive dysfunction
- May increase depressive symptoms
What is the action of dopamine antagonists in the nigrostriatal pathway?
Impairs motor function (via substantia nigra pars compacta)
What is the action of antipsychotics in the synapse?
Block dopamine postsynaptic receptors
-> decreased dopamine levels
How are D2 antagonist antipsychotics used as mood stabilisers?
> Treat manic symptoms or prevent manic relapse
> Few antipsychotics treat depressive episodes in bipolar disorder
> Most antipsychotics block D2 receptors AND 5HT receptors (5HT2, 5HT1A, 5HT7)
What is Quetiapine and its action?
Dopamine antipsychotic
- prevents both manic and depressive recurrence
- blocks D2 and 5-HT2A receptors
What is Olanzapine and its action?
Dopamine antipsychotic
- used to treat mania and bipolar depression
- blocks D2 and 5-HT2A receptors, histamine H1 receptors, and the alpha-1 receptor
What is Aripiprazole and its action?
Antipsychotic dopamine stabiliser
- prevents manic relapse
- blocks D2, 5-HT1A, and 5-HT2A receptors
What is the main target of benzodiazepines?
GABA-A receptor binding site
- main inhibitory system
What are benzodiazepines used for?
Short term treatment of anxiety disorders
- e.g. Diazepam, Clonazepam
What are Z type hypnotics used for?
Short term treatment of sleep impairment
- through GABA-A binding site
- e.g. Zopiclone, Zolpidem
What is Sodium Valproate used for?
Mood stabiliser
- act in part through changing GABA levels
What are second messenger systems?
Intracellular signalling molecules that are activated when neurotransmitter binds to G-protein coupled receptors
- e.g. cyclic AMP, Inositol triphosphate
- actions include increasing neurotransmitter release
Why are second messenger systems important?
> Many drugs for mood disorders may act by altering second messenger systems
- lithium
- sodium valproate
- carbamazepine
> Effects of these drugs on neurotransmitter release and other neuronal functions remain poorly understood
What is the effect of mood disorder drugs on second messenger systems?
Inositol depletion hypothesis and bipolar disorder:
- medication blocks transfer of Inositol into neuronal cells
- Lithium and Valproate may affect the activation of second messenger systems within neuron
What is lithium and its role in mood disorders?
One of the most effective mood stabilisers
- prevents manic recurrence
- less effective against depression
- as monotherapy it’s probably effective for a minority of patients
- levels greater than0.6mmol/L generally needed in prophylaxis may benefit patients with predominantly manic symptoms
- reduces risk of suicide
What is prophylaxis?
Measures designed to preserve health and prevent spread of disease
What is the currently observed action of lithium in the brain?
- Adjusts neurotransmitter balances
- Adjusts basal and/or stimulated fluctuations in second messenger and protein kinases
- Protects neurons from toxic insults
- Modulates expression of specific genes
- Modifies cytoskeletal function
- Adjusts basal and/or stimulated fluctuations in transcription factors
