Depression - Physiology & Pharmacology Flashcards
What is depression?
The most common mental health issue - ICD10 mood [affective] disorders (F30-39)
What are the 2 patterns of depressive states?
- Unipolar: low level of mood affecting QoL treated with CBT/ADs - includes dysthymia (low level, chronic) + MDD (clinical depression including atypical)
- Bipolar: recurrent episodes/cycles of mania + depression treated with antipsychotics - includes bipolar disorder + cyclothymia (low level)
What are the 2 forms of bipolar disorder?
1 - classic type with cycles of mania and depression
2 - milder version presenting with hypomania (enhanced mood etc.) but no psychotic symptoms
What are the key symptoms of depression?
Persistent sadness or low mood
Marked loss of interests or pleasure
What symptoms should you look for if key symptoms of depression present?
Disturbed sleep Altered appetite/weight Fatigue/loss of energy Agitation or slowing of movements Poor concentration or indecisiveness Feeling worthless or excessive/inappropriate guilt Suicidal thoughts/acts
How would you diagnose major depressive disorder (MDD)?
Patient has either 1 or both key symptoms with an additional 2/3 of the others
What are the 3 grades of major depressive disorder (MDD)?
- Mild: few if any symptoms in excess of 4/5 required to make diagnosis and only minor functional impairment
- Moderate: symptoms or functional impairment between mild + severe
- Severe: most symptoms that markedly interfere with functioning w/ or w/o psychotic symptoms
What does the DSMV require for a depression diagnosis?
More than 5 symptoms occurring nearly everyday for 2 weeks for diagnosis of mild depression and for more than 2 years for chronic depression - more commonly used for Psychiatry over ICD-10 (requires more than 4 symptoms)
What circuitry is involved in depression?
- Reward vs stress circuits
- Decreased activity in prefrontal cortex and hippocampus
- Increased activity in amygdala and hypothalamus
What does imaging show in patients with depression?
Differences in regional activation reversed by AD use - myriad results
What theories for depression exist?
- Neurotransmitter: monoamine (5-HT and NA) decrease
- Neurohormonal: steroids + HPA axis (stress/anxiety)
- Immuno (auto?)
- Circadian
Where is serotonin (5-HT) produced? What does it do?
Produced mainly at raphe nuclei (also ENS) of brainstem acting centrally in multiple areas and involved in mood, agitation, OCD, anxiety, appetite, insomnia, sexual function, nausea/vomiting and GI function
Where is noradrenaline (NA) produced? What does it do?
Produced mainly at locus coeruleus (LC) and lateral tegmental area (LTC) acting centrally + peripherally (particularly involved in ANS transmission) having multiple functions such as depression, attention, energy homeostasis, agitation, emotions, BP, HR, bladder control + motor function
How do serotonin (5-HT) and noradrenaline (NA) interact?
Large interaction between 5HT and NA neurons centrally - interactions in brainstem speed activity whilst in cortex, activity is slowed
What is the role of inflammation in depression?
Inflammatory mediators lead to microglia activation, cell dysfunction and cell death which can lead to a spectrum of disorders - perhaps chronic low level inflammatory response in CNS in depression
What is the gut-brain axis?
Significant communication between ENS, ANS + CNS - gut microflora acts as barrier so nothing can get through to change brain function but inflammation in gut can trigger altered brain activity where altered microbiota can lead to breakdown of protection (‘leaky gut’) so substances can get into brain via circulation and leaky part of hypothalamus which is why probiotics reduce anxiety and improve mood
What is the role of neurogenesis in depression?
Depression associated with decreased dendritic arborisation also with decreased no. of synapses and overproduction of receptors - deficit can be reversed by neuronal growth factors (e.g. BDNF) + ADs
What are the non-pharmacological treatments for depression?
CBT TMS tDCS ECT DBS
What pharmacological treatments are there for depression?
SSRIs TCAs MAOI-A Atypical ADs Ketamine (being trialled)
What is the placebo affect associated with depression?
30% patients respond to placebo which can actually change neuronal activity levels with some similarities but also differences to AD effects
What is transcranial magnetic stimulation (TMS)?
Magnetic pulses targeted at prefrontal cortex and limbic system increasing activity
What are the pros and cons of transcranial magnetic stimulation (TMS)?
Pros: good for severely depressed patients unresponsive to ADs, less stigma than ECT + fewer side effects
Cons: debate as to whether its effective + possible that other areas affected as limbic system deep in cortex
What is electroconvulsive therapy (ECT)?
Fast and strong ‘jolt’ of electrical current to system to alter cortical activity - gold standard for severe depression as 50% of patients show improvement
What are the side effects of electroconvulsive therapy (ECT)?
Memory loss
Short-term muscles aches
What are the cons of electroconvulsive therapy (ECT)?
