Depression Flashcards
1
Q
Profile of affective disorder
A
2
Q
Overview of affective disorder
A
- Depression is the most common of the affective (mood) disorders
- It varies in severity from mild (Dysthymia: low grade but long term) to major depression, where delusions may occur psychotic depression
- Two distinct types of syndrome
- Unipolar- low mood which alternates with normality-
- Bipolar- low mod which alternates with mania
3
Q
Occurrence of depression
A
- Major depression has a lifetime prevalance of 2-4% in males and 5-9% in females
- Age of onset mid-late 30s
- Most antidepressant therapy continues for at least 6 and up to 12 months after acute response th therapy
- Recurrence found in >50% of patients who recover from a single episode
- 75% of cases are considered reactive depression (in response to external events).
- While 25% are endogenous depression (Biologically based). Available drugs do not differentiate between the two
4
Q
Diagnostic Criteria for Major Depressive Disorder and Depressive Episodes
A
- DSM-IV Criteria for Major Depressive Disorder (MDD)
- Depressed mood or a loss of interest or pleasure in daily activities for more than 2 weeks
- Mood represents a change from the person’s baseline
- Impaired function: social, occupational, educational
5
Q
Specific symptoms (>5)
A
- Depressed mood or irritable most of the day, nearly every day, as indicated by either subjective report. Misery , apathy, pessimism
- Decreased interest or pleasure in activities. Loss of motivation- anhedonia
- Significant weight change (5%) or change in appetite
- Change in sleep patterns: Insomnia or hypersomnia
- Change in activity: Psychomotor agitation or retardation
- Fatigue or loss of energy
- Guilt, low self esteem, feelings of inadequacy or worthlessness
- Diminished ability to think or concentrate, or more indecisiveness
- Loss of libido
- Suicidal thoughts
6
Q
Symptoms of depression
A
- A significant change from the individual’s normal level of functioning. Together the symptoms cause significant distress or impairment in the individual’s life and his/her ability to function.
7
Q
Implicated Brain Regions
Depression symptoms
A
- Depression symptoms
- Reduced drive
- Reduced energy
- Memory problems
- Attention, cognitive impairment
- Anxiety
- Immune system issues
8
Q
Brain regions
A
- Reward systems- VTA, NAcc
- HPA axis
- Hippocampus
- PFC, anterior cingulate
- Limibc system, PAG, amygdala
9
Q
The monoamine hypothesis
A
- 1950s
- Reserpine for BP patients - became depressed. Iproniazid for TB patients - became ‘happier’- blocks reuptake into synaptic cleft
- Monoamine hypothesis proposed in 1965
- Lack of amines = depression
- To many amines= mania
- NADR/5-HT affecting drugs could elevate mood
10
Q
Antidepressant targets
A
11
Q
Pharmacological support for the monoamine hypothesis
A
- The MAO inhibitors cause increases in the concentrations of these amines by inhibition of their catabolism
- Inhibiting the reuptake of amines into the presynaptic terminal increases the concentration and residence time in the synaptic cleft
- Reserpine which depletes the monoamines exacerbates depression
12
Q
Problems with the monoamine hypothesis
A
- The pharmacological effects are correlated with the blood plasma concentrations but the therapeutic effects are delayed 3-4 weeks
- Some effective atypical antidepressants do not modulate amine levels in synaptic cleft
- Cocaine potently inhibits uptake of NADR but is not an effective antidepressant
- Precursor amino acids increase levels of amines but are not generally effective antidepressants
13
Q
Other hypothesis about depression
A
- Genetic vulnerability
- Polymorphisms in the 5HT transporter and the enzyme COMT show positive correlations
- It is clear that stress precipitates and exacerbates mood disorders
- The hippocampus, amygdala and frontal cortex are prone to changes in their basic structure as a consequence of adrenal steroid action
14
Q
Depression is linked to stress factors and HPA axis
Depressed patients show
A
- High levels of circulating cortisol
- Elevated levels of CRH in CSF
- Increased number of CRH-secreting neurons
- CRH binding sites reduced in frontal cortex
- Dysregulated circadian cortisol patterns
- Reduced hippocampal volume
- Increased amygdala sensitivity
- Blockade of CRF-1 receptors reduces anxiety and depressive symptom
15
Q
Depression is linked to stress factors and HPA axis
Administration of CRH produces symptoms resembling depression
A
- decreased appetite
- sleep disruption
- decreased libido
- increased anxiety
- neophobia
16
Q
HPA axis
A
- Hypothalamic neurones receive NA and 5HT
- Hypothalamic neurons release corticotrophin-releasing hormone (CRH)
- CRH stimulates secretion of adrenocortico-trophic releasing hormone (ACTH) from the pituitary
- ACTH causes the secretion of cortisol from the adrenals
17
Q
The Dexamethasone (suppression) test
A
- Cortisol levels are generally high in depressed patients and fail to respond to challenge with a synthetic steroid, dexamethasone, which, in normals produces a decrease in cortisol levels
18
Q
In conclusion
A
- Depression involves NADR and 5-HT as well as the HPA axis
- These systems innervate and influence many areas of the brain and probably should be thought of as regulators of adaptive responses
19
Q
Depression: management
A
- Stepped care programme
- Mild depression is generally not treated because the risk-benefit ratio is poor; psychotherapies are first line
- ie Cognitive Behavioural Therapy (CBT), self help
- Moderate to severe depression may require CBT and/or pharmacological intervention
- Remember that the drug therapeutic effect is delayed
20
Q
Pharmacological intervention
A
- TCA
- Amitriptyline, chlomipramine, imipramine
- MAO
- Irreversible- isocarboxazid
- Reversible- moclobomide
- SSRI
- Citalopram, sertraline, fluoxetine
- Atypicals
- Mirtrazepine (A2-antagonist)
- ECT
- Severe life threatening depression
- TMS- Transcranial Magnetic Stimulation
21
Q
Current therapeutic interventions
NICE- clinical judgement is guided by
A
- previous response to treatment
- tolerability of adverse effects
- likely side-effect profile with regard to co-morbid conditions
- lethality if history indicates suicide risk
- cost
NB SSRI is recommended as the initial treatment in adults
NB many people don’t take medication due to delayed effect
22
Q
TCA
A
23
Q
Action of Tricyclic Antidepressants (TCAs)
A
- Inhibit amine reuptake increasing concentration in synaptic cleft.
