Affective disorders: Neurobiology and treatment Flashcards
Factors - neurobiology of major depression
- Adverse childhood experience
- Current stress
- Genetic factors
–> Decrease in 5HT and NA function
How do adverse childhood experience, current stress and genetic factors cause a decrease in 5HT and NA function
HPA axis function –> Cortisol –> 5HT and NA function
Aetiology of depression
- Multifactorial
- Incompletely understood
- Interactions of genetic factors, childhood adversities, past hx of mood disorders, psychological predisposition (neuroticism)
- Often precipitated by stressful life events
Monoamine dysfunction in depression
- All traditional antidepressants affect 5-HT/NA systems
First MAOi
- Iproniazid
First tricyclic
- Imipramine
What type of receptor is reduced in depression
- Reduced 5-HT transporter in depression
Where are 5-HT cell bodies located
- raphe nuclei
Where are NA cells located in a large cluster
- Locus coeruleus
What are the raphe nuclei and locus coeruleus believed to be involved in
- Each of these midbrain nuclei has ascending tracts, which project to brain regions thought to be involved in depressive symptoms, as well as ascending and descending tracts involved in pain suppression
What is the monoamine theory of depression
- Suggests that a relative deficiency in synaptic levels of serotonin and noradrenaline in key central nervous system pathways underlies depressive illness (CNS = brain + spinal cord)
Where do 5-HT and NA- secreting neurons project
- Project upward from their respective nuclei in the brainstem, directly stimulating many areas of the brain
What brain areas are stimulated by 5-HT and NA
- Prefrontal cortex, which is involved in executive functions, and the limbic system which include anatomical structures involved in behaviour, motivation, and emotion, such as the hippocampus, anterior cingulate cortex, hypothalamus, and amygdala
1st generation antidepressants
- MAOi - Phenelzine, tranylcypromine
- Tricyclic antidepressants - Amytryptiline, clomipramine
Action of MAOi
- Nonselectively inhibit enzymes involved in the breakdown of monoamines, including serotonin, dopamine, and norepinephrine
Action of tricyclic antidepressants
- Nonselectively inhibit the reuptake of monoamines, including serotonin, dopamine, and norepinephrine
2nd generation antidepressants
• SSRI: Selective serotonin reuptake inhibitors
Sertraline, Citalopram, Escitalopram, Fluoxetine
• SNRI: Serotonin-noradrenaline reuptake inhibitors
Venlafaxine, Duloxetine
• alpha2 and 5-HT2 antagonist [modulate serotonin and NA release]
Mirtazapine
• Dopamine-noradrenaline reuptake inhibitor
Bupropion (not approved as antidepressant in UK)
Efficacy comparison - SSRIs and tricyclics
- Equal in outpatients
Spectrum of action - SSRIs
- Large spectrum of action
- OCD, PTSD, Panic, GAD, social anxiety
Toxicity of SSRIs
- Low toxicity and safe in oversdose
Initial treatment phase of SSRIs
- Initial treatment phase is the most delicate, due to prevalence of side effects over benefits - Slow titration
Side effects of SSRIs
- Gastro-intestinal symptoms(nausea, diarrhoea)
- Headache, irritability, anxiety
- Reduction of libido and sexual dysfunction
How can withdrawal symptoms be avoided with SSRIs
Gradual suspension to avoid withdrawal symptoms (worse with venlafaxine and paroxetine due to short half-ife)
Side effects of tricyclics
Constipation, orthostatic hypotension, dry mouth, drowsiness, cardiac toxicity in overdose
Side effects of MAOi
Dry mouth, GI side effects, headache, drowsiness, insomnia, dizziness, food interactions (hypertension crises)
Side effects of venlafaxine
nausea,vertigo, headache, insomnia
Side effects of mirtazapine
drowsiness, sedation, hypotension, increased appetite and weight gain
Gene-environment interaction - Influence of life stress
- Influence of life stress on depression
- Moderation by a polymorphism in the 5-HTT gene
What is the HPA axis
- HPA axis is an abbreviation for a subsystem in your body called the hypothalamic-pituitary-adrenal axis
What is the HPA axis response for
- Responsible for the neuroendocrine adaptation component of the stress response
Mechanism for HPA dysfunction in response to stress
- CRF is released by the hypothalamus and binds to CRF receptors on the anterior pituitary gland
- ACTH is released
- ACTH binds to receptors on the adrenal cortex and stimulates adrenal release of cortisol
- In response to stressors, cortisol will be released for several hours
Negative feedback effect of cortisol
- At a certain blood concentration of cortisol, this protection is ostensibly achieved and the cortisol exerts negative feedback to the hypothalamic release of CRF and the pituitary release of ACTH
- Systemic homeostasis resumes
What is CRF
- Corticotropin-releasing factor AKA corticotropin-releasing hormone
What is ACTH
- Adrenocorticotropic hormone
What causes HPA dysfunction in mood disorders
- Lack of dexamethasone suppression
- Glucocorticoid receptor alterations
- Depression in cushing’s disease
High comorbidity in depression
- High comorbidity between chronic inflammation and depression
- Raised plasma cytokine levels(IL-6, TNF-alpha) and inflammatory markers
- Administration of cytokines provokes depressive symptoms
- Microglial activation in brain of depressed patients(PET studies)
Neural systems involved in depression
- increase in activity of Amy; VST, PFC, to neg emotional stimuli(fearful faces)
- Decrease in activity of VST to positive emotional stimuli, and during receipt and anticipation of reward
- Overall, a bias of attention towards neg emotional stimuli, and away from positive emotional and reward - related stimuli
Parts of the system modulated by serotonin that are compromised in major depressive disorders
- Medial prefrontal-limbic network, including amygdala, anterior cingulate cortex and medial prefrontal cortex
Parts of the system modulated by dopamine that are compromised in major depressive disorders
- Reward network centered on ventral striatum and interconnected orbito- frontal and medial prefrontal cortices
What evidence have neuroimaging studies of major depressive disorders found for specific functional abnormalities
- Converging findings from these studies suggest abnormally increased amygdala, ventral striatal, and medial prefrontal cortex activity, mostly to negative emotional stimuli, such as fearful faces.
