Mood Disorders + Antidepressant Drugs Flashcards
DSM-IV
Major depression
Bipolar
DSM-V
Major depressive disorder
Disruptive mood dysregulation disorder
Depression Signs and Symptoms
Psychomotor retardation Fatigue/loss of energy Diminished ability to concentrate Diminished social activity interest Insomnia Guilt + worthlessness Weight loss + decreased appetite
Bipolar chance
Increased if related to patient with bipolar
Depression chance
Increases if related to patient with bipolar
Increases even more if related to patient with major depression
Genes linked to depression
GRIK4
CRHR1
SLC6A4
MAOA
Pathophysiology of depression
Dysfunction of noradrenergic and serotonergic pathways
Key players, but not only players
Brain regions associated with depression
Amygdala- fear and anxiety Ventrolateral prefrontal cortex Dorsolateral prefrontal cortex Medial prefrontal cortex Striatal regions (ventral striatum) Hippocampus
Raphe
Place of origin of most of innervation of cortical structures
Neurones in raphe have slow activity in waking
Subgenual prefrontal cortex abnormalities- PET scan
Decreased metabolism- significant reduction in glucose consumption
Subgenual prefrontal cortex abnormalities- MRI scan
Mean grey matter volume of subgenual anterior cingulate cortex is REDUCED in patients with major depressive or bipolar disorder
Cortical Thickness
Depressed patients have significant cortical matter loss
12-15% change
–> structure abnormality/volume loss –> grey/white matter
Default mode network
Network of brain regions active when brain is at wakeful rest
Increased DMN connectivity in subjects with major depression
Gene-environment interactions
5HT transporter polymorphism is associated with a higher risk of major depression
Different alleles lead to different transcription of the transporter
Short allele, more at risk of depression
Long allele, more resistant
Genetic variations + CNS connectivity
Correlation between decreased connectivity amygdala-prefrontal cortex, certain MAOA isoforms (affect activity of enzyme) and state of clinical depression
Amygdala-prefrontal cortex
Connectivity is significantly reduced in depressed patients + carries of the higher active MAOA risk alleles (MAOA-H)
Reduced coupling in this circuit –> longer + more severe course of disease
MAOA gene genetic variation
Encodes enzyme which controls monoaminergic signalling
May affect the course of major depression by disrupting cortico-limbic connectivity
Higher active MAOA
Disrupts cortico-limbic connectivity
Rumination
Regions involved in persistent recurring thoughts in depression include amygdala + hippocampus
Hyperactivation in amygdala + hippocampus –> increased activity in subgenual cingulate cortex, region that integrates limbic feedback + relays to prefrontal cortex
–> increased subgenual activity increases activity in MPFC, region associated with internal representations of oneself
Activation decreased in DLPFC and VLPFC- areas associated with cognitive control
TCAs MOA
Inhibit reuptake of amines
Have affinity for H1, muscarinic, alpha-1 and alpha-2 adrenoreceptors
TCA examples
Clomipramine
Imipramine
Amitriptyline
TCA Side effects
Muscarinic- dry mouth, blurred vision, constipation, urinary retention Adrenoreceptors- Postural hypotension Fatigue Sedation Weight gain Dizziness Loss of libido
TCA overdose
Dangerous
Cardiotoxicity
Monoamine oxidase inhibitors MOA
Irreversible inhibition of enzyme
Non-selective MAOa vs MAOb
MAOIs examples
Phelzine
Iproniazid
Tranylcypromine
MAOI - tyramine
Interactions with tyramine-containing foods –> mature cheese, pickled fish + meat, red wine, beer, yeast
With MAOIs, tyramine accumulates in brain –> will penetrate monoaminergic presynaptic terminals containing noradrenaline, pushing it out, leading to higher BP, headaches etc.
MAOI side effect
Hepatotoxicity
Massive hypotensive activities
MAO enzymes
Breakdown of noradrenaline, dopamine and serotonin
SSRI MOA
Increased selectivity for serotonin reuptake
–> leave serotonin in synapse
SSRI examples
Citalopram- most effective
Fluoxetine
Paroxetine
SSRI side effects
Nausea Headaches GI problems Increased aggression Insomnia Anxiety Sexual dysfunction
S-isomer of citalopram
Escitalopram
Reversible MAOIs
Moclobemide
Increased selectivity for MAOa
Safer than irreversible MAOIs
Adverse effects- nausea, agitation, confusion
Venlafaxine
Serotonin noradrenaline reuptake inhibitors (SNRIs)
Reboxetine
Noradrenaline reuptake inhibitors (NARIs)
Mirtazapine
Noradrenergic and specific serotonergic antidepressants (NaSSAs)
Antagonism at 5HT2 and alpha-2 adrenergic receptors
Trazodone
Serotonin antagonist and reuptake inhibitor (SARI)
Mainly antagonist at 5HT2 receptors + serotonin reuptake inhibition
Agomelatine
Agonist at melatonin MT1 + 2 receptors and antagonist at 5HT2c receptors
Noradrenaline/dopamine disinhibitor
Antidepressant drug Discontinuation Syndrome
Can occur after decrease in dose of drug taken, after interruption of treatment, or abrupt cessation of treatment
Dependant on medication
Discontinuation syndrome symptoms
Insomnia Anxiety Nausea Headaches Electric shock sensations Agitations
Delay of action of antidepressant drugs
Changes in autoreceptors (5HT1a)
Autoreceptors activated due to immediate increase in synaptic amine concentration
–> decrease firing of neurones
They then become desensitised –> neurones back to normal firing rate
–> effect no longer inhibited
Bipolar- Lithium
Narrow therapeutic margin
Renal + thyroid function must me checked
Adverse effects- thirst, nausea, fine tremor, polyuria, weight gain, oedema, acne
Bipolar- carbamazepine, sodium valproate
Mood stabilisers
Risk order for mania switch
TCAs> SNRIs> MAOIs> SSRIs
Principals Depression management
Ensure optimum thyroid function Treat co-morbidity (substance misuse) Ensure full symptom control Monitor course of illness (mood chart) Adapt and review treatment Prevent recurrence
Phases of treatment
Acute
Continuation
Maintenance
Acute treatment
First 6-12 weeks
Aims at remission (control of symptoms)
Continuation treatments
For 6 months after full symptom control
Maintain remission status
Prevent relapse
Maintenance treatment
Prevention of recurrence of further episode
Non-pharmacological approaches
Electroconvulsive therapy- treatment for refractory depression with suicide risk, treatment-resistant depression
CBT
Vagal nerve stimulation
DBS- subcallosal cingulate white mater, subgenual cingulate cortex
Hippocampus
Neuronal loss + neurogenesis in hippocampus affects whole spectrum of symptoms associated with depression
Increases in cortisol + pro-inflammatory cytokines –> neuronal loss + structural changes in hippocambus