- Later further changes occur: ie reduction of presynaptic α2 receptor sensitivity which enhances release.
- Increased postsynaptic Β1 receptor sensitivity which enhances efficacy of released transmitter.
- These later events probably more important than reuptake inhibition
24
Q
Side effects of TCA
A
- Anti-muscarinic affects- blurred vision, dry mouth, urinary retention, constipation and excessive perspiration
- Cardiovascular effects by block of HERG K+ channel
- Postural Hypotension, tachycardia and palapatations
- Antihistamine H1- Sedation and weight gain
- a-Adrenoreceptor block- Postural Hypotenision
- Interactions with other drugs- alcohol, anaesthetics, hypotensive drugs, NSAIDs, not given with MAOI
- Toxic levels of the TCAs are obtained at only 10x therapeutic dose; fatalities may occur in overdose thus only 1 week supply should be given in patients at risk
25
Q
MAOI
A
MAOA implicated in depression which appears to preferentially metabolise 5-HT.
- An MAOB selective drug do not have antidepressant effect ie selegiline
- Old MAOIs non-selective and irreversible eg phenelzine leads to a hypersensitive response to tyramine-containing foods (cheese reaction).
- Therefore superseded by TCAs
- But undergoing a revival as newer drugs are selective for MAOA and reversible eg moclobemide
26
Q
Side effects of MAOIs
A
- hypertensive crisis are a rare occurrence but can be fatal: irreversible MAO inhibition results in tyramine being absorbed giving sympathomimetic effects ie acute hypertension , headache and occasionally haemorrhage
- Postural hypotension – sympathetic block
- Weight gain
- CNS stimulation - insomnia, restlessness and in acute overdose convulsions.
- Not given with TCAs, SSRIs or pethidine
27
Q
SSRI
A
- First-line pharmacological intervention
- Developed specifically to target 5-HT reuptake
- Similar in efficacy and time course to TCAs
- 3-4 week delay before we see an effect
- Acute toxicity less that TCAs or MAOi.
- Currently most commonly prescribed antidepressants
28
Q
Side effects of SSRI
A
- Generally better tolerated but can produce
- nausea
- insomnia
- sexual dysfunction
- Increase in anxiety particularly during the early phases of treatment
- Serotonin syndrome when given in combination with MAOi: confusion, hypothermia, muscle rigidity, cardiovascular collapse
29
Q
SSRI and adolescents
A
- There are concerns about the use of SSRIs in adolescents where the risk benefit ratio is less clear than in adults
- Specifically
- Psychological therapies should used as first line treatment
- Fluoxetine may be added should psychological treatment alone fail.
- Only under defined circumstances should alternative SSRIs be used – sertraline or citalopram
- In all cases of exposure to SSRIs particular attention should be paid to the appearance of: suicidal behaviour, self-harm, hostility
30
Q
Current clinical understanding
A
- Compliance problems may because of non-response
- The response is unlikely if no improvement after 4 weeks.
- Continuation of medication for > 6 months: halves relapse rate.
- Maintenance treatment reduces recurrence in those with more than 2 episodes; Maintain on a therapeutic dose.
- Discontinuation symptoms if treatment stops abruptly
31
Q
Antidepressant discontinuation/Withdrawal
A
- It is important that patients understand that exposure to antidepressants not associated with tolerance or craving but symptoms may occur on stopping or missing doses
- dizziness
- numbness and tingling
- GI disturbances
- headache
- sweating
- anxiety and sleep disturbance
32
Q
Other Interventions
A
- Fewer side effects, lower toxicity, rapid action eg mirtazapine
- No common mechanism of action. May increase amine release by blocking presynaptic receptors (α2).
- Natural antidepressants – St Johns wort (advise against)
- Electroconvulsive therapy (ECT)
- Repeatative Transcranial magnetic stimulation (rTMS)
- More focused on magnetic stimulation on the cortex to stimulate 5-HT release