- Abnormally reduced ventral striatal activity to positive emotional stimuli, and during receipt and anticipation of reward.
- These findings support a bias of attention towards negative emotional stimuli, and away from positive emotional and reward- related stimuli in individuals with major depression
Goal of short-term bipolar treatment
- To reduce the severity and shorten the duration of the acute episode and achieve remission of symptoms
Goal of long-term bipolar treatment
- Prevention of new episodes and to achieve adequate inter-episode control of residual or chronic mood symptoms
Drug categories for bipolar disorder treatment
- Antipsychotics
- Lithium
- Anticonvulsants
- Antidepressants
Action of haloperidol
- Antipsychotic
- 1st gen
- D2/D3 antagonist
Examples of antipsychotics that target D2/D3 receptors(also target 5-HT)
- 2nd gen
- Olanzapine, Risperidone, Quetiapine, Lurasidone, Asenapine, Amisulpride, Clozapine
Action of aripiprazole
- DA partial agonist
Effects of antipsychotics on bipolar
- Rapid anti-manic effect
- Often used long-term to maintain same treatment effective in acute episode
- Long-term adverse effects on weight, glucose regulation and lipids [except for Aripiprazole, Amisulpride, and Lurasidone]
- Full D2 antagonism (Haloperidol) may cause EPSEs
Mechanisms of actions - Lithium
○ Multiple neurotransmitters (including DA)
○ Cellular signalling
○ Neurotrophic factors
Effects of lithium in bipolar
- Anti-suicidal effects
- Possible efficacy on impulsive and violent behaviours
- Strongest evidence for prevention of relapses of any polarity
Why must lithium use be monitored
- Narrow therapeutic index
- blood tests every 3 months for the 1st year
- Adverse long-term effects on Kidney function with excessive levels
- Risk of Lithium toxicity
Actions of valporate
- Anticonvulsant
○ Actions via GABA, intracellular signalling, sodium channel blockade, epigenetic modulation, etc.
○ Anti-manic and effective in prevention of mania
○ Useful in combination, but potential pharmacokinetic interactions
○ not be used for women of child bearing potential because of its unacceptable risk to the foetus of teratogenesis and impaired intellectual development
Actions of lamotrigine
○ actions via GABA, Glutamate and sodium channel blockade
○ Mostly effective in prevention of depressive relapses
○ Ineffective as anti-manic agent
Actions of carbamazepine
○ less effective in maintenance treatment than lithium but may be used as monotherapy if lithium ineffective
○ especially in patients who do not show the classical pattern of episodic euphoric mania
○ almost exclusively effective against manic relapse
○ pharmacokinetic interactions
Drugs used to treat depressive episodes of bipolar
Antipsychotics (Quetiapine, lurasidone)
Fluoxetine/Olanzapine combinations
Antidepressants to be co-prescribed with an anti-manic drug
Consider Lamotrigine (usually with antimanic drug)
Drugs used to treat acute manic episodes
Dopamine antagonists (haloperidol, olanzapine, risperidone and quetiapine) Valproate Discontinue any antidepressant treatment
Long-term treatment prevention of new episodes
Consider long-term treatment following a single severe manic episode
Lithium as initial monotherapy (target serum level range: 0.6-0.8 mmol/l)
Alternatives (if Lithium ineffective, poorly tolerated or unlikely adherence to treatment):
• Valproate
• Dopamine antagonists/partial agonists
• Carbamazepine
Adverse effects of long-term pharmacological treatments in bipolar disorder
- Weight gain (most medications, particularly Olanzapine and Quetiapine)
- Metabolic syndrome (Olanzapine, Quetiapine, Risperidone)
- Hyperprolactinemia (Dopamine antagonists)
- Tardive dyskinesia (much reduced risk with newer agents)
- Liver damage (e.g. Valproate)
- Kidney and Thyroid dysfunction (poorly regulated Lithium)