Stigma attached to it as used to be a horrible treatment so patients dont always want it
May need repeat applications
What is transcranial direct current stimulation (tDCS)?
Lower and slower level of electrical current applied in similar way to ECT over 20-30mins to alter cortical activity except patient is awake and alert
What is the relationship between exercise and depression?
Exercise has been shown to improve mood probably through neurotransmitter release however, a recent UoW study has shown that it does not improve mood of care home residents with depression so perhaps environmental factors are involved such as exercising at different times of day, changing it up and stimulating brain
How do selective serotonin (5-HT) reuptake inhibitors (SSRIs)work?
Increases 5HT levels by inhibiting re-uptake pump
Give some examples of selective serotonin (5-HT) reuptake inhibitors (SSRIs).
Sertraline
Citalopram
Paroxetine
Fluoxetine (AKA Prozac)
What are the side effects of selective serotonin (5-HT) reuptake inhibitors (SSRIs)?
Slow onset so have -ve symptoms e.g. increased suicidal ideation at first and also:
- Nausea
- Sleep disorders
- Sexual dysfunction
- Increased bleeding
- 5-HT syndrome via overdose on HPA axis and ANS (hyperthermia, CVD problems, aggression, tremor + rigidity) = medical emergency
What are some examples of atypical antidepressants (ADs)?
- NaRIs e.g. Reboxetine
- SNRI e.g. Venlafaxine
- 5HT1A partial agonists e.g. Buspirone, Trazadone + Tandospirone
How do serotonin (5-HT1A) partial agonists? Why is this good?
Allow the body to reset by reducing activity and APs allowing transmitter to build up in vesicles so once post-synaptic terminal receptors have reset and vesicles release, there is a bigger effect - have fewer side effects than SSRIs e.g. no sedation or loss of co-ordination
How may light therapy influence depression?
Light therapy enhances mood because sleep pattern disruption depresses mood
How can melatonin be used in depression?
Melatonin agonist Agomelatine increases SWS and is currently in use for depression (not recommended at the moment) as a result of circadian rhythm theory of depression as it gives patients longer levels of sleep affecting mood indirectly
What are the 5 main actions of tricyclic antidepressants (TCA)?
Main:
1. NA reuptake blocker
Other:
- 5HT reuptake blocker (variable effect)
- α1 adrenoreceptor antagonist
- H1 receptor antagonist
- M1 receptor antagonist
What are the main tricyclic antidepressant (TCA) examples?
Amitriptyline
Nortriptyline
What are the side effects of tricyclic antidepressants (TCAs)?
Accumulation may lead to slowly developing side effects such as sedation, postural hypotension, confusion, visual problems, cardiac dysrhythmia, mania and many drug interactions (aspirin-alcohol)
How do monoamine oxidase inhibitors (MAOI-A) work? Give some examples of them.
Increase NA/5-HT levels by inhibiting enzymatic breakdown e.g.
Reversible:
Moclobemide (Reversible Inhibitor of MA - RIMA)
Irreversible:
Phenelzine Isocarboxazide
Why are monoamine oxidase inhibitors (MAOI-A) not commonly used until other drugs have not worked?
The irreversible ones show a slow recovery - have to wait a while for effects to reverse
What are the side effects of monoamine oxidase inhibitors (MAOI-A)?
Similar to TCAs: Many cross-drug reactions (SSRIs/TCAs) Postural hypotension Restlessness Convulsions Sleep disorders Cheese reaction (tyramine/tyrosine increases NA/5-HT overloading system)
How do drugs acting on α-adrenoceptors work?
Normally, α1 receptors increase transmitter release whilst α2 slow release so α1 agonists and α2 antagonists (e.g. Mirtazapine) increase transmission
What are the side effects of α-adrenoceptor drugs?
Decreased vascular flow in extremities Postural hypotension Fatigue Bronchoconstriction Cardiac failure Bradycardia Sleep disorders Impotence Depression
What is treatment resistant depression? What can be done about it?
If depression is not responsive to treatments with psychotic episodes, inpatient treatment is necessary with high intensity psychological interventions and perhaps ECT, TMS/DCS or mood stabilisers (last resort - normally reserved for bipolar)
What is lithium?
General mood stabiliser although CNS mechanisms not well understood although it is thought to act to reduce G-protein function and inhibit IP pathway signalling inhibiting various kinases, supressing gene function and increasing neurogenesis - salt used but slow absorption so modified release form often used - side effects vary depending on intoxication levels
What are some future prospectives for depression treatment?
NDRI (Bupropion) DRI (Brasofensine) NMDA antagonist - stop Na/Ca entry in channel(Ketamine) DBS Peptide modulators (e.g. substance P, CRG, VP, NK) GABA modulation Glucocorticoids Other enzyme inhibitors (e.g. PDE) Neurotrophins (e.g. BDNF) Sleep deprivation
- problems in trials due to placebo effect
