18. Antidepressants and Antipsychotics Flashcards
Depression and schizophrenia are associated with …
dysregulation of monoamine neurotransmitter function
Give the monoamine neurotransmitters
What are they involved in?
- 5-hydroxytryptamine (5-HT, serotonin) - depression, anxiety
- dopamine - schizophrenia
- noradrenaline - depression and anxiety
What’s the dopamine theory of SZ?
- that SZ is associated with increased dopamine/DA function
Give 3 main dopamine pathways in the brain
- nigrostriatal
- mesolimbic and memocortical projections
- tuberoinfundibular
Explain the nigrostriatal dopamine pathway
- substantia nigra go to dorsal striatum
- controls fine movement (EPS)
- linked to Parkinson’s in dysfunction
Explain mesocortical/mesolimbic dopamine pathway
- VTA to frontal cortex/ventral striatum
- for cognition/mood (cortex) and reward/addiction (ventral striatum)
- linked to SZ in dysfunction
Role of dopamine in regulation of prolactin secretion
- suckling
- sensed in hypothalamic nuclei
- dopamine (prolactin releasing inhibiting factor) and prolactin releasing factor released from here
- affects the anterior pituitary to inhibit prolactin release to mammary tissues
- mammary tissue can’t produce milk and no differentiation of mammary tissue during pregnancy during maternal behaviour
Explain tuberoinfundibular pathway
- hypothalamus to pituitary stalk
- tonic inhibition of prolactin secretion
How do dopamine receptors affect SZ?
- use D2 antagonists to counteract increase of dopamine function in SZ
- D2 antagonists are effective antipsychotics
D2 antagonism in nigrostriatal DA pathway causes what?
Explain
- extrapyramidal side effects (EPS)
- Parkinson’s syndrome - tremor, muscle rigidity, loss of facial expression
- tardive dyskinesia - repetitive rhythmical involuntary movement, lip smacking, chewing etc, rocking rotation of ankles, legs, marching in place etc, humming, grunting
D2 antagonism in tuberoinfundibular DA pathway causes …
- hyperprolactinaemia
- can be galactorrhoea or gynaecomastea
Antipsychotics have an affinity for …
List some
- nondopaminergic receptors
- histamine receptors
- muscarinic receptors
- adrenergic reeptors
Antipsychotics which are H1 mediated cause what?
- sedation
- weight gain
Antipsychotics which are M1 mediated cause what?
- dry mouth
- blurred vision
- constipation
- urinary retention
Antipsychotics are classified on basis of …
side effects
There are … groups of phenothiazines
3
Group 1 penothiazines are …
Group 2?
Group 3?
- chlorpromazine
- thioridazine
- fluphenazine
Side effect profile of the phenothiazine classification of antipsychotics
- sedation (affinity for H1)
- anticholinergic (affinity for M1)
- EPS (mainly D2)
List the antipsychotic classfiications
- phenothiazine
- thioxanthenes
- butyrophenones
Fluphenazone is … times more potent than other phenothiazines
50
Side effect profile of thioxantheses is similar to …
Give an example of one
- phenothiazines
- flupenthixol
Give an example of a butyrophenone
haloperidol
Side effect profile of butyrophenones
- selective to D2
- lack muscarinic and antihistamine activity (no sedation)
- but EPS a problem
Limitations of classical antipsychotics
- around 1/3 of SZ patients fail to respond
- limited efficacy against negative symptoms
- high proportion of patient relapse
- side effects and compliance issues
How to improve classic antipsychotics?
- find drugs that are low in extrapyramidal side effects
Positive symptoms of SZ
- disorders of thought/disorganised behaviour
- hallucinations (aural and visual)
- paranoia
Negative symptoms of SZ
- blunted emotions/anhedonia
- social withdrawal
- apathy/loss of energy
List atypical antipsychotics
- clozapine
- olanzapine
- risperidone
- amisulpiride
- quetiapine
Positives to atypical antipsychotics
- better EPS side effect profile without loss of antipsychootic efficacy
- better at treating negative symptoms (lower affinity for D2 receptor, higher for D3, D4 (D2 family) and 5-HT2a receptor
- effective in treatment resistant patients?
Negatives to atypical antipsychotics
- clozapine associated with agranulocytosis
- high incidence of metabolic syndrome, weight gain in risperidone and olanzapine
Hypothesis for mechanism of action of atypical antipsychotics
- do have affinity for D2 but much faster dissociation rate from it (Koff) (loose binding)
- so these drugs can be displaced by physiological phasic bursts of DA transmission (important in DA striatal pathways)
- results in less distortion of physiological DA signalling in striatal pathways
Types of antidepressants
- tricyclic antidepressants (TCA)
- selective serotonin reuptake inhibitor (SSRI)
- monoamine oxidase inhibitors
Examples of TCAs
- amitriptyline
- imipramine
- lofepramine
How do TCAs work?
- inhibit 5-HT and NA uptake
Negatives to TCA in regards to receptors
- block M1 receptors (cause dry mouth, blurred vision, constipation, urinary retention)
- block H1 receptors (sedation, weight gain)
- block alpha 1 receptors (postural hypotension)
TCAs are not used in …
- elderly
- cardiac patients
- hepatic insufficiency
- suicidal patients (overdose)
- drivers and workers (sedations)
Why are TCAs not used for cardiac patients?
- increase chance of conduction abnormalities
TCAs are useful for …
- severe treatment resistant depression
- where sedation is also required
- where disease history indicates efficacy and tolerance
- CHEAP
What are
- SNRI?
- NARI?
Give examples
- serotonin/noradrenaline reuptake inhibitors like venlafaxine
- noradrenaline reuptake inhibitor like reboxitine
SSRI, SNRI and NARI are …
How do they work?
- 2nd generation antidepressants
- selective for 5-HT and NA transporter and don’t have affinity for postsynaptic receptors
Why do 2nd generation antidepressants have less sidde effects?
- don’t have affinity for postsynaptic receptors
SSRIs and TCAs have … antidepressant efficacy
equivalent
SSRIs have a … adverse side effect profile than TCAs
better
SSRI side effects
- sexual dysfunction/impotence
- gastrointestinal
- precipitate anxiety
- no sedation or anticholinergic
Other uses of SSRI
- effective in treating panic disorder, OCD and eating disorders
Explain the 2 isoforms of monoamine oxidases
- MAOa breaks down 5-HT and a bit of DA
- MAOb breaks down DA
Compare old and new monoamine oxidases
- old ones blocked both isoforms irreversably like tranylcypromine, phenelzine - caused stimulant effects and dangerous in overdose
- new ones are selective for MAOa - reversable inhibitors of monoamine oxidase A like moclobemide
- less stimulant and safer
Explain MAOI and cheese effect
- hypertensive crisis
- results from excess of dietary tyramine
- either activates sympathetic nervous system itself or displaces endogenous amines from vesicles and indirectly activates sympathetic nervous system
How do MAOI and SSRI’s interact?
- serotonin syndrome
- hyperthermia, confusion, hypertensive crisis
Antiparkinson drugs lead to …
severe hypertension
